Advertisement
Mayo Clinic Proceedings Home

New-Onset Diabetes After Acute and Critical Illness

A Systematic Review

      Abstract

      Hyperglycemia is commonly observed during acute and critical illness. Recent studies have investigated the risk of developing diabetes after acute and critical illness, but the relationship between degree of in-hospital hyperglycemia and new-onset diabetes has not been investigated. This study examines the evidence for the relationship between in-hospital hyperglycemia and prevalence of new-onset diabetes after acute and critical illness. A literature search was performed of the MEDLINE, EMBASE, and Scopus databases for relevant studies published from January 1, 2000, through August 4, 2016. Patients with no history of diabetes before hospital discharge were included in the systematic review. In-hospital glucose concentration was classified as normoglycemia, mild hyperglycemia, or severe hyperglycemia for the meta-analysis. Twenty-three studies were included in the systematic review, and 18 of these (111,078 patients) met the eligibility criteria for the meta-analysis. The prevalence of new-onset diabetes was significantly related to in-hospital glucose concentration and was 4% (95% CI, 2%-7%), 12% (95% CI, 9%-15%), and 28% (95% CI, 18%-39%) for patients with normoglycemia, mild hyperglycemia, and severe hyperglycemia, respectively. The prevalence of new-onset diabetes was not influenced by disease setting, follow-up duration, or study design. In summary, this study found stepwise growth in the prevalence of new-onset diabetes with increasing in-hospital glucose concentration. Patients with severe hyperglycemia are at the highest risk, with 28% developing diabetes after hospital discharge.

      Abbreviations and Acronyms:

      ACS (acute coronary syndrome), ADA (American Diabetes Association), AMI (acute myocardial infarction), FPG (fasting plasma glucose), HF (heart failure), ICU (intensive care unit), MH (mild hyperglycemia), MI (myocardial infarction), NF-kB (nuclear factor-κβ), NG (normoglycemia), PG (plasma glucose), SAP (severe acute pancreatitis), SCFA (short-chain fatty acid), STEMI (ST-segment elevation myocardial infarction)
      Article Highlights
      • The relationship between degree of in-hospital hyperglycemia and development of new-onset diabetes is largely unknown.
      • This study found that hyperglycemia in acute and critically ill patients increases the risk of new-onset diabetes after hospital discharge.
      • The prevalence of new-onset diabetes increases with the degree of in-hospital hyperglycemia. Patients with severe hyperglycemia have the greatest risk, with 28% developing diabetes after hospital discharge.
      • These findings suggest that prevention programs after hospital discharge might need to be considered in patients with acute and critical illness.
      Acute and critical illness describes a group of life-threatening conditions that affect millions of people around the world every year. In 2013 alone, 8.6 million people experienced acute myocardial infarction, 10.3 million stroke, 17.2 million pancreatitis, and 33.4 million burns.
      • Vos T.
      • Barber R.M.
      • Bell B.
      • et al.
      Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
      The mortality of acute and critical illness ranges from 7% in patients with ST-segment elevation myocardial infarction to 50% to 60% in patients with septic shock.
      • Adhikari N.K.
      • Fowler R.A.
      • Bhagwanjee S.
      • Rubenfeld G.D.
      Critical care and the global burden of critical illness in adults.
      In addition, acute and critical illness carries a large economic burden, with the average cost of treatment in an intensive care unit ranging from $4000 to $8500 per day.
      • Huynh T.N.
      • Kleerup E.C.
      • Wiley J.F.
      • et al.
      The frequency and cost of treatment perceived to be futile in critical care.
      • Dasta J.F.
      • McLaughlin T.P.
      • Mody S.H.
      • Piech C.T.
      Daily cost of an intensive care unit day: the contribution of mechanical ventilation.
      Moreover, the global burden of acute and critical illness is expected to increase as the population ages and nonfatal outcomes require more resources from health care systems.
      • Vos T.
      • Barber R.M.
      • Bell B.
      • et al.
      Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
      Transient elevations in blood glucose concentration during acute and critical illness have been recognized for decades.
      • McCowen K.C.
      • Malhotra A.
      • Bistrian B.R.
      Stress-induced hyperglycemia.
      • Brealey D.
      • Singer M.
      Hyperglycemia in critical illness: a review.
      This response in patients without a known history of diabetes was classically considered benign
      • Marik P.E.
      • Bellomo R.
      Stress hyperglycemia: an essential survival response!.
      • Soeters M.R.
      • Soeters P.B.
      The evolutionary benefit of insulin resistance.
      and commonly referred to as stress hyperglycemia.
      • Dungan K.M.
      • Braithwaite S.S.
      • Preiser J.-C.
      Stress hyperglycaemia.
      In recent years, the focus has shifted from immediate health outcomes to long-term outcomes, including the development of new-onset diabetes after acute and critical illness. Several studies have reported that acute and critically ill patients may have a greater risk of subsequent diabetes than the general population.
      • Yasuda T.
      • Ueda T.
      • Takeyama Y.
      • et al.
      Long-term outcome of severe acute pancreatitis.
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      However, evidence is conflicting,
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      even within the same disease setting.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      A recent systematic review found that hyperglycemia in patients admitted to intensive care units was associated with an increased risk of subsequent diabetes
      • Abdelhamid Y.A.
      • Kar P.
      • Finnis M.E.
      • et al.
      Stress hyperglycaemia in critically ill patients and the subsequent risk of diabetes: a systematic review and meta-analysis.
      ; however, this association has not been explored in broader settings of acute and critical illness. In addition, the relationship between degree of hyperglycemia and development of new-onset diabetes remains largely unknown. Therefore, the aim of this study was to systematically review the best available evidence on the relationship between degree of in-hospital hyperglycemia and prevalence of new-onset diabetes after acute and critical illness.

      Methods

      Search Criteria and Identification

      A search strategy was developed to identify all clinical studies that reported the prevalence of new-onset diabetes after hospital discharge following acute and critical illness. Three major electronic databases (MEDLINE, EMBASE, and Scopus) were searched to identify relevant literature from January 1, 2000, through August 4, 2016. The following key words were searched: (blood glucose or hyperglycemia) AND diabetes AND (acute or critically) ill AND clinical studies AND (predict or risk) AND hospital. See the Supplemental Appendix (available online at http://www.mayoclinicproceedings.org) for the full search strategy. Abstracts were reviewed for relevance, and full-text articles were obtained for potentially eligible studies. References in the included studies were also reviewed for eligibility.

      Eligibility Criteria

      The study inclusion criteria were diabetes onset after hospitalization, no history of diabetes (including the need for insulin therapy or oral hypoglycemic agents during hospitalization), older than 17 years, and hospital admission with acute and critical illness. The study exclusion criteria were in-hospital glucose concentration not reported, pediatric or transplant patients, and reviews, commentaries, and letters to the editor.
      If data from the same cohort had been reported in multiple studies, only the most recent study or the most detailed population (with respect to relevant methods and results) was included. Eligibility assessment was conducted by 2 of us (C.J.J. and V.M.A.), and discrepancies were resolved by discussion with the senior author (M.S.P.) or via e-mail with authors of primary studies.

