Dataset Information

Harmine and Exendin-4 Combination Therapy Safely Expands Human Beta Cell Mass In Vivo

ABSTRACT: 537 million people globally suffer from diabetes. Insulin-producing beta cells are reduced in number in most people with diabetes, but the majority still have some residual beta cells. Disappointingly, none of the many diabetes drugs in common use can increase human beta cell numbers. Recently, small molecules that inhibit the kinase, Dual Tyrosine-Regulated Kinase 1A (DYRK1A), have been shown to induce immunohistochemical markers of human beta cell replication, and this is enhanced by drugs that stimulate the GLP1 receptor (GLP1R) on beta cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human beta cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human beta cell survival. Here, we demonstrate for the first time that combination of a DYRK1A inhibitor with exendin-4 increases actual human beta cell mass in vivo by 400-700% in diabetic and non-diabetic mice over three months, reverses diabetes in vivo, without significant alteration in human alpha cell mass. The augmentation in human beta cell mass occurs through mechanisms that include enhanced human beta cell proliferation, function, and survival. The increase in human beta cell survival is mediated in part by the islet prohormone, VGF. Taken together, these findings demonstrate the remarkable therapeutic potential and safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249310 | GEO | 2024/06/28

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Relative beta cell deficit and increased beta cell apoptosis are hallmarks of type 2 diabetes (T2D). The Insulin/Insulin Growth Factor (Igf) signaling pathway is an established regulator of beta cell survival and is found downregulated in human T2D islets. The Insulin Receptor Substrate 2 (Irs2) plays a central role in the coordination of this pathway in beta cells. Thus, Irs2 knockout mice (Irs2 -/-) exhibit increased beta cell apoptosis that leads to a progressive decline of beta cell mass and hyperglycaemia. In this study, we sought to determine whether the anti-diabetic compound sodium tungstate could prevent the onset of diabetes in Irs2 -/- mice. Oral administration of tungstate resulted in an overall improvement in whole-body glucose tolerance in Irs2 -/- mice which correlated with increased beta cell mass. Enhanced beta cell mass was due to a dramatic reduction of beta cell apoptosis without changes in proliferation. Whole genome gene profiling analysis of islets isolated from treated Irs2 -/- mice confirmed a broad impact of tungstate on cell death pathways. Mechanistically, tungstate induced Erk1/2 phosphorylation in islets in vitro and, in agreement, treated Irs2 -/- islets exhibited increased basal Erk1/2 phosphorylation. Tungstate also downregulated expression of apoptosis-related genes in Irs2-/- islets in vitro, uncovering a direct effect of this compound in islets. All together, our data demonstrate that tungstate can restore beta cell mass and glucose homeostasis in a context of deficient Insulin/Igf signaling. This study underscores the importance of developing strategies specifically designed to arrest beta cell apoptosis as a means to prevent progressive beta cell failure in diabetes. 10-week old WT and Irs2 -/- mice were randomly divided into two treatment group, in a total of 4 experimental groups. For 21 days one group received distilled water as drinking water (untreated group) whilst the other received ad libitum a solution of 2mg/ml of sodium tungstate in distilled water (treated group). For each experimental group 2 independent samples were analysed, in a total of 8 samples.

Dataset Information

Harmine and Exendin-4 Combination Therapy Safely Expands Human Beta Cell Mass In Vivo

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets