题名：Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes.
作者：FU Z; GILBERT ER; LIU D;
来源：Curr Diabetes Rev. 2013 Jan 1;9(1):25-53. [ IF= 0.00 ] ]
URL ：N U L L
摘要：Pancreatic beta-cell dysfunction plays an important role in the pathogenesis of
both type 1 and type 2 diabetes. Insulin, which is produced in beta-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
beta-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
beta-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 beta-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 beta-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
beta-cell dysfunction, thereby triggering the pathogenesis of diabetes.