      Data Extraction and Reporting

      Data were extracted from all eligible studies and entered into a predesigned data collection form. The following study and patient characteristics were extracted: author(s), year of publication, country, study design, disease setting, follow-up duration, total study population, age, percentage males, number of patients who met the inclusion criteria, in-hospital glucose categorization, and prevalence of new-onset diabetes. Patients with incomplete data sets were not eligible for analysis (ie, patients unable to complete follow-up or without an in-hospital glucose concentration measured). For studies that included patients with and without diabetes or that had multiple study arms, only patients without a history of diabetes, an in-hospital diabetes diagnosis (including those discharged on insulin therapy), or a need for intensive glucose-lowering therapy during hospitalization were eligible for analysis. The conventional treatment arms of randomized controlled trials were considered prospective cohorts for the purpose of this systematic review.
      Reporting of this study was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols statement and checklist.
      • Moher D.
      • Shamseer L.
      • Clarke M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.

      Quality Assessment

      The methodological quality of studies was assessed by the Newcastle-Ottawa Scale.

      Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2015. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed December 6, 2016.

      Studies were allocated a maximum of 9 points based on 3 perspectives of study design: the selection of the study groups, the comparability of the study groups, and the ascertainment of the outcome of interest. Studies were considered to be of high quality if 5 or more points were scored and of low quality if 4 or fewer points were scored.
      • Das S.L.
      • Singh P.P.
      • Phillips A.R.
      • Murphy R.
      • Windsor J.A.
      • Petrov M.S.
      Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis.

      Definitions

      Diabetes

      Diabetes diagnosis was as reported by authors of primary studies. Diagnosis criteria included the American Diabetes Association (ADA)
      • Moher D.
      • Shamseer L.
      • Clarke M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      or World Health Organization

      Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2015. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed December 6, 2016.

      guidelines (fasting plasma glucose [FPG] level ≥126 mg/dL [to convert to mmol/L, multiply by 0.0555], random or 2-hour plasma glucose [PG] level during an oral glucose tolerance test ≥200 mg/dL, or hemoglobin A1c level ≥6.5% [to convert to proportion, multiply by 0.01]), clinical diagnosis, or need for insulin therapy or oral hypoglycemic agents. Fasting plasma glucose was defined as nil caloric intake for at least 8 hours, and 2-hour PG was obtained after a 75-g oral glucose tolerance test.
      World Health Organization and International Diabetes Federation
      Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation.

      New-Onset Diabetes

      New-onset diabetes was defined as diabetes diagnosed after hospital discharge for patients with no history of diabetes. Patients receiving insulin therapy or oral hypoglycemic agents at hospital discharge were deemed to have preexisting diabetes and were not included in the analysis.

      In-hospital Glycemia

      Patients were categorized into normoglycemia, mild hyperglycemia, and severe hyperglycemia groups according to in-hospital glucose concentration.

      Normoglycemia

      Because ADA and World Health Organization guidelines for normoglycemia differ (FPG level <100 mg/dL and <110 mg/dL, respectively),
      World Health Organization and International Diabetes Federation
      Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation.
      American Diabetes Association
      2. Classification and diagnosis of diabetes.
      patients were classified as having normoglycemia according to author-reported guidelines. If the criteria for glucose classification were not specified by the authors, the ADA guidelines were applied.
      American Diabetes Association
      2. Classification and diagnosis of diabetes.
      Thus, normoglycemia was defined as an FBG level less than 100 mg/dL or a random or 2-hour PG level less than 140 mg/dL.

      Mild Hyperglycemia

      Patients with author-defined impaired fasting glucose levels or impaired glucose tolerance, FPG levels of 100 to 125 mg/dL, or random or 2-hour PG levels of 140 to 199 mg/dL were classified as having mild hyperglycemia.

      Severe Hyperglycemia

      Patients with in-hospital FPG levels of 126 mg/dL or greater or random or 2-hour PG levels of 200 mg/dL or greater without preexisting diabetes were classified as having severe hyperglycemia.

      Statistical Analyses

      Proportion meta-analyses were conducted to determine the pooled prevalence of new-onset diabetes in patients after acute and critical illness. Studies with patients who could be categorized by in-hospital glucose concentration were eligible for analysis. Data were pooled using statistical software (StatsDirect Version 3.0 for Windows; StatsDirect Ltd). Forest plots of pooled prevalence with 95% CIs were generated for all analyses, and a random effects model was applied to provide the most conservative estimate of new-onset diabetes prevalence. If there was no overlap in CIs, the difference between groups was considered statistically significant (P<.05). A sensitivity analysis was also conducted by removing 1 study at a time from the meta-analysis and recalculating the summary effect. Heterogeneity across studies was assessed by the Cochran Q statistic at a significance level of P<.10 and quantified by I2, with cutoff values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      • Higgins J.
      • Green S.
      9.5.2 Identifying and measuring heterogeneity.
      Publication bias was assessed by the Begg-Mazumdar, Egger, and Harbord tests, with P<.05 considered statistically significant.
      A meta-analysis was conducted to investigate the relationship between degree of in-hospital hyperglycemia and prevalence of new-onset diabetes. If in-hospital glucose concentrations did not align with the criteria for normoglycemia, mild hyperglycemia, or severe hyperglycemia, data were fit into the most appropriate category. Subgroup analyses were also conducted. One subgroup analysis investigated the effect of different acute disease settings on the prevalence of new-onset diabetes. A particular acute disease setting was included in this analysis if specified in 2 or more studies. Another subgroup analysis investigated the effect of follow-up duration on the prevalence of new-onset diabetes. Studies were categorized arbitrarily into follow-up intervals of less than 24 months, 24 to 48 months, and greater than 48 months. The reported follow-up duration was assumed to be the mean, unless stated otherwise. If studies reported multiple follow-up intervals, the longest duration or the most complete data set was used. A third subgroup analysis investigated the effect of study design on the prevalence of new-onset diabetes. For the purpose of this review, the conventional arms of randomized controlled trials were classified as prospective cohorts.

      Results

      Study Identification

      A total of 1138 potentially relevant articles were identified and screened. Of these, 50 articles were assessed for eligibility, and 23 were included in the systematic review (Figure 1).
      • Yasuda T.
      • Ueda T.
      • Takeyama Y.
      • et al.
      Long-term outcome of severe acute pancreatitis.
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Gray C.S.
      • Scott J.F.
      • French J.M.
      • Alberti K.
      • O'Connell J.E.
      Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke.
      • Moura F.A.
      • Figueiredo V.N.
      • Teles B.S.
      • et al.
      Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Sinha D.P.
      • Ahmed S.
      • Baneerjee A.K.
      • Das M.
      • Hassan H.
      Significance of an index of insulin resistance in non-diabetic patients with impaired fasting glucose with acute myocardial infarction and its correlation to short term outcome.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Usami M.
      • Sakata Y.
      • Nakatani D.
      • et al.
      Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      Eighteen of the 23 included articles were eligible for meta-analysis of new-onset diabetes by in-hospital glucose concentration.
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.

      Study Characteristics

      A total of 121,501 patients were identified in the 23 included studies, with 52.8% being male (Table 1). Data for 111,078 patients who completed follow-up and had no history of diabetes before hospital discharge were eligible for meta-analysis.
      Table 1Baseline Characteristics of the 23 Included Studies
      ACS = acute coronary syndrome; AMI = acute myocardial infarction; HF = heart failure; ICU = intensive care unit; MH = mild hyperglycemia; MI = myocardial infarction; NG = normoglycemia; STEMI = ST-segment elevation myocardial infarction.
      Reference, yearCountryStudy designDisease settingFollow-up duration (mo), meanTotal study population (No.)Male sex (%)Age (y), mean ± SDPatients who met inclusion criteria (No.)Patients with new-onset diabetes (No.)
      Bronisz et al,
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      2011
      PolandProspective cohortSTEMI320077.556.5±8.71722
      Choi et al,
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      2005
      KoreaProspective cohortAMI33073.360.1±9.1202
      Dave et al,
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      2010
      South AfricaProspective cohortStroke34440.962 (53-71)
      Median (interquartile range).
      271
      Gornik et al,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      2010
      CroatiaProspective cohortSepsis6058452.758 (22-84)
      Median (range).
      17312
      Gornik et al,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      2010
      CroatiaProspective cohortACS and HF
      Patients with sepsis in the study by Gornik et al29 overlapped with the cohort reported by Gornik et al30 and were excluded from the analyses. The remaining patients were divided into ACS (n=43) and HF (n=31) cohorts.
      6025853.5NG 57 (48-65)
      Median (interquartile range).


