Glucose‐stimulated insulin secretion: A newer perspective

Abstract

Existing concepts and models for glucose-stimulated insulin secretion (GSIS) are overviewed and a newer perspective has been formulated toward the physiological understanding of GSIS. A conventional model has been created on the basis of in vitro data on application of a square wave high glucose in the absence of any other stimulatory inputs. Glucose elicits rapid insulin release through an adenosine triphosphate-sensitive K + channel (K ATP channel)-dependent mechanism, which is gradually augmented in a K ATP channel-independent manner. Biphasic GSIS thus occurs. In the body, the b-cells are constantly exposed to stimulatory signals, such as glucagon-like peptide 1 (GLP-1), parasympathetic inputs, free fatty acid (FFA), amino acids and slightly suprathreshold levels of glucose, even at fasting. GLP-1 increases cellular cyclic adenosine monophosphate, parasympathetic stimulation activates protein kinase C, and FFA, amino acids and glucose generate metabolic amplification factors. Plasma glucose concentration gradually rises postprandially under such tonic stimulation. We hypothesize that these stimulatory inputs together make the b-cells responsive to glucose independently from its action on K ATP channels. Robust GSIS in patients with a loss of function mutation of the sulfonylurea receptor, a subunit of K ATP channels, is compatible with this hypothesis. Furthermore, pre-exposure of the islets to an activator of protein kinase A and/or C makes b-cells responsive to glucose in a K ATP channel-and Ca 2+-independent manner. We hypothesize that GSIS occurs in islet b-cells without glucose regulation of K ATP channels in vivo, for which priming with cyclic adenosine monophosphate, protein kinase C and non-glucose nutrients are required. To understand the physiology of GSIS, comprehensive integration of accumulated knowledge is required. (J Diabetes Invest,

LKB1 couples glucose metabolism to insulin secretion in mice

“…As shown in Fig. 2d, both LABKO and control islets responded to tolbutamide in the presence of diazoxide, indicating that if LKB1 acts on the K ATP channel it likely does so in a SUR1-independent manner, a mechanism that has been reported for glucosestimulated secretion (reviewed in [36]). …”

Berberine inhibits glucose oxidation and insulin secretion in rat islets

“…In our study, berberine significantly suppressed OCR and ATP production induced by glucose. The inhibition of ATP synthesis in turn alters the ATP/AMP ratio, which blocks K ATP channel closure and thereby inhibits insulin secretion [11]. Interestingly, berberine markedly inhibited OCR at 25 mmol/L glucose in rat islets, but without effect on GSIS, which is similar to the effects of metformin on GSIS and OCR in beta-cells [15].…”

“…Although the stimulussecretion coupling is complex and still incompletely understood, multiple metabolic signaling factors including ATP, fatty acyl-CoA, glutamate and adenine nucleotides, are believed to take part in this process [11,21]. Although berberine has been reported to block the activ- ity of respiratory chain complex I [22,23], little is known about the metabolic effects of berberine on islets.…”

“…Pancreatic beta-cells secrete insulin in response to blood nutrient for maintaining metabolic homeostasis [11]. Glucose is the most important driver for insulin secretion, and its action in beta-cells is tightly linked to glycolysis and mitochondrial metabolism for the quantitative flux of glucose carbons into mitochondria [12].…”

“…The activation of L-type voltage-dependent Ca 2+ channels leads to a rise in intracellular Ca 2+ and triggers insulin exocytosis [13]. In addition to the classical ATP/K ATP /Ca 2+ signaling pathway, compelling evidence supports the existence of additional metabolic molecules that provide amplification signals (e.g., fatty acyl-CoA, glutamate, adenine nucleotides) for GSIS [11,14]. Recently, it has been reported that glucose increases oxygen consumption, ATP production, free fatty acid (FFA) content and release from rat islets and INS-1 cell [12].…”