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- Title
Pancreatic β-Cell Rest Replenishes Insulin Secretory Capacity and Attenuates Diabetes in an Extreme Model of Obese Type 2 Diabetes.
- Authors
Boland, Brandon B.; Brown Jr., Charles; Boland, Michelle L.; Cann, Jennifer; Sulikowski, Michal; Hansen, Gitte; Grønlund, Rikke V.; King, Wanda; Rondinone, Cristina; Trevaskis, James; Rhodes, Christopher J.; Grimsby, Joseph S.; Brown, Charles Jr; Sulikowski, Michael
- Abstract
The onset of common obesity-linked type 2 diabetes (T2D) is marked by exhaustive failure of pancreatic β-cell functional mass to compensate for insulin resistance and increased metabolic demand, leading to uncontrolled hyperglycemia. Here, the β-cell-deficient obese hyperglycemic/hyperinsulinemic KS db/db mouse model was used to assess consequential effects on β-cell functional recovery by lowering glucose homeostasis and/or improving insulin sensitivity after treatment with thiazolidinedione therapy or glucagon-like peptide 1 receptor agonism alone or in combination with sodium/glucose cotransporter 2 inhibition (SGLT-2i). SGLT-2i combination therapies improved glucose homeostasis, independent of changes in body weight, resulting in a synergistic increase in pancreatic insulin content marked by significant recovery of the β-cell mature insulin secretory population but with limited changes in β-cell mass and no indication of β-cell dedifferentiation. Restoration of β-cell insulin secretory capacity also restored biphasic insulin secretion. These data emphasize that by therapeutically alleviating the demand for insulin in vivo, irrespective of weight loss, endogenous β-cells recover significant function that can contribute to attenuating diabetes. Thus, this study provides evidence that alleviation of metabolic demand on the β-cell, rather than targeting the β-cell itself, could be effective in delaying the progression of T2D.
- Subjects
PANCREATIC beta cells; DIABETES; OVERWEIGHT persons; TYPE 2 diabetes; CELL differentiation; ANIMAL experimentation; COMPARATIVE studies; FLOW cytometry; GLUCAGON; GLUCOSE; GLUCOSE tolerance tests; IMMUNOHISTOCHEMISTRY; INSULIN; ISLANDS of Langerhans; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; EVALUATION research
- Publication
Diabetes, 2019, Vol 68, Issue 1, p131
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db18-0304