β‐Cell glutamate signaling: Its role in incretin‐induced insulin secretion

Abstract

Insulin secretion from the pancreatic β‐cell (referred to as β‐cell hereafter) plays a central role in glucose homeostasis. Impaired insulin secretion is a major factor contributing to the development of diabetes and, therefore, is an important target for treatment of the disease. Cyclic adenosine monophosphate is a key second messenger in β‐cells that amplifies insulin secretion. Incretins released by the gut potentiate insulin secretion through cyclic adenosine monophosphate signaling in β‐cells, which is the basis for the incretin‐based diabetes therapies now being used worldwide. Despite its importance, the interaction between glucose metabolism and incretin/cyclic adenosine monophosphate signaling in β‐cells has long been unknown. A recent study showed that cytosolic glutamate produced by glucose metabolism in β‐cells is a key signal in incretin‐induced insulin secretion. Here we review the physiological and pathophysiological roles of β‐cell glutamate signaling in incretin‐induced insulin secretion.

Amino acid transporters in the regulation of insulin secretion and signalling

“…PKA has numerous targets involved in recruitment and fusion of insulin granules to the membrane (133,134). Gheni et al identified cytosolic β-cells glutamate as an essential signal mediating incretin-induced potentiation of insulin secretion in rodents models of diabetes, obesity and in insulin-producing cell lines (109,135). Incretin signalling induced the loading of glutamate into secretory granules, which was subsequently necessary for enhanced insulin release.…”

Molecular and genetic regulation of pig pancreatic islet cell development

“…Additionally, we found significant enrichment of band a-cell gene sets involved in specific developmental signaling pathways. However only a subset of these pathways, like mTOR, retinoic acid receptor, glutamate receptor and TGF-b signaling, have been previously linked to b-and a-cell biology [72][73][74][75] The cost basis of pancreas procurement and islet isolation from pigs is currently lower than for humans. In 2019, reimbursement for a single human cadaveric donor pancreas is between $4,500 and $7,000 (US dollars).…”

Regulation of Insulin Secretion and Mechanism of Production-Secretion

“…26 Yapılan çalışmalara göre, yanıtın büyüklüğü sitozolik serbest Ca 2+ 'nın 500 nM'den 1,3 μM'ye yükselmesine benzerdir. 27 Α-ketoglutarat, malat veya sitrat gibi TCA döngüsünün ara maddeleri, insülin sekresyonunda anlamlı bir artışa neden olmamıştır. İnsülin salınımının uyarılması hem TCA döngüsüne karbon tedarik etmeyi hem de mitokondriyal Ca 2+ seviyelerini artırmayı gerektirmektedir.…”

“…Bu iki durum da süksinat ile sağlanmaktadır. 26,27 İzole edilmiş INS-1 hücre mitokondrisinin süksinata maruz kalmasının, önemli miktarda glutamat üretmesine neden olduğu bildirilmiştir. Mitokondrideki glutamat, glutamat dehidrogenaz enzimi aracılığıyla TCA döngüsündeki α-ketoglutarattan üretilmektedir.…”

“…Bu ilişkiyi gösteren mevcut kanıtların çoğu, metabolomik temelli çalışmalardan türetilmiştir. 27,28 Ca 2+ , β-hücrelerinde insülin sekresyonunun düzenlenmesinde önemli bir rol oynamasına rağmen glutamat, β-hücrelerden insülin ekzositozunu sağlayan sinyal verme sürecinin bir güçlendiricisi olarak gereklidir. Bununla birlikte, hücre dışı glutamat iyonotropik alıcıları aktive ederken; glutamat, hücre içi veya hücre dışı oluşuna bağlı olarak insülin sekresyonunu artırmakta veya baskılamaktadır.…”