Intraislet glucagon signaling is critical for maintaining glucose homeostasis

Glucagon, a hormone released from pancreatic a cells, plays a key role in maintaining proper glucose homeostasis and has been implicated in the pathophysiology of diabetes. In vitro studies suggest that intraislet glucagon can modulate the function of pancreatic ß cells. However, because of the lack of suitable experimental tools, the in vivo physiological role of this intraislet cross-talk has remained elusive. To address this issue, we generated a mouse model that selectively expressed an inhibitory designer GPCR (Gi DREADD) in a cells only. Drug-induced activation of this inhibitory designer receptor almost completely shut o? glucagon secretion in vivo, resulting in markedly impaired insulin secretion, hyperglycemia, and glucose intolerance. Additional studies with mouse and human islets indicated that intraislet glucagon stimulates insulin release primarily by activating β cell GLP-1 receptors. These fndings strongly suggest that intraislet glucagon signaling is essential for maintaining proper glucose homeostasis in vivo. Our work may pave the way toward the development of novel classes of antidiabetic drugs that act by modulating intraislet cross-talk between a and ß cells

Impaired Muscarinic Type 3 (m3) Receptor/pkc And Pka Pathways In Islets From Msg-obese Rats

Monosodium glutamate-obese rats are glucose intolerant and insulin resistant. Their pancreatic islets secrete more insulin at increasing glucose concentrations, despite the possible imbalance in the autonomic nervous system of these rats. Here, we investigate the involvement of the cholinergic/protein kinase (PK)-C and PKA pathways in MSG β-cell function. Male newborn Wistar rats received a subcutaneous injection of MSG (4 g/kg body weight (BW)) or hyperosmotic saline solution during the first 5 days of life. At 90 days of life, plasma parameters, islet static insulin secretion and protein expression were analyzed. Monosodium glutamate rats presented lower body weight and decreased nasoanal length, but had higher body fat depots, glucose intolerance, hyperinsulinemia and hypertrigliceridemia. Their pancreatic islets secreted more insulin in the presence of increasing glucose concentrations with no modifications in the islet-protein content of the glucose-sensing proteins: the glucose transporter (GLUT)-2 and glycokinase. However, MSG islets presented a lower secretory capacity at 40 mM K+ (P < 0.05). The MSG group also released less insulin in response to 100 μM carbachol, 10 μM forskolin and 1 mM 3-isobutyl-1-methyl-xantine (P < 0.05, P < 0.0001 and P < 0.01). These effects may be associated with a the decrease of 46 % in the acetylcholine muscarinic type 3 (M3) receptor, and a reduction of 64 % in PKCα and 36 % in PKAα protein expressions in MSG islets. 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