      MH 60 (48.5-65)
      Median (interquartile range).
      746
      Gray et al,
      • Gray C.S.
      • Scott J.F.
      • French J.M.
      • Alberti K.
      • O'Connell J.E.
      Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke.
      2004
      EnglandProspective cohort
      Conventional treatment arm of a randomized controlled trial.
      Stroke36253.275 (40-93)
      Median (range).
      6213
      Jia et al,
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      2010
      ChinaProspective cohortStroke310763.859.1±12.86810
      Knudsen et al,
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      2009
      NorwayProspective cohortSTEMI322482.658 (51-67)
      Median (interquartile range).
      1795
      Lankisch et al,
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      2008
      GermanyProspective cohortAMI39672.063 ± 13438
      MacIntyre et al,
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      2012
      CanadaProspective cohortPneumonia60212451.468.1±18.52124239
      McAllister et al,
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      2014
      ScotlandRetrospective cohortInternal medicine or surgery43.2 (32.4-56.4)
      Median (interquartile range).
      86,51246.966.3±15.186,5122724
      Meisinger et al,
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      2010
      GermanyRetrospective cohortAMI56.4123976.025-74
      Range.
      1239108
      Moura et al,
      • Moura F.A.
      • Figueiredo V.N.
      • Teles B.S.
      • et al.
      Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.
      2015
      BrazilProspective cohortSTEMI22.8 (13.2-33.6)
      Median (interquartile range).
      32677.461±1132627
      Shore et al,
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      2014
      USARetrospective cohortAMI610,49997.954.2% <65 y10,330482
      Sinha et al,
      • Sinha D.P.
      • Ahmed S.
      • Baneerjee A.K.
      • Das M.
      • Hassan H.
      Significance of an index of insulin resistance in non-diabetic patients with impaired fasting glucose with acute myocardial infarction and its correlation to short term outcome.
      2009
      IndiaProspective cohortAMI67065.758±7.2706
      Sud et al,
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      2015
      CanadaRetrospective cohortHF27.1 (6.4-63.5)
      Median (interquartile range).
      16,52449.179 (70-85)
      Median (interquartile range).
      92751220
      Tenerz et al,
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      2001
      SwedenProspective cohortAMI2.528564.269.3±11.316710
      Tenerz et al,
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      2003
      SwedenProspective cohortAMI314571.963.2±9.49510
      Terlecki et al,
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      2015
      PolandRetrospective cohortMI48.2±13.919080.061.3±11.319015
      Usami et al,
      • Usami M.
      • Sakata Y.
      • Nakatani D.
      • et al.
      Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction.
      2014
      JapanProspective cohortAMI30.4149375.565.5±12.01493196
      Van Ackerbroek et al,
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      2015
      BelgiumProspective cohortMixed medical/surgical ICU833866.0NG 56 (18-82)
      Median (range).


      MH 62 (20-88)
      Median (range).
      33824
      Vancheri et al,
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      2005
      ItalyProspective cohortStroke310661.371.0 (63.2-77.0)
      Median (interquartile range).
      528
      Yasuda et al,
      • Yasuda T.
      • Ueda T.
      • Takeyama Y.
      • et al.
      Long-term outcome of severe acute pancreatitis.
      2008
      JapanProspective cohortAcute pancreatitis56±64580.052±23712
      a ACS = acute coronary syndrome; AMI = acute myocardial infarction; HF = heart failure; ICU = intensive care unit; MH = mild hyperglycemia; MI = myocardial infarction; NG = normoglycemia; STEMI = ST-segment elevation myocardial infarction.
      b Median (interquartile range).
      c Median (range).
      d Patients with sepsis in the study by Gornik et al
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      overlapped with the cohort reported by Gornik et al
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      and were excluded from the analyses. The remaining patients were divided into ACS (n=43) and HF (n=31) cohorts.
      e Conventional treatment arm of a randomized controlled trial.
      f Range.

      Quality Assessment and Publication Bias

      The Newcastle-Ottawa Scale of methodological quality was applied to each of the studies (Table 2). The median score was 8 (range, 6-8), and all the studies were considered high quality. There was no evidence of publication bias using the Begg-Mazumdar (P=.55), Egger (P=.15), and Harbord (P=.11) tests.
      Table 2Quality Assessment Using the Newcastle-Ottawa Scale
      Reference, yearSelection scoreComparability scoreOutcome scoreTotal score
      Bronisz et al,
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      2011
      3238
      Choi et al,
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      2005
      3137
      Dave et al,
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      2010
      3227
      Gornik et al,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      2010
      3238
      Gornik et al,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      2010
      3126
      Gray et al,
      • Gray C.S.
      • Scott J.F.
      • French J.M.
      • Alberti K.
      • O'Connell J.E.
      Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke.
      2004
      3126
      Jia et al,
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      2010
      3238
      Knudsen et al,
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      2009
      3238
      Lankisch et al,
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      2008
      3227
      MacIntyre et al,
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      2012
      3238
      McAllister et al,
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      2014
      3238
      Meisinger et al,
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      2010
      3238
      Moura et al,
      • Moura F.A.
      • Figueiredo V.N.
      • Teles B.S.
      • et al.
      Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.
      2015
      3238
      Shore et al,
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      2014
      3238
      Sinha et al,
      • Sinha D.P.
      • Ahmed S.
      • Baneerjee A.K.
      • Das M.
      • Hassan H.
      Significance of an index of insulin resistance in non-diabetic patients with impaired fasting glucose with acute myocardial infarction and its correlation to short term outcome.
      2009
      3137
      Sud et al,
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      2015
      3238
      Tenerz et al,
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      2001
      3126
      Tenerz et al,
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      2003
      3238
      Terlecki et al,
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      2015
      3238
      Usami et al,
      • Usami M.
      • Sakata Y.
      • Nakatani D.
      • et al.
      Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction.
      2014
      3238
      Van Ackerbroek et al,
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      2015
      3238
      Vancheri et al,
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      2005
      3238
      Yasuda et al,
      • Yasuda T.
      • Ueda T.
      • Takeyama Y.
      • et al.
      Long-term outcome of severe acute pancreatitis.
      2008
      3137

