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GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.

ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet ?-cell loss. Thus, an effective therapy may require ?-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet ?-cells and immune system. Unlike in adult brain or islet ?-cells in which GABA exerts hyperpolarizing effects, in islet ?-cells, GABA produces membrane depolarization and Ca(2+) influx, leading to the activation of PI3-K/Akt-dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves ?-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores ?-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The ?-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application.

SUBMITTER: Soltani N

PROVIDER: S-EPMC3136292 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other

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GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.

Soltani Nepton N Qiu Hongmin H Aleksic Mila M Glinka Yelena Y Zhao Fang F Liu Rui R Li Yiming Y Zhang Nina N Chakrabarti Rabindranath R Ng Tiffany T Jin Tianru T Zhang Haibo H Lu Wei-Yang WY Feng Zhong-Ping ZP Prud'homme Gerald J GJ Wang Qinghua Q

Proceedings of the National Academy of Sciences of the United States of America 20110627 28

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet β-cell loss. Thus, an effective therapy may require β-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet β-cells and immune system. Unlike in adult brain or islet α-cells in which GABA exerts hyperpolarizing effects, in islet β-cells, GABA produces membrane depolarizatio ...[more]

PMID: 21709230

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Project description:Aims/hypothesisThe islet vasculature, including its constituent islet endothelial cells, is a key contributor to the microenvironment necessary for normal beta cell health and function. In type 2 diabetes, islet amyloid polypeptide (IAPP) aggregates, forming amyloid deposits that accumulate between beta cells and islet capillaries. This process is known to be toxic to beta cells but its impact on the islet vasculature has not previously been studied. Here, we report the first characterisation of the effects of IAPP aggregation on islet endothelial cells/capillaries using cell-based and animal models.MethodsPrimary and immortalised islet endothelial cells were treated with amyloidogenic human IAPP (hIAPP) alone or in the presence of the amyloid blocker Congo Red or the Toll-like receptor (TLR) 2/4 antagonist OxPAPc. Cell viability was determined0 along with mRNA and protein levels of inflammatory markers. Islet capillary abundance, morphology and pericyte coverage were determined in pancreases from transgenic mice with beta cell expression of hIAPP using conventional and confocal microscopy.ResultsAggregated hIAPP decreased endothelial cell viability in immortalised and primary islet endothelial cells (by 78% and 60%, respectively) and significantly increased expression of inflammatory markers Il6, Vcam1 and Edn1 mRNA relative to vehicle treatment in both cell types (p<0.05; n=4). Both cytotoxicity and the proinflammatory response were ameliorated by Congo Red (p<0.05; n=4); whereas TLR2/4-inhibition blocked inflammatory gene expression (p<0.05; n=6) without improving viability. Islets from high-fat-diet-fed amyloid-laden hIAPP transgenic mice also exhibited significantly increased expression of most markers of endothelial inflammation (p<0.05; n=5) along with decreased capillary density compared with non-transgenic littermates fed the same diet (p<0.01). Moreover, a 16% increase in capillary diameter was observed in amyloid-adjacent capillaries (p<0.01), accompanied by a doubling in pericyte structures positive for neuron-glial antigen 2 (p<0.001).Conclusions/interpretationIslet endothelial cells are susceptible to hIAPP-induced cytotoxicity and exhibit a TLR2/4-dependent proinflammatory response to aggregated hIAPP. Additionally, we observed amyloid-selective effects that decreased islet capillary density, accompanied by increased capillary diameter and increased pericyte number. Together, these data demonstrate that the islet vasculature is a target of the cytotoxic and proinflammatory effects of aggregated hIAPP that likely contribute to the detrimental effects of hIAPP aggregation on beta cell function and survival in type 2 diabetes.

Dataset Information

GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.

Publications

GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.

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