Abstract
Objective
To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients
with type 2 diabetes mellitus.
Methods
This retrospective cohort study included enterprise-wide Mayo Clinic patients using
Informatics for Integrating Biology at the Bedside from January 1994 through December
2019. The antidiabetic outcomes (change in hemoglobin A1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly
senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly
senolytic tyrosine kinase inhibitor, imatinib (n=32).
Results
Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7
mg/dL (P=.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply
by 0.0555) and required 28.8 fewer total daily insulin units (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight;
P=.045). Linear regression analysis suggests that the relative difference in weight
accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative
to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P=.05) reduction in hemoglobin A1c and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight;
P=.06).
Conclusion
Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments
and may be considered for use as a novel diabetic therapy. Future studies are needed
to determine whether these results are translatable to patients with type 2 diabetes
mellitus without underlying malignant diseases and to determine whether the antidiabetic
effects of dasatinib are due to its senolytic properties.
Abbreviations and Acronyms:
T2DM (type 2 diabetes mellitus), TKI (tyrosine kinase inhibitor)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Mayo Clinic ProceedingsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- IDF Diabetes Atlas.http://www.diabetesatlas.org/Date accessed: April 1, 2020
- Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services, Atlanta, Ga2020
- Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment.J Clin Oncol. 2004; 22: 4653-4655
- Imatinib and regression of type 2 diabetes.N Engl J Med. 2005; 352: 1049-1050
- Fasting glucose improvement under dasatinib treatment in an accelerated phase chronic myeloid leukemia patient unresponsive to imatinib and nilotinib.Leuk Res. 2008; 32: 1626-1628
- Tyrosine kinase inhibitor sunitinib allows insulin independence in long-standing type 1 diabetes.Diabetes Care. 2014; 37: e87-e88
- Erlotinib appears to produce prolonged remission of insulin requiring type 2 diabetes associated with metabolic syndrome and chronic kidney disease.Br J Diabetes Vasc Dis. 2012; 12: 87-90
- Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia.BMJ Case Rep. 2016; 2016 (bcr2015214284)
- Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.J Oncol Pharm Pract. 2011; 17: 197-202
- How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review.Leuk Res. 2014; 38: 1392-1398
- Imatinib and type 2 diabetes.Endocr Pract. 2007; 13: 126-130
- Imatinib does not substantially modify the glycemic profiles in patients with chronic myeloid leukaemia.Leuk Res. 2010; 34: e5-e7
- Cellular senescence in type 2 diabetes: a therapeutic opportunity.Diabetes. 2015; 64: 2289-2298
- Targeting senescent cells alleviates obesity-induced metabolic dysfunction.Aging Cell. 2019; 18: e12950
- The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell. 2015; 14: 644-658
- Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.Diabetes Care. 2009; 32: 193-203
- Association between glycosylated hemoglobin and intentional weight loss in overweight and obese patients with type 2 diabetes mellitus: a retrospective cohort study.Diabetes Educ. 2012; 38: 417-426
- Rapid amelioration of hyperglycemia facilitated by dasatinib in chronic myeloid leukemia patient with type 2 diabetes mellitus.Intern Med. 2012; 51: 2763-2766
- [No influence of imatinib on type 2 diabetes.].Przegl Lek. 2007; 64: 370-371
- Tyrosine kinase inhibitors and diabetes: a novel treatment paradigm? [erratum appears in Trends Endocrinol Metab. 2016;27(1):65].Trends Endocrinol Metab. 2015; 26: 643-656
- A crucial role for adipose tissue p53 in the regulation of insulin resistance.Nat Med. 2009; 15: 1082-1087
- Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy.J Diabetes Complications. 2014; 28: 604-611
- Reducing senescent cell burden in aging and disease.Trends Mol Med. 2020; 26: 630-638
- Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine. 2018; 36: 18-28
Article info
Publication history
Published online: November 09, 2021
Footnotes
Potential Competing Interests: J.L.K. has the most relevant financial interest related to this paper: patents on senolytic drugs are held by Mayo Clinic. Research findings related to those patents that are cited in this paper were previously reviewed by the Mayo Clinic Conflict of Interest Review Board and are in compliance with Mayo Clinic Conflict of Interest policies.
Grant Support: This publication was supported by the National Center for Advancing Translational Sciences (UL1 TR002377) and the Robert and Arlene Kogod Professorship in Geriatric Medicine (to R.J.P.); the National Institute on Aging (R37 AG13925), the Noaber Foundation Professorship in Aging, the Connor Group, and the Robert J. and Theresa W. Ryan Foundation (to J.L.K.); and the Travelers Chair in Geriatrics and Gerontology (to G.A.K.). This work was not supported in any way by pharmaceutical companies, private industry, or other for-profit agencies.
Identification
Copyright
© 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- In the Limelight: December 2021Mayo Clinic ProceedingsVol. 96Issue 12