      In-hospital Hyperglycemia

      The pooled prevalence of new-onset diabetes was 8% (95% CI, 6%-11%), and the sensitivity analysis after removal of each study did not change it significantly. The association between in-hospital normoglycemia and prevalence of subsequent diabetes was reported in 17 studies, and these patients had a prevalence of 4% (95% CI, 2%-7%) (Figure 2A).
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      The association between in-hospital mild hyperglycemia and prevalence of subsequent diabetes was reported in 18 studies, and these patients had a prevalence of 12% (95% CI, 9%-15%) (Figure 2B).
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      The association between in-hospital severe hyperglycemia and prevalence of subsequent diabetes was reported in 5 studies, and the prevalence of new-onset diabetes for patients with severe hyperglycemia was 28% (95% CI, 18%-39%) (Figure 2C).
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      The absence of overlapping CIs indicated a significant difference between the groups (P<.05). Statistical heterogeneity was high for all the glycemic groups (Q: P<.001 for each group; I2: 98.7%, 95.4%, and 92.5% for normoglycemia, mild hyperglycemia, and severe hyperglycemia groups, respectively).
      Figure thumbnail gr2
      Figure 2A, Prevalence of new-onset diabetes for patients with normoglycemia. Normoglycemia was classified as a hospital admission plasma glucose (PG) level less than 124 mg/dL (to convert to mmol/L, multiply by 0.0555) in the study by McAllister et al.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      B, Prevalence of new-onset diabetes for patients with mild hyperglycemia. Patients with random PG levels of 140 mg/dL or greater were classified as having mild hyperglycemia in the studies by Van Ackerbroeck et al,
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      Gornik et al,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      and Shore et al
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      because data were not available for patients with severe hyperglycemia (random PG levels ≥200 mg/dL). Mild hyperglycemia was classified as a hospital admission PG level of 126 to 198 mg/dL in the study by McAllister et al
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      and 128 mg/dL or greater in the study by Meisinger et al.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      C, Prevalence of new-onset diabetes for patients with severe hyperglycemia.

      Effect of Disease Setting

      The 18 meta-analyzed studies were conducted in 7 disease settings. Nine studies included patients with myocardial infarction,
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      3 included patients with stroke,
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      2 included patients with heart failure,
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      and single studies reported on sepsis,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      acute coronary syndrome,
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      pneumonia,
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      internal medicine or surgery,
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      or mixed medical/surgical intensive care unit patients.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      Of the disease settings, myocardial infarction, stroke, and heart failure were suitable for meta-analysis. The pooled prevalence of new-onset diabetes was 7% (95% CI, 4%-9%) for myocardial infarction, 13% (95% CI, 7%-20%) for stroke, and 13% (95% CI, 12%-14%) for heart failure.

      Effect of Follow-up Duration

      The prevalence of new-onset diabetes increased with follow-up duration; however, the trend was not statistically significant. Of the 18 studies, 11 had a follow-up duration of less than 24 months, and the prevalence of new-onset diabetes in this timeframe was 7% (95% CI, 5%-10%).
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      Two studies had a follow-up duration of 24 to 48 months, and the prevalence was also 7% (95% CI, 1%-20%).
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      A further 5 studies had a follow-up duration longer than 48 months, and the prevalence was 9% (95% CI, 8%-11%).
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.

      Effect of Study Design

      Of the 18 studies included in the meta-analyses, 13 were prospective cohorts
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Lankisch M.
      • Füth R.
      • Gülker H.
      • et al.
      Screening for undiagnosed diabetes in patients with acute myocardial infarction.
      • Bronisz A.
      • Kozinski M.
      • Magielski P.
      • et al.
      Value of oral glucose tolerance test in the acute phase of myocardial infarction.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Van Ackerbroeck S.
      • Schepens T.
      • Janssens K.
      • et al.
      Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
      • Gornik I.
      • Vujaklija A.
      • Lukic E.
      • Madzarac G.
      • Gasparovic V.
      Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Knudsen E.C.
      • Seljeflot I.
      • Abdelnoor M.
      • et al.
      Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
      • MacIntyre E.J.
      • Majumdar S.R.
      • Gamble J.M.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Eurich D.T.
      Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      and 5 were retrospective cohorts.
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Terlecki M.
      • Bryniarski L.
      • Bednarek A.
      • et al.
      The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Meisinger C.
      • Beck J.
      • Heier M.
      • et al.
      Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      There was no statistically significant difference in the prevalence of new-onset diabetes by study design, with the prevalence being 8% (95% CI, 6%-11%) for prospective cohort studies and 7% (95% CI, 3%-12%) for retrospective cohort studies.

      Discussion

      This systematic review summarizes all available clinical evidence on the association between degrees of in-hospital glucose concentration and subsequent onset of diabetes in acute and critically ill patients. Twenty-three studies with more than 120,000 patients were included in the systematic review. In the meta-analysis, the combined prevalence of new-onset diabetes was 8%, and this estimate depended on the degree of in-hospital hyperglycemia. Prevalence did not seem to be influenced by acute disease setting, follow-up duration, or study design. The patients included in this review were relatively homogenous and comprised acute and critically ill adults with no history of diabetes before hospital discharge and no glucose-lowering medications during hospitalization. In addition, all included patients were treated conventionally during hospitalization, and none of the studies included in the meta-analysis were interventional.
      This systematic review and meta-analysis suggests that the degree of in-hospital hyperglycemia in acute and critically ill patients increases susceptibility to new-onset diabetes after hospitalization. We found a stepwise increase in the prevalence of new-onset diabetes, with 28% of patients with severe hyperglycemia developing new-onset diabetes after hospital discharge. This is strikingly higher than the 8.5% global prevalence of diabetes in adults.
      • Roglic G.
      WHO Global report on diabetes: a summary.
      Diabetes is a growing epidemic and is used as an encompassing term for diseases associated with elevated blood glucose concentrations. Conventional risk factors for diabetes have been investigated in the general population for decades,
      • Wild S.
      • Roglic G.
      • Green A.
      • Sicree R.
      • King H.
      Global prevalence of diabetes estimates for the year 2000 and projections for 2030.
      and subtypes of diabetes, such as gestational and pancreatogenic diabetes, are well established.
      • Kim C.
      • Newton K.M.
      • Knopp R.H.
      Gestational diabetes and the incidence of type 2 diabetes: a systematic review.
      • Das S.L.
      • Kennedy J.I.
      • Murphy R.
      • Phillips A.R.
      • Windsor J.A.
      • Petrov M.S.
      Relationship between the exocrine and endocrine pancreas after acute pancreatitis.
      Recently, evidence has emerged about diabetes after myocardial infarction, stroke, and other acute and critical illness.
      • Sud M.
      • Wang X.
      • Austin P.C.
      • et al.
      Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
      • Gray C.S.
      • Scott J.F.
      • French J.M.
      • Alberti K.
      • O'Connell J.E.
      Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke.
      • McAllister D.A.
      • Hughes K.A.
      • Lone N.
      • et al.
      Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
      • Shore S.
      • Borgerding J.A.
      • Gylys-Colwell I.
      • et al.
      Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
      • Hsu C.-W.
      • Lin C.-S.
      • Chen S.-J.
      • Lin S.H.
      • Lin C.L.
      • Kao C.H.
      Risk of type 2 diabetes mellitus in patients with acute critical illness: a population-based cohort study.
      The outcomes of these studies suggest that the stress of acute and critical illness tips glucose homeostasis over the edge in susceptible patients and contributes to overt diabetes later in life. A systematic review of patients with acute pancreatitis found that the prevalence of new-onset diabetes is 23% at 5 years after the first episode of acute pancreatitis,
      • Das S.L.
      • Singh P.P.
      • Phillips A.R.
      • Murphy R.
      • Windsor J.A.
      • Petrov M.S.
      Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis.
      and this is similar to the 28% prevalence of new-onset diabetes in the severe hyperglycemia group. However, that study did not investigate the concentration-dependent increase in risk of diabetes and was restricted to only 1 disease setting. The findings of the present study suggest that in-hospital hyperglycemia is not benign
      • Marik P.E.
      • Bellomo R.
      Stress hyperglycemia: an essential survival response!.
      and raises the question as to whether this represents an unrecognized subtype of diabetes or a new risk factor for type 2 diabetes mellitus. Prospective observational studies are now warranted to determine whether acute and critical illness is a causative factor for the development of new-onset diabetes.
      Stress in acute and critical illness is a systemic response to injury or infection
      • Van Cromphaut S.
      Hyperglycaemia as part of the stress response: the underlying mechanisms.
      characterized by a rise in PG, pro-inflammatory cytokine, and counterregulatory hormone levels (Figure 3).
      • Kajbaf F.
      • Mojtahedzadeh M.
      • Abdollahi M.
      Mechanisms underlying stress-induced hyperglycemia in critically ill patients.
      Stress-induced hypermetabolism and inflammation can disturb carbohydrate metabolism by increasing hepatic glucose production, decreasing peripheral glucose uptake, and promoting insulin resistance in the liver and skeletal muscles.
      • Van Cromphaut S.
      Hyperglycaemia as part of the stress response: the underlying mechanisms.
      • Kajbaf F.
      • Mojtahedzadeh M.
      • Abdollahi M.
      Mechanisms underlying stress-induced hyperglycemia in critically ill patients.
      The subsequent hyperinsulinemia and hyperglycemia exacerbates inflammatory and counterregulatory hormone responses, impeding the insulin signalling pathway and maintaining hyperglycemia.
      • Dungan K.M.
      • Braithwaite S.S.
      • Preiser J.-C.
      Stress hyperglycaemia.
      It is generally believed that blood glucose levels peak several days after the initial insult and then return to normal during recovery.
      • Van Cromphaut S.
      Hyperglycaemia as part of the stress response: the underlying mechanisms.
      • Desborough J.
      The stress response to trauma and surgery.
      Recently, several authors have suggested that this stress signaling associated with transient hyperglycemia can continue after hospital discharge.
      • Ceriello A.
      • Esposito K.
      • Piconi L.
      • et al.
      Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.
      This is thought to relate to glycemic memory and is used to explain the development of diabetes.
      • Bailey C.J.
      • Day C.
      Glycaemic memory.
      • Siebel A.L.
      • Fernandez A.Z.
      • El-Osta A.
      Glycemic memory associated epigenetic changes.
      Hyperglycemia stimulates the production of reactive oxygen species that activate cell signaling pathways involving the nuclear factor-κβ transcription factor and formation of nitrogen oxide and lipid peroxides.
      • El-Osta A.
      Glycemic memory.
      • Berezin A.
      Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives.
      Although reactive oxygen species have short half-lives, the damage to protein and lipids can persist and, once modified, can exert altered cellular function over a prolonged period.
      • Nishikawa T.
      • Edelstein D.
      • Du X.L.
      • et al.
      Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.
      This contributes to the systemic inflammatory response and insulin resistance that characterizes acute and critical illness. Furthermore, hyperglycemia can lead to changes in gene expression. Epigenetic changes, such as DNA methylation and histone acetylation, can modulate antioxidant and inflammatory genes, also contributing to systemic inflammation.
      • Siebel A.L.
      • Fernandez A.Z.
      • El-Osta A.
      Glycemic memory associated epigenetic changes.
      • El-Osta A.
      Glycemic memory.
      • Berezin A.
      Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives.
      • Prattichizzo F.
      • Giuliani A.
      • Ceka A.
      • et al.
      Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes.
      DNA methylation has been linked to human insulin secretion and resistance,
      • Ling C.
      • Del Guerra S.
      • Lupi R.
      • et al.
      Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.
      and the level of DNA methylation has been found to be a predictive biomarker of diabetes susceptibility, diagnosis, and progression.
      • Berezin A.
      Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives.
      Figure thumbnail gr3
      Figure 3Hypothesized changes in glucose homeostasis after acute and critical illness. aAcute and critical stress is a systemic response to injury associated with hypermetabolism and increased circulating glucose, cytokine, and counterregulatory hormone levels. bOvert in-hospital stress hyperglycemia is characterized by disturbed carbohydrate metabolism, peripheral insulin resistance, and decreased insulin secretion. cGut injury results in impaired motility, disturbed barrier function, luminal translocation of bacteria, or altered endocrine and immune function. dPersistent stress signaling describes the production of reactive oxygen species, DNA methylation and histone acetylation, and modulation of anti-inflammatory and antioxidant genes. eAltered microbiota can lead to the loss of health-promoting bacteria and the proliferation of pathogenic bacteria. Pathogenic bacteria may promote further gut dysfunction (dashed arrow). NF-kB = nuclear factor-κβ; SCFA = short-chain fatty acid.
      The presence of systemic inflammation and insulin resistance might be exacerbated by gut injury, which is a common feature of acute and critical illness (Figure 3). Changes in gut motility, barrier function, microbial composition, or endocrine function have been noted in various disease settings.
      • Hill L.T.
      Gut dysfunction in the critically ill: mechanisms and clinical implications.
      • Ma J.
      • Pendharkar S.A.
      • O'Grady G.
      • Windsor J.A.
      • Petrov M.S.
      Effect of nasogastric tube feeding vs nil per os on dysmotility in acute pancreatitis: results of a randomized controlled trial.
      • Söderholm J.D.
      • Perdue II, M.H.
      Stress and intestinal barrier function.
      • Petrov M.S.
      • Windsor J.A.
      Nutritional management of acute pancreatitis: the concept of “gut rousing”.
      • Blaser A.R.
      • Malbrain M.L.
      • Starkopf J.
      • et al.
      Gastrointestinal function in intensive care patients: terminology, definitions and management: recommendations of the ESICM Working Group on Abdominal Problems.
      • Puleo F.
      • Arvanitakis M.
      • Van Gossum A.
      • Preiser J.C.
      Gut failure in the ICU.
      Moreover, a meta-analysis of acute pancreatitis studies indicated that 3 in every 5 patients have evidence of gut barrier dysfunction, independent of disease severity.
      • Wu L.M.
      • Sankaran S.J.
      • Plank L.D.
      • Windsor J.A.
      • Petrov M.S.
      Meta-analysis of gut barrier dysfunction in patients with acute pancreatitis.
      Disturbances in gut barrier function are thought to include translocation of luminal bacteria and bacterial products,
      • Balzan S.
      • de Almeida Quadros C.
      • De Cleva R.
      • Zilberstein B.
      • Cecconello I.
      Bacterial translocation: overview of mechanisms and clinical impact.
      reflecting changes in the composition of intestinal microbiota.
      • McKenzie S.J.
      • Premkumar R.
      • Askelund K.J.
      • et al.
      The effect of enteral nutrition on adipokines in patients with acute pancreatitis.
      • Pendharkar S.A.
      • Singh R.G.
      • Petrov M.S.
      Cross-talk between innate cytokines and the pancreatic polypeptide family in acute pancreatitis.
      This may lead to a loss of normal health-promoting commensal microbes and overgrowth of pathogenic bacteria.
      • Petrov M.S.
      • Windsor J.A.
      Nutritional management of acute pancreatitis: the concept of “gut rousing”.
      Proliferation of unfavorable microbiota during acute and critical illness may result in a reduction of short-chain fatty acid production, prolonged exposure to bacterial endotoxins, and increased exposure to circulating proinflammatory factors.
      • Boulangé C.L.
      • Neves A.L.
      • Chilloux J.
      • Nicholson J.K.
      • Dumas M.E.
      Impact of the gut microbiota on inflammation, obesity, and metabolic disease.
      These changes in the gut associated with inflammation and insulin resistance may increase a patient's susceptibility to diabetes later in life.
      • Musso G.
      • Gambino R.
      • Cassader M.
      Obesity, diabetes, and gut microbiota.
      Furthermore, gut injury during acute and critical illness can affect the circulating concentration of regulatory peptides produced by the pancreas, gut, and adipose tissues.
      • Puleo F.
      • Arvanitakis M.
      • Van Gossum A.
      • Preiser J.C.
      Gut failure in the ICU.
      • Pendharkar S.A.
      • Asrani V.M.
      • Xiao A.Y.
      • et al.
      Relationship between pancreatic hormones and glucose metabolism: a cross-sectional study in patients after acute pancreatitis.
      Variations in adipokines, gut peptides, and pancreatic hormones have been associated with disturbances in glucose metabolism and future risk of diabetes.
      • Wu L.M.
      • Premkumar R.
      • Phillips A.R.
      • Windsor J.A.
      • Petrov M.S.
      Ghrelin and gastroparesis as early predictors of clinical outcomes in acute pancreatitis.
      • Kennedy J.I.
      • Askelund K.J.
      • Premkumar R.
      • et al.
      Leptin is associated with persistence of hyperglycemia in acute pancreatitis: a prospective clinical study.
      • Pendharkar S.A.
      • Asrani V.M.
      • Murphy R.
      • Cutfield R.
      • Windsor J.A.
      • Petrov M.S.
      The role of gut-brain axis in regulating glucose metabolism after acute pancreatitis.
      • Gillies N.
      • Pendharkar S.A.
      • Asrani V.M.
      • Mathew J.
      • Windsor J.A.
      • Petrov M.S.
      Interleukin-6 is associated with chronic hyperglycemia and insulin resistance in patients after acute pancreatitis.
      However, no prospective cohort studies have specifically measured changes in these peptides from baseline to follow-up in acute and critically ill patients. This measurement is crucial in determining whether the observed changes in glucose homeostasis are a risk factor for type 2 diabetes or hallmarks of a novel diabetes subtype.
      The finding of a statistically significant association between degree of in-hospital hyperglycemia and prevalence of new-onset diabetes after acute and critical illness suggests that prevention strategies for high-risk patients may need to be considered. Type 2 diabetes is a preventable disease, and prevention programs in the United States,
      Diabetes Prevention Program Research Group
      10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.
      China,
      • Li G.
      • Zhang P.
      • Wang J.
      • et al.
      The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study.
      and Finland
      • Lindström J.
      • Ilanne-Parikka P.
      • Peltonen M.
      • et al.
      Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study.
      have found that patients allocated to dietary and lifestyle modification had a significantly lower incidence of diabetes than those in control groups. However, it remains to be investigated whether such programs would be useful in reducing the risk of diabetes after acute and critical illness.
      This review has several limitations. First, the statistical heterogeneity across studies was high for all the glycemic groups. This may be attributed to different study settings or the timing of glucose measurements across the course of disease. However, we conducted a sensitivity analysis and a series of prespecified subgroup analyses on the effect of disease setting, study duration, and study design to investigate whether these potential confounders could explain the discrepancy across studies. In addition, random effects models were used as the most conservative approach to estimating the prevalence of new-onset diabetes. Second, we were not able to investigate whether the stepwise increase in prevalence of new-onset diabetes was independent of conventional risk factors for type 2 diabetes, such as family history of diabetes, age, sex, body mass index, physical activity, and socioeconomic status.
      • Wild S.
      • Roglic G.
      • Green A.
      • Sicree R.
      • King H.
      Global prevalence of diabetes estimates for the year 2000 and projections for 2030.
      • Bray G.A.
      • Jablonski K.A.
      • Fujimoto W.Y.
      • et al.
      Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program.
      • Lee I.-M.
      • Shiroma E.J.
      • Lobelo F.
      • et al.
      Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy.
      • Xiao A.Y.
      • Tan M.L.
      • Wu L.M.
      • et al.
      Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies.

