Human pluripotent stem cell-derivedβcells:Truly immature isletβcells for type 1 diabetes therapy?

A century has passed since the Nobel Prize winning discovery of insulin,which still remains the mainstay treatment for type 1 diabetes mellitus(T1DM)to this day.True to the words of its discoverer Sir Frederick Banting,“insulin is not a cure for diabetes,it is a treatment”,millions of people with T1DM are dependent on daily insulin medications for life.Clinical donor islet transplantation has proven that T1DM is curable,however due to profound shortages of donor islets,it is not a mainstream treatment option for T1DM.Human pluripotent stem cell derived insulin-secreting cells,pervasively known as stem cell-derivedβcells(SC-βcells),are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy.Here we briefly review how isletβcells develop and mature in vivo and several types of reported SC-βcells produced using different ex vivo protocols in the last decade.Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown,the SC-βcells have not been directly compared to their in vivo counterparts,generally have limited glucose response,and are not yet fully matured.Due to the presence of extra-pancreatic insulin-expressing cells,and ethical and technological issues,further clarification of the true nature of these SC-βcells is required.

Neurotransmitters regulateβcells insulin secretion:A neglected factor

βcells are the main cells responsible for the hypoglycemic function of pancreatic islets,and the insulin secreted by these cells is the only hormone that lowers blood glucose levels in the human body.βcells are regulated by various factors,among which neurotransmitters make an important contribution.This paper discusses the effects of neurotransmitters secreted by various sympathetic and parasympathetic nerves onβcells and summarizes the mechanisms by which various neurotransmitters regulate insulin secretion.Many neurotransmitters do not have a single source and are not only released from nerve terminals but also synthesized byβcells themselves,allowing them to synergistically regulate insulin secretion.Almost all of these neurotransmitters depend on the presence of glucose to function,and their actions are mostly related to the Ca^(2+)and cAMP concentrations.Although neurotransmitters have been extensively studied,many of their mechanisms remain unclear and require further exploration by researchers.

Apoptosis of Pancreatic Beta Cells in Pregnant Insulin-resistant Rats Fed with High-fat Diet

Objective The aim of this study is by observing the number change of islets beta cells in gestational rats exposed to high fat diet, tofurther reveal the mechanism of gestational diabetes mellitus. Methods Female Wistar rats were exposed to high fat diet for five weeks, and then became pregnant. During pregnancy dynamically detected indicators of glucose and fat. Until the third trimester of pregnancy evaluated the sensitivity of insulin and glucose tolerance. After executed rats, selected pancreatic tail tissue and fixed, further slides were stained with insulin antibody by immunohistochemistry to confirm the location of beta cells. Image analysis system determined mean area stained positive cells in each islet, which stood for total number of beta cells. The apoptotic beta cells in islet were detected and quantified by the Tunel technology to calculate apoptosis ratio. Results The level of free fatty acids in rats exposed to high fat diet was significantly higher than the control groups, and insulin resistance was more serious. Compared mean stained positive area among each group, the largest was gestational rats fed high fat diet, and gestational rats was larger than virgin rats, but the difference had no statistical significance. About apoptoticratio of beta cells was higher in diet intervened rats, gestational rats were higher than virgin rats. The same trend happened in the number of positive cells, but discrepancy was not remarkable. Conclusion Based on insulin resistance, apoptosis of pancreatic beta cellsincreased in gestational ratstaking high fat diet, through changing the number of beta cells to down regulate the pancreas endocrine function. That may be the mechanism of gestational mellitus.

25-Hydroxyvitamin D Is Associated with Islet Homeostasis in Type-2 Diabetic Patients with Abdominal Obesity

Objective Isletαcells input is essential for insulin secretion fromβcells.The present study aims to investigate the association between 25-hydroxyvitamin D[25(OH)D]and islet function homeostasis in type-2 diabetes(T2D)patients.Methods A total of 4670 T2D patients from seven communities in Shanghai,China were enrolled.The anthropometric indices,biochemical parameters,serum 25(OH)D,and islet function[including C-peptide(C-p)and glucagon]were measured.Results The fasting plasma glucose(FPG),glycated hemoglobin(HbA1c),glucagon,and C-p levels exhibited a significantly decreasing trend in T2D patients as the 25(OH)D levels increased.Next,the population was divided into two groups:abdominal obesity and non-abdominal obesity groups.After adjustment,the 25(OH)D level was found to be associated with HbA1c,glucagon,and homeostasis model assessment ofβ(HOMA-β)in the non-abdominal obesity group.There was a significant relationship between 25(OH)D and HbA1c,glucagon,HOMA-IR,baseline insulin or C-p in the abdominal obesity group.In the abdominal obesity group,the ordinary least squares(OLS)regression and quantile regression revealed that 25(OH)D was obviously associated with glucagon and fasting C-p levels.In the abdominal obesity group,the moderate analysis revealed a significant interaction effect of 25(OH)D and glucagon on C-p(P=0.0124).Furthermore,the conditional indirect effect of 25(OH)D on the glucagon/C-p ratio was significantly lower at 1 standard deviation(SD)below the mean(P=0.0002),and lower at the mean of the course of diabetes(P=0.0007).Conclusion 25(OH)D was found to be negatively correlated to glucagon and C-p in T2D patients with abdominal obesity.The 25(OH)D influenced C-p in part by influencing glucagon.The effect of 25(OH)D on the glucagon/C-p ratio in T2D patients with abdominal obesity,in terms of islet homeostasis,is influenced by the course of diabetes.

