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Preserving Mafa expression in diabetic islet ?-cells improves glycemic control in vivo.

ABSTRACT: The murine Mafa transcription factor is a key regulator of postnatal islet ?-cell activity, affecting insulin transcription, insulin secretion, and ?-cell mass. Human MAFA expression is also markedly decreased in islet ?-cells of type 2 diabetes mellitus (T2DM) patients. Moreover, levels are profoundly reduced in db/db islet ?-cells, a mouse model of T2DM. To examine the significance of this key islet ?-cell-enriched protein to glycemic control under diabetic conditions, we generated transgenic mice that conditionally and specifically produced Mafa in db/db islet ?-cells. Sustained expression of Mafa resulted in significantly lower plasma glucose levels, higher plasma insulin, and augmented islet ?-cell mass. In addition, there was increased expression of insulin, Slc2a2, and newly identified Mafa-regulated genes involved in reducing ?-cell stress, like Gsta1 and Gckr. Importantly, the levels of human GSTA1 were also compromised in T2DM islets. Collectively, these results illustrate how consequential the reduction in Mafa activity is to islet ?-cell function under pathophysiological conditions.

SUBMITTER: Matsuoka TA

PROVIDER: S-EPMC4367268 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Preserving Mafa expression in diabetic islet β-cells improves glycemic control in vivo.

Matsuoka Taka-aki TA Kaneto Hideaki H Kawashima Satoshi S Miyatsuka Takeshi T Tochino Yoshihiro Y Yoshikawa Atsushi A Imagawa Akihisa A Miyazaki Jun-ichi J Gannon Maureen M Stein Roland R Shimomura Iichiro I

The Journal of biological chemistry 20150202 12

The murine Mafa transcription factor is a key regulator of postnatal islet β-cell activity, affecting insulin transcription, insulin secretion, and β-cell mass. Human MAFA expression is also markedly decreased in islet β-cells of type 2 diabetes mellitus (T2DM) patients. Moreover, levels are profoundly reduced in db/db islet β-cells, a mouse model of T2DM. To examine the significance of this key islet β-cell-enriched protein to glycemic control under diabetic conditions, we generated transgenic ...[more]

PMID: 25645923

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Project description:ObjectivesLoss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D.MethodsThe gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed.ResultsIn this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice.ConclusionsOur results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.

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Preserving Mafa expression in diabetic islet ?-cells improves glycemic control in vivo.

Publications

Preserving Mafa expression in diabetic islet β-cells improves glycemic control in vivo.

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