      Pendharkar SA, Mathew J, Petrov MS. Age- and sex-specific prevalence of diabetes associated with diseases of the exocrine pancreas: a population-based study published online Dec 21, 2016]. Dig Liver Dis. doi:10.1016/j.dld.2016.12.010.

      • Valdez R.
      • Yoon P.W.
      • Liu T.
      • Khoury M.J.
      Family history and prevalence of diabetes in the U.S. population: the 6-year results from the National Health and Nutrition Examination Survey (1999–2004).
      However, this is a common limitation of systematic reviews, which are secondary analyses of the literature. Third, not all included studies screened for undiagnosed diabetes at the time of hospitalization, hence it is possible that a fraction of the patients included in the analyses may have had unrecognized diabetes before hospital admission. However, 9 studies did test for hemoglobin A1c during hospitalization and excluded patients who presented with undiagnosed diabetes.
      • Dave J.A.
      • Engel M.E.
      • Freercks R.
      • et al.
      Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
      • Choi K.
      • Lee K.
      • Kim S.
      • et al.
      Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
      • Gray C.S.
      • Scott J.F.
      • French J.M.
      • Alberti K.
      • O'Connell J.E.
      Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke.
      • Moura F.A.
      • Figueiredo V.N.
      • Teles B.S.
      • et al.
      Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.
      • Tenerz A.
      • Norhammar A.
      • Silveira A.
      • et al.
      Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
      • Jia Q.
      • Zheng H.
      • Liu L.
      • et al.
      Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
      • Tenerz A.
      • Lonnberg I.
      • Berne C.
      • Nilsson G.
      • Leppert J.
      Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
      • Usami M.
      • Sakata Y.
      • Nakatani D.
      • et al.
      Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction.
      • Vancheri F.
      • Curcio M.
      • Burgio A.
      • et al.
      Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
      Last, the findings from this review may not be generalizable to all disease settings. Although the meta-analysis included 7 disease settings, it was limited to studies that reported the effect of in-hospital glucose concentration on the prevalence of new-onset diabetes. Furthermore, patients undergoing transplant were excluded from the review because many had end-stage diseases. In addition, the findings of the systematic review were limited to adults only.

      Conclusion

      The degree of in-hospital hyperglycemia in acute and critically ill patients is significantly associated with the prevalence of new-onset diabetes. Patients with severe hyperglycemia have the greatest risk, with 28% developing diabetes after hospital discharge. Pathogenesis of new-onset diabetes after acute and critical illness needs to be investigated in mechanistic and longitudinal prospective studies.

      Acknowledgments

      This study was part of the Clinical and epidemiOlogical inveStigations in Metabolism, nutritiOn, and pancreatic diseaseS (COSMOS) program. COSMOS is supported in part by the Health Research Council of New Zealand (grant 15/035 to M.S.P.).

