No abstract

A progressive reduction in β-cell mass occurs in the evolution of diabetes. Thus understanding the mechanisms responsible for this reduction in β-cell mass is important for understanding the pathogenesis of diabetes and in developing novel approaches to prevention and treatment. Pancreatic duodenal homeobox 1 (Pdx1) is a transcription factor that plays a central role in pancreatic β-cell function and survival. Complete deficiency of Pdx1 is associated with pancreatic agenesis, and partial deficiency leads to severe β-cell dysfunction, and increases β-cell death and diabetes both in rodent and human. Chronic hyperglycaemia and dyslipidaemia, which are major features of type 2 diabetes, cause β-cell dysfunction via reduced Pdx1 expression. Inhibition of insulin/insulin-like growth factor (Igf) signalling followed by reduced Pdx1 expression is a common pathway induced by the majority of the mechanisms in apoptotic β-cells. Although the report so far paid little attention to non-apoptotic β-cell death (autophagy and necrosis), we expect these are also involved in the pathogenesis of diabetes. The potential role of Pdx1 in non-apoptotic β-cell death should also be considered in future studies in diabetes, and in attempts to develop novel agents that target this process for prevention and treatment of the disorder.

There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1 ؉/؊ mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1 ؉/؊ mice to Normal pancreatic beta cell function is essential for normal glucose tolerance, and abnormal beta cell function leads to glucose intolerance and diabetes. A progressive reduction in beta cell mass has been shown to occur in the evolution of diabetes (1). Thus understanding the mechanisms responsible for the reduction in beta cell mass is important for understanding the pathogenesis of diabetes and in developing novel approaches to prevention and treatment.There are three types of cell death; apoptosis, necrosis, and autophagy (2). Previous studies have focused on apoptosis as the mechanism underlying beta cell death (1, 3-5). The possibility that activation of the macroautophagy (hereafter referred to as autophagy) pathway may increase beta cell death has not been systematically studied. Autophagy is a regulated lysosomal pathway leading to the degradation and recycling of longlived proteins and organelles. During autophagy, cytoplasmic constituents are sequestered into autophagosomes with double membranes and fused to lysosomes (autolysosomes), where degradation occurs. Under certain circumstances such as in response to nutrient deprivation, autophagy may function as a pro-survival pathway by mediating cellular turnover of proteins and organelles (6 -8). On the other hand, an increase in autophagy can cause autophagic cell death distinct from apoptosis (9, 10). It has been suggested that autophagy plays a key role in the turnover of insulin secretory granules and of mitochondria within the beta cell, thereby regulating insulin secretion (11,12). Complete genetic ablation of Atg7 in beta cells resulted in degradation of islets and impaired glucose tolerance, suggesting that "basal autophagy" is important for maintenance of normal islet architecture and function (13,14).The present study was designed to determine whether activation of autophagy can contribute to pancreatic beta cell death that occurs with reduced expression of Pdx1 (pancreas duodenal homeobox 1). We chose to study Pdx1 deficiency because this homeodomain-containing transcription factor is essential for normal pancreatic beta cell function and survival. Complete...

Evaluation of OGTT Normal type: if both values belong to normal range Diabetic type a : if any of the two values falls into diabetic range Borderline type: neither normal nor diabetic types Even for normal type, if 1-h value is C180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for \180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow up observation, etc.). Fasting plasma glucose level of 100-109 mg/dL (5.5-6.0 mmol/L) is called ''high-normal'': within the range of normal fasting plasma glucose. Plasma glucose level after glucose load in OGTT is not included in casual plasma glucose levels a Casual plasma glucose C200 mg/dL (C11.1 mmol/L) and HbA1c C6.5 % are also regarded as to indicate diabetic type Evidence-based practice guideline 2013 153