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Metformin Preserves ?-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats.

ABSTRACT: Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic ?-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and ?-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on ?-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human ?-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on ?-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited ?-cell glucose-stimulated insulin secretion in vitro, stimulation of ?-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, ?-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress ?-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on ?-cell function or cell mass and, instead, early metformin treatment may help protect ?-cells from exhaustion and decompensation.

SUBMITTER: Huang H

PROVIDER: S-EPMC7794750 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Metformin Preserves β-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats.

Huang Hui H Lorenz Bradi R BR Zelmanovitz Paula Horn PH Chan Catherine B CB

International journal of molecular sciences 20210103 1

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characte ...[more]

PMID: 33401592

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Project description:AIMS/HYPOTHESIS:Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. METHODS:We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. RESULTS:DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3?±?121.3 vs 633.3?±?148.7; p?<?0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9?±?1593.7 vs 4416.8?±?1230.5 pg islet-1 h-1; p?<?0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1?×?109?±?9.5?×?107 vs 3.8?×?109?±?5.8?×?107 ?m3; p?=?0.044) and small sized islets (1.6?×?109?±?5.1?×?107 vs 1.4?×?109?±?4.5?×?107 ?m3; p?=?0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1?±?16.8 vs 76.9?±?11.8 ?l min-1 [g pancreas]-1; p?=?0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. CONCLUSIONS/INTERPRETATION:The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

Dataset Information

Metformin Preserves ?-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats.

Publications

Metformin Preserves β-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats.

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