      Supplemental Online Material

      Supplemental Online Material

      Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

      References

        • Vos T.
        • Barber R.M.
        • Bell B.
        • et al.
        Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2015; 386: 743-800
        • Adhikari N.K.
        • Fowler R.A.
        • Bhagwanjee S.
        • Rubenfeld G.D.
        Critical care and the global burden of critical illness in adults.
        Lancet. 2010; 376: 1339-1346
        • Huynh T.N.
        • Kleerup E.C.
        • Wiley J.F.
        • et al.
        The frequency and cost of treatment perceived to be futile in critical care.
        JAMA Intern Med. 2013; 173: 1887-1894
        • Dasta J.F.
        • McLaughlin T.P.
        • Mody S.H.
        • Piech C.T.
        Daily cost of an intensive care unit day: the contribution of mechanical ventilation.
        Crit Care Med. 2005; 33: 1266-1271
        • McCowen K.C.
        • Malhotra A.
        • Bistrian B.R.
        Stress-induced hyperglycemia.
        Crit Care Clin. 2001; 17: 107-124
        • Brealey D.
        • Singer M.
        Hyperglycemia in critical illness: a review.
        J Diabetes Sci Technol. 2009; 3: 1250-1260
        • Marik P.E.
        • Bellomo R.
        Stress hyperglycemia: an essential survival response!.
        Crit Care. 2013; 17: 305
        • Soeters M.R.
        • Soeters P.B.
        The evolutionary benefit of insulin resistance.
        Clin Nutr. 2012; 31: 1002-1007
        • Dungan K.M.
        • Braithwaite S.S.
        • Preiser J.-C.
        Stress hyperglycaemia.
        Lancet. 2009; 373: 1798-1807
        • Yasuda T.
        • Ueda T.
        • Takeyama Y.
        • et al.
        Long-term outcome of severe acute pancreatitis.
        J Hepatobiliary Pancreat Surg. 2008; 15: 397-402
        • Sud M.
        • Wang X.
        • Austin P.C.
        • et al.
        Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.
        Eur Heart J. 2015; 36: 924-931
        • Dave J.A.
        • Engel M.E.
        • Freercks R.
        • et al.
        Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review.
        QJM. 2010; 103: 495-503
        • Lankisch M.
        • Füth R.
        • Gülker H.
        • et al.
        Screening for undiagnosed diabetes in patients with acute myocardial infarction.
        Clin Res Cardiol. 2008; 97: 753-759
        • Bronisz A.
        • Kozinski M.
        • Magielski P.
        • et al.
        Value of oral glucose tolerance test in the acute phase of myocardial infarction.
        Cardiovasc Diabetol. 2011; 10: 21
        • Abdelhamid Y.A.
        • Kar P.
        • Finnis M.E.
        • et al.
        Stress hyperglycaemia in critically ill patients and the subsequent risk of diabetes: a systematic review and meta-analysis.
        Crit Care. 2016; 20: 301
        • Moher D.
        • Shamseer L.
        • Clarke M.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
      1. Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2015. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed December 6, 2016.

