Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

Abstract

Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes.

Nutrient regulation of insulin secretion and action

“…Insulin exocytosis is a highly controlled process, and many factors actively promote insulin release (refer to Fu et al (2013) for more detail). As carbohydrates are normally the primary source of fuel in food and glucose is the primary insulin secretagogue (see Flatt & Lenzen (1994) and Fu et al (2013)), traditional models of insulin exocytosis are based on an increase in the b-cell intracellular ATP:ADP ratio, following elevated glucose metabolism.…”

“…As carbohydrates are normally the primary source of fuel in food and glucose is the primary insulin secretagogue (see Flatt & Lenzen (1994) and Fu et al (2013)), traditional models of insulin exocytosis are based on an increase in the b-cell intracellular ATP:ADP ratio, following elevated glucose metabolism. Enhanced flux through the glycolytic pathway and tricarboxylic acid cycle (TCA) results in elevated mitochondrial ATP generation, following substrate-level phosphorylation and electron transport in the mitochondria utilising the electron donors NADH and FADH 2 .…”

“…Furthermore, various reports have suggested that multiple coupling factors may amplify K ATP -independent GSIS, such as NADPH, NADH, glutamate and malonyl-CoA (Komatsu et al 2001). As the precise biochemical mechanisms of K ATPdependent and -independent GSIS are not the sole focus of this article, readers are advised to refer to recent review articles (Fu et al 2013, Komatsu et al 2013) for more detail. However, it is clear that b-cell nutrient metabolism is central and critical to the insulin secretory mechanism described above, and consequently elevated glucose and lipid levels, as observed in T2DM patients, can chronically impact insulin secretion.…”

Glikokortykosteroidy a czynność komórek beta

“…Normally, a glucose-induced rise in intracellular ATP enables the closure of the ATP-dependent K + channels, which results in depolarisation of the plasma membrane and opening of the voltagedependent Ca 2+ channels, leading to the influx of calcium and efficient insulin exocytosis [64]. Glucose cycling is the simultaneous phosphorylation of glucose to glucose--6-phosphate and its dephosphorylation back to glucose, resulting in ineffective ATP consumption [65].…”

“…Normalnie indukowany glukozą wzrost wewnątrzkomórkowego stężenia ATP umożliwia zamknięcie ATP-zależnych kanałów potasowych, co powoduje depolaryzację błony komórkowej i otwarcie zależnych od napięcia kanałów wapniowych, wywołując napływ wapnia i wydajną egzocytozę insuliny [64]. Glucose cycling jest procesem szybkiego przechodzenia między fosforylacją glukozy do glukozo-6-fosforanu i jego defosforylacją z powrotem do glukozy, co powoduje nieefektywne zużywanie ATP [65].…”