High density lipoproteins and type 2 diabetes:Emerging concepts in their relationship

Patients with type 2 diabetes mellitus(T2DM) frequently exhibit macrovascular complications of atherosclerotic cardiovascular(CV) disease. High density lipoproteins(HDL) are protective against atherosclerosis. Low levels of HDL cholesterol(HDL-C) independently contribute to CV risk. Patients with T2 DM not only exhibit low HDL-C, but also dysfunctional HDL. Furthermore, low concentration of HDL may increase the risk for the development of T2 DM through a decreased β cell survival and secretory function. In this paper, we discuss emerging concepts in the relationship of T2 DM with HDL.

Exposure to perfluorooctane sulfonate reduced cell viability and insulin release capacity of β cells

Per-and polyfluoroalkyl substances(PFAS)are found to have multiple adverse outcomes on human health.Recently,epidemiological and toxicological studies showed that exposure to PFAS had adverse impacts on pancreas and showed association with insulin abnormalities.To explore how PFAS may contribute to diabetes,we studied impacts of perfluorooctane sul-fonate(PFOS)on cell viability and insulin release capacity of pancreatic β cells by using in vivo and in vitro methods.We found that 28-day administration with PFOS(10 mg/(kg body weight·day))caused reductions of pancreas weight and islet size in male mice.PFOS admin-istration also led to lower serum insulin level both in fasting state and after glucose infusion among male mice.For cell-based in vitro bioassay,we used mouse β-TC-6 cancer cells and found 48-hr exposure to PFOS decreased the cell viability at 50 μmol/L.By measuring insulin content in supernatant,48-hr pretreatment of PFOS(100 μmol/L)decreased the insulin re-lease capacity of β-TC-6 cells after glucose stimulation.Although these concentrations were higher than the environmental concentration of PFOS,it might be reasonable for high con-centration of PFOS to exert observable toxic effects in mice considering mice had a faster removal efficiency of PFOS than human.PFOS exposure(50 μmol/L)to β-TC-6 cells induced intracellular accumulation of reactive oxidative specie(ROS).Excessive ROS induced the re-active toxicity of cells,which eventually invoke apoptosis and necrosis.Results in this study provide evidence for the possible causal link of exposure to PFOS and diabetes risk.

Stress Hyperglycemia:A Problem that Cannot be Ignored

Stress hyperglycemia is a strong neuroendocrine reaction in the hypothalamic pituitary adrenal cortex under severe infection,trauma,burns,hemorrhage,surgery and other harmful stimulated,resulting in increased secretion of counter-regulatory hormones.These hormones promoted the production of sugar and cause glucose metabolism disorders with cytokines and insulin resistance.In this condition,the production of sugar exceeds the utilization of sugar by the tissues,which eventually leads to an increase in blood glucose levels in plasma.In the intensive care unit,stress hyperglycemia is very common and can occur in patients with or without diabetes.The incidence is as high as 96%,and it is an independent factor in the death of critically ill patients.Hyperglycemia not only prolongs the hospitalization time,mechanical ventilation time and increased the incidence of serious infections in critically ill patients,but can also lead to the occurrence of type 2 diabetes.Therefore,it is very important to learn the pathological mechanism of stress hyperglycemia,the harm of hyperglycemia and blood sugar management.

Glucokinase and glucokinase activator

Glucokinase (GK) plays a pivotal role in glucose homeostasis as the glucose sensor in the pancreas and liver. Loss of function of GK results in hyperglycemia, and gain of function causes congenital hyperinsulinemic hypoglycemia. We speculate that the progressive loss of GK at both messenger RNA (mRNA) and protein levels in the islets and liver would be the key mechanism for Type 2 diabetes (T2D) pathogenesis. The development of GK activator (GKA) as an anti-diabetic drug has been endeavored for several decades. The failure of the early development of GKAs is due to the limitation of understanding the mode of GKA action. The success of dorzagliatin in the treatment of T2D has brought new hope for GK in setting a good model for repairing the underlying defects in the pancreatic islets and liver of T2D patients.

A small molecule UPR modulator for diabetes identified by high throughput screening

Unfolded protein response(UPR) is a stress response that is specific to the endoplasmic reticulum(ER).UPR is activated upon accumulation of unfolded(or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones.In addition,UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER.Herein,we describe a cell-based ultra-high throughput screening(uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models.Using asialoglycoprotein receptor 1(ASGR) fused with Cypridina luciferase(CLuc) as reporter assay for folding capacity,we have screened a million small molecule library and identified APC655 as a potent activator of protein folding,that appears to act by promoting chaperone expression.Furthermore,APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines.APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient(ob/ob) mouse model.These results demonstrate a successful uHTS campaign that identified a modulator of UPR,which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.