        • Das S.L.
        • Singh P.P.
        • Phillips A.R.
        • Murphy R.
        • Windsor J.A.
        • Petrov M.S.
        Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis.
        Gut. 2014; 63: 818-831
        • World Health Organization and International Diabetes Federation
        Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation.
        World Health Organization, Geneva, Switzerland2006
        • American Diabetes Association
        2. Classification and diagnosis of diabetes.
        Diabetes Care. 2016; 39: S13-S22
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Higgins J.
        • Green S.
        9.5.2 Identifying and measuring heterogeneity.
        in: Cochrane Handbook for Systematic Reviews of Interventions. Vol 5.0.1. Wiley-Blackwell, Chichester, UK2008
        • Choi K.
        • Lee K.
        • Kim S.
        • et al.
        Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus.
        J Clin Endocrinol Metab. 2005; 90: 175-180
        • Gray C.S.
        • Scott J.F.
        • French J.M.
        • Alberti K.
        • O'Connell J.E.
        Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke.
        Age Ageing. 2004; 33: 71-77
        • Moura F.A.
        • Figueiredo V.N.
        • Teles B.S.
        • et al.
        Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.
        Atherosclerosis. 2015; 243: 124-130
        • Tenerz A.
        • Norhammar A.
        • Silveira A.
        • et al.
        Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes.
        Diabetes Care. 2003; 26: 2770-2776
        • Terlecki M.
        • Bryniarski L.
        • Bednarek A.
        • et al.
        The risk of diabetes development in long-term observation of patients with acute hyperglycaemia during myocardial infarction.
        Kardiol Pol. 2015; 73: 606-612
        • Van Ackerbroeck S.
        • Schepens T.
        • Janssens K.
        • et al.
        Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study.
        Crit Care. 2015; 19: 355
        • Gornik I.
        • Vujaklija A.
        • Lukic E.
        • Madzarac G.
        • Gasparovic V.
        Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus.
        Acta Diabetol. 2010; 47: 29-33
        • Gornik I.
        • Vujaklija A.
        • Lukic E.
        • Madzarac G.
        • Gasparovic V.
        Hyperglycemia in sepsis is a risk factor for development of type II diabetes.
        J Crit Care. 2010; 25: 263-269
        • Jia Q.
        • Zheng H.
        • Liu L.
        • et al.
        Persistence and predictors of abnormal glucose metabolisms in patients after acute stroke.
        Neurol Res. 2010; 32: 359-365
        • Knudsen E.C.
        • Seljeflot I.
        • Abdelnoor M.
        • et al.
        Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction: a cohort study on 224 patients.
        Cardiovasc Diabetol. 2009; 8: 6
        • MacIntyre E.J.
        • Majumdar S.R.
        • Gamble J.M.
        • Minhas-Sandhu J.K.
        • Marrie T.J.
        • Eurich D.T.
        Stress hyperglycemia and newly diagnosed diabetes in 2124 patients hospitalized with pneumonia.
        Am J Med. 2012; 125: 1036e17-1036e23
        • McAllister D.A.
        • Hughes K.A.
        • Lone N.
        • et al.
        Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study.
        PLoS Med. 2014; 11: e1001708
        • Meisinger C.
        • Beck J.
        • Heier M.
        • et al.
        Myocardial infarction and incidence of type 2 diabetes mellitus: is admission blood glucose an independent predictor for future type 2 diabetes mellitus?.
        Am Heart J. 2010; 159: 258-263
        • Shore S.
        • Borgerding J.A.
        • Gylys-Colwell I.
        • et al.
        Association between hyperglycemia at admission during hospitalization for acute myocardial infarction and subsequent diabetes: insights from the veterans administration cardiac care follow-up clinical study.
        Diabetes Care. 2014; 37: 409-418
        • Sinha D.P.
        • Ahmed S.
        • Baneerjee A.K.
        • Das M.
        • Hassan H.
        Significance of an index of insulin resistance in non-diabetic patients with impaired fasting glucose with acute myocardial infarction and its correlation to short term outcome.
        Indian Heart J. 2009; 61: 40-43
        • Tenerz A.
        • Lonnberg I.
        • Berne C.
        • Nilsson G.
        • Leppert J.
        Myocardial infarction and prevalence of diabetes mellitus: is increased casual blood glucose at admission a reliable criterion for the diagnosis of diabetes?.
        Eur Heart J. 2001; 22: 1102-1110
        • Usami M.
        • Sakata Y.
        • Nakatani D.
        • et al.
        Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction.
        J Cardiol. 2014; 63: 274-280
        • Vancheri F.
        • Curcio M.
        • Burgio A.
        • et al.
        Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.
        QJM. 2005; 98: 871-878
        • Roglic G.
        WHO Global report on diabetes: a summary.
        Int J Noncommun Dis. 2016; 1: 3
        • Wild S.
        • Roglic G.
        • Green A.
        • Sicree R.
        • King H.
        Global prevalence of diabetes estimates for the year 2000 and projections for 2030.
        Diabetes Care. 2004; 27: 1047-1053
        • Kim C.
        • Newton K.M.
        • Knopp R.H.
        Gestational diabetes and the incidence of type 2 diabetes: a systematic review.
        Diabetes Care. 2002; 25: 1862-1868
        • Das S.L.
        • Kennedy J.I.
        • Murphy R.
        • Phillips A.R.
        • Windsor J.A.
        • Petrov M.S.
        Relationship between the exocrine and endocrine pancreas after acute pancreatitis.
        World J Gastroenterol. 2014; 20: 17196-17205
        • Hsu C.-W.
        • Lin C.-S.
        • Chen S.-J.
        • Lin S.H.
        • Lin C.L.
        • Kao C.H.
        Risk of type 2 diabetes mellitus in patients with acute critical illness: a population-based cohort study.
        Intensive Care Med. 2016; 42: 38-45
        • Van Cromphaut S.
        Hyperglycaemia as part of the stress response: the underlying mechanisms.
        Best Pract Res Clin Anaesthesiol. 2009; 23: 375-386
        • Kajbaf F.
        • Mojtahedzadeh M.
        • Abdollahi M.
        Mechanisms underlying stress-induced hyperglycemia in critically ill patients.
        Therapy. 2007; 4: 97-106
        • Desborough J.
        The stress response to trauma and surgery.
        Br J Anaesth. 2000; 85: 109-117
        • Ceriello A.
        • Esposito K.
        • Piconi L.
        • et al.
        Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.
        Diabetes. 2008; 57: 1349-1354
        • Bailey C.J.
        • Day C.
        Glycaemic memory.
        Br J Diabetes Vasc Dis. 2008; 8: 242-247
        • Siebel A.L.
        • Fernandez A.Z.
        • El-Osta A.
        Glycemic memory associated epigenetic changes.
        Biochem Pharmacol. 2010; 80: 1853-1859
        • El-Osta A.
        Glycemic memory.
        Curr Opin Lipidol. 2012; 23: 24-29
        • Berezin A.
        Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives.
        Diabetes Metab Syndr. 2016; 10: S176-S183
        • Nishikawa T.
        • Edelstein D.
        • Du X.L.
        • et al.
        Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.
        Nature. 2000; 404: 787-790
        • Prattichizzo F.
        • Giuliani A.
        • Ceka A.
        • et al.
        Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes.
        Clin Epigenetics. 2015; 7: 56
        • Ling C.
        • Del Guerra S.
        • Lupi R.
        • et al.
        Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.
        Diabetologia. 2008; 51: 615-622
        • Hill L.T.
        Gut dysfunction in the critically ill: mechanisms and clinical implications.
        S Afr J Crit Care. 2013; 29: 11-15
        • Ma J.
        • Pendharkar S.A.
        • O'Grady G.
        • Windsor J.A.
        • Petrov M.S.
        Effect of nasogastric tube feeding vs nil per os on dysmotility in acute pancreatitis: results of a randomized controlled trial.
        Nutr Clin Pract. 2016; 31: 99-104
        • Söderholm J.D.
        • Perdue II, M.H.
        Stress and intestinal barrier function.
        Am J Physiol Gastrointest Liver Physiol. 2001; 280: G7-G13
        • Petrov M.S.
        • Windsor J.A.
        Nutritional management of acute pancreatitis: the concept of “gut rousing”.
        Curr Opin Clin Nutr Metab Care. 2013; 16: 557-563
        • Blaser A.R.
        • Malbrain M.L.
        • Starkopf J.
        • et al.
        Gastrointestinal function in intensive care patients: terminology, definitions and management: recommendations of the ESICM Working Group on Abdominal Problems.
        Intensive Care Med. 2012; 38: 384-394
        • Puleo F.
        • Arvanitakis M.
        • Van Gossum A.
        • Preiser J.C.
        Gut failure in the ICU.
        Semin Respir Crit Care Med. 2011; 32: 626-638
        • Wu L.M.
        • Sankaran S.J.
        • Plank L.D.
        • Windsor J.A.
        • Petrov M.S.
        Meta-analysis of gut barrier dysfunction in patients with acute pancreatitis.
        Br J Surg. 2014; 101: 1644-1656
        • Balzan S.
        • de Almeida Quadros C.
        • De Cleva R.
        • Zilberstein B.
        • Cecconello I.
        Bacterial translocation: overview of mechanisms and clinical impact.
        J Gastroenterol Hepatol. 2007; 22: 464-471
        • McKenzie S.J.
        • Premkumar R.
        • Askelund K.J.
        • et al.
        The effect of enteral nutrition on adipokines in patients with acute pancreatitis.
        J Nutr Sci. 2015; 4: e33
        • Pendharkar S.A.
        • Singh R.G.
        • Petrov M.S.
        Cross-talk between innate cytokines and the pancreatic polypeptide family in acute pancreatitis.
        Cytokine. 2017; 90: 161-168
        • Boulangé C.L.
        • Neves A.L.
        • Chilloux J.
        • Nicholson J.K.
        • Dumas M.E.
        Impact of the gut microbiota on inflammation, obesity, and metabolic disease.
        Genome Med. 2016; 8: 42
        • Musso G.
        • Gambino R.
        • Cassader M.
        Obesity, diabetes, and gut microbiota.
        Diabetes Care. 2010; 33: 2277-2284
        • Pendharkar S.A.
        • Asrani V.M.
        • Xiao A.Y.
        • et al.
        Relationship between pancreatic hormones and glucose metabolism: a cross-sectional study in patients after acute pancreatitis.
        Am J Physiol Gastrointest Liver Physiol. 2016; 311: G50-G58
        • Wu L.M.
        • Premkumar R.
        • Phillips A.R.
        • Windsor J.A.
        • Petrov M.S.
        Ghrelin and gastroparesis as early predictors of clinical outcomes in acute pancreatitis.
        Pancreatology. 2016; 16: 181-188
        • Kennedy J.I.
        • Askelund K.J.
        • Premkumar R.
        • et al.
        Leptin is associated with persistence of hyperglycemia in acute pancreatitis: a prospective clinical study.
        Medicine. 2016; 95: e2382
        • Pendharkar S.A.
        • Asrani V.M.
        • Murphy R.
        • Cutfield R.
        • Windsor J.A.
        • Petrov M.S.
        The role of gut-brain axis in regulating glucose metabolism after acute pancreatitis.
        Clin Transl Gastroenterol. 2017; 8: e210
        • Gillies N.
        • Pendharkar S.A.
        • Asrani V.M.
        • Mathew J.
        • Windsor J.A.
        • Petrov M.S.
        Interleukin-6 is associated with chronic hyperglycemia and insulin resistance in patients after acute pancreatitis.
        Pancreatology. 2016; 16: 748-755
        • Diabetes Prevention Program Research Group
        10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.
        Lancet. 2009; 374: 1677-1686
        • Li G.
        • Zhang P.
        • Wang J.
        • et al.
        The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study.
        Lancet. 2008; 371: 1783-1789
        • Lindström J.
        • Ilanne-Parikka P.
        • Peltonen M.
        • et al.
        Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study.
        Lancet. 2006; 368: 1673-1679
        • Bray G.A.
        • Jablonski K.A.
        • Fujimoto W.Y.
        • et al.
        Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program.
        Am J Clin Nutr. 2008; 87: 1212-1218
        • Lee I.-M.
        • Shiroma E.J.
        • Lobelo F.
        • et al.
        Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy.
        Lancet. 2012; 380: 219-229
        • Xiao A.Y.
        • Tan M.L.
        • Wu L.M.
        • et al.
        Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies.
        Lancet Gastroenterol Hepatol. 2016; 1: 45-55
      2. Pendharkar SA, Mathew J, Petrov MS. Age- and sex-specific prevalence of diabetes associated with diseases of the exocrine pancreas: a population-based study published online Dec 21, 2016]. Dig Liver Dis. doi:10.1016/j.dld.2016.12.010.

        • Valdez R.
        • Yoon P.W.
        • Liu T.
        • Khoury M.J.
        Family history and prevalence of diabetes in the U.S. population: the 6-year results from the National Health and Nutrition Examination Survey (1999–2004).
        Diabetes Care. 2007; 30: 2517-2522