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Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

ABSTRACT: We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.

SUBMITTER: Wang MY

PROVIDER: S-EPMC7936318 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

Wang May-Yun MY Dean E Danielle ED Quittner-Strom Ezekiel E Zhu Yi Y Chowdhury Kamrul H KH Zhang Zhuzhen Z Zhao Shangang S Li Na N Ye Reshing R Lee Young Y Zhang Yiyi Y Chen Shiuhwei S Yu Xinxin X Leonard Derek C DC Poffenberger Greg G Von Deylen Alison A McCorkle S Kay SK Schlegel Amnon A Sloop Kyle W KW Efanov Alexander M AM Gimeno Ruth E RE Scherer Philipp E PE Powers Alvin C AC Unger Roger H RH Holland William L WL

Proceedings of the National Academy of Sciences of the United States of America 20210301 9

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin<sup>+</sup> islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust as ...[more]

PMID: 33619103

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Project description:BackgroundPancreatic islets are heavily vascularized in vivo yet lose this vasculature after only a few days in culture. Determining how to maintain islet vascularity in culture could lead to better outcomes in transplanting this tissue for the treatment of type 1 diabetes as well as provide insight into the complex communication between beta-cells and endothelial cells (ECs). We previously showed that islet ECs die in part due to limited diffusion of serum albumin into the tissue. We now aim to determine the impact of hypoxia on islet vascularization.MethodsWe induced hypoxia in cultured mouse islets using the hypoxia mimetic cobalt chloride (100 μM CoCl2). We measured the impact on islet metabolism (two-photon NAD(P)H and Rh123 imaging) and function (insulin secretion and survival). We also measured the impact on hypoxia related transcripts (HIF-1α, VEGF-A, PDK-1, LDHA, COX4) and confirmed increased VEGF-A expression and secretion. Finally, we measured the vascularization of islets in static and flowing culture using PECAM-1 immunofluorescence.ResultsCoCl2 did not induce significant changes in beta cell metabolism (NAD(P)H and Rh123), insulin secretion, and survival. Consistent with hypoxia induction, CoCl2 stimulated HIF-1α, PDK-1, and LDHA transcripts and also stimulated VEGF expression and secretion. We observed a modest switch to the less oxidative isoform of COX4 (isoform 1 to 2) and this switch was noted in the glucose-stimulated cytoplasmic NAD(P)H responses. EC morphology and survival were greater in CoCl2 treated islets compared to exogenous VEGF-A in both static (dish) and microfluidic flow culture.ConclusionsHypoxia induction using CoCl2 had a positive effect on islet EC morphology and survival with limited impact on beta-cell metabolism, function, and survival. The EC response appears to be due to endogenous production and secretion of angiogenic factors (e.g. VEGF-A), and mechanistically independent from survival induced by serum albumin.

Dataset Information

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

Publications

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

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