Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells

Glucose uptake into pancreatic beta cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal beta-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of beta cells to hyperglycemia may improve the management and prevention of diabetes.     

Mitochondrial dysfunction and type 2 diabetes

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.     

A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 x 10(-7)) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit-related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG (linear regression coefficient beta = -0.06 millimoles per liter per A allele, combined P = 4 x 10(-23)) and with pancreatic beta cell function (Homa-B model, combined P = 3 x 10(-13)) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic beta cells.     

不同维持剂量聚乙二醇修饰的FGF-21在Ⅰ型糖尿病小鼠中降糖作用的研究

成纤维细胞生长因子21(FGF-21)是一种具有调节血糖功能的蛋白,且FGF-21聚乙二醇化可增加其半衰期、降低其免疫原性,有望成为临床治疗糖尿病新药。为推进聚乙二醇化FGF-21(pFGF-21)临床应用,在I型糖尿病小鼠模型上探索使用剂量。研究以1 mg·kg~(-1)pFGF-21作为启动剂量治疗小鼠15 d;后降低治疗剂量,分别以0.25、0.5 mg·kg~(-1)pFGF-21作为维持剂量持续治疗30 d。试验期间检测小鼠血糖、口服葡萄糖耐受量(OGTT)、糖化血红蛋白(HbA1c)、血清功能及肝脏糖代谢相关基因mRNA表达水平。结果发现,试验方法对Ⅰ型糖尿病治疗效果显著;此外,通过生化指标对比显示经pFGF-21治疗后,可显著改善肝脏功能和脂代谢紊乱(P0.01)。结果证明,1 mg·kg~(-1)pFGF-21启动后,以0.25和0.5 mg·kg~(-1)作为维持剂量,即高剂量启动,低剂量维持,治疗效果良好,对pFGF-21临床应用具有重要意义。     

Diabetes mellitus: induction in mice by encephalomyocarditis virus

Hyperglycemia and lesions of the pancreatic islets of Langerhans developed in some, but not all, adult mice infected with a variant of the encephalomyocarditis virus. Large amounts of virus were recovered from the pancreas during acute stages of infection. At this time blood glucose concentrations were markedly elevated and the islets of Langerhans exhibited focal necrosis and degranulation of beta cells. Evidence of abnormal glucose metabolism persisted for varying periods after recovery from the infection. The islets of Langerhans of chronically hyperglycemic mice were distorted and decreased in size, and the beta cells were degranulated. Encephalomyocarditis virus appears to cause diabetes mellitus by reducing the mass of functional beta cells of the islets of Langerhans.     

TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver

Insulin resistance is a major hallmark in the development of type II diabetes, which is characterized by the failure of insulin to promote glucose uptake in muscle and to suppress glucose production in liver. The serine-threonine kinase Akt (PKB) is a principal target of insulin signaling that inhibits hepatic glucose output when glucose is available from food. Here we show that TRB3, a mammalian homolog of Drosophila tribbles, functions as a negative modulator of Akt. TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. Amounts of TRB3 RNA and protein were increased in livers of db/db diabetic mice compared with those in wild-type mice. Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance. Our results suggest that, by interfering with Akt activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type II diabetes.     

Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker

Administration of a monoclonal antibody (GK1.5) that recognizes the L3T4 marker present on helper T cells prevented the development of experimental allergic encephalomyelitis (EAE) in mice. Furthermore, treatment with GK1.5 reversed EAE when the antibody was given to paralyzed animals. In vivo injection of GK1.5 selectively reduced the number of L3T4+ cells in the spleen and the lymph nodes. These results suggest that manipulation of the human equivalent of the murine L3T4+ T-cell subset with monoclonal antibodies may provide effective therapy for certain autoimmune diseases.     

Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes

An accelerated rate of glucose transport is among the most characteristic biochemical markers of cellular transformation. To study the molecular mechanism by which transporter activity is altered, cultured rodent fibroblasts transfected with activated myc, ras, or src oncogenes were used. In myc-transfected cells, the rate of 2-deoxy-D-glucose uptake was unchanged. However, in cells transfected with activated ras and src oncogenes, the rate of glucose uptake was markedly increased. The increased transport rate in ras- and src-transfected cells was paralleled by a marked increase in the amount of glucose transporter protein, as assessed by immunoblots, as well as by a markedly increased abundance of glucose transporter messenger RNA. Exposure of control cells to the tumor-promoting phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) for 18 hours had a similar effect of increasing the rate of glucose transport and the abundance of transporter messenger RNA. For ras, src, and TPA, the predominant mechanism responsible for activation of the transport system is increased expression of the structural gene encoding the glucose transport protein.     

Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution

A cure for type 1 diabetes will probably require the provision or elicitation of new pancreatic islet beta cells as well as the reestablishment of immunological tolerance. A 2003 study reported achievement of both advances in the NOD mouse model by coupling injection of Freund's complete adjuvant with infusion of allogeneic spleen cells. It was concluded that the adjuvant eliminated anti-islet autoimmunity and the donor splenocytes differentiated into insulin-producing (presumably beta) cells, culminating in islet regeneration. Here, we provide data indicating that the recovered islets were all of host origin, reflecting that the diabetic NOD mice actually retain substantial beta cell mass, which can be rejuvenated/regenerated to reverse disease upon adjuvant-dependent dampening of autoimmunity.     

Differences in adrenergic recognition by pancreatic A and B cells

The adrenergic control of glucose homeostasis is mediated in part through variations in the release of pancreatic hormones. In this study, purified pancreatic A and B cells were used to identify the recognition and messenger units involved in the adrenergic regulation of glucagon and insulin release. Catecholamines induced beta-adrenergic receptor activity in A cells and alpha 2-adrenergic receptor activity in B cells. The two recognition units provoked opposite variations in the production of cellular cyclic adenosine monophosphate, the beta-adrenergic unit enhancing the nucleotide's permissive effect on amino acid-induced glucagon release and the alpha 2-adrenergic unit inhibiting that upon glucose-induced insulin release. In both cell types, catecholamines interact powerfully with the synergistic control of hormone release by nutrient- and (neuro)hormone-driven messenger systems.     

Visfatin: a protein secreted by visceral fat that mimics the effects of insulin

Fat tissue produces a variety of secreted proteins (adipocytokines) with important roles in metabolism. We isolated a newly identified adipocytokine, visfatin, that is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre-B cell colony-enhancing factor (PBEF), a 52-kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. Mice heterozygous for a targeted mutation in the visfatin gene had modestly higher levels of plasma glucose relative to wild-type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Further study of visfatin's physiological role may lead to new insights into glucose homeostasis and/or new therapies for metabolic disorders such as diabetes.     

人参皂苷Rb3对肝糖异生作用机理的研究

为了探讨人参皂苷Rb3在降低血糖方面的分子调控机制,利用HepG2细胞为研究材料,系统分析了人参皂苷Rb3对肝糖异生关键酶PEPCK、G6Pase和转录因子FOXO1、HNF4α的影响。结果表明,人参皂苷Rb3可以显著抑制HepG2细胞肝糖异生途径关键转录因子FOXO1、HNF4α蛋白表达,从而抑制PEPCK和G6Pase酶活性及糖异生作用,该作用能够被AMPK抑制剂Compound C部分阻断,推测人参皂苷Rb3抑制肝糖异生作用是通过激活AMPK信号通路实现。AMPK信号转导通路作为重要的糖脂代谢靶点,在糖尿病及相关代谢类疾病的调控中发挥着重要的作用,为探讨人参皂苷Rb3治疗糖尿病的作用机制提供了新的理论依据。     

Islet regeneration during the reversal of autoimmune diabetes in NOD mice

Nonobese diabetic (NOD) mice are a model for type 1 diabetes in humans. Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund's adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. We now show that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet and ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal.     

壳寡糖对试验性糖尿病大鼠餐后血糖及肝肌糖原含量的影响

[目的]研究不同剂量的壳寡糖对链脲佐菌素（STZ）诱导的糖尿病大鼠餐后2h血糖及肝、肌糖原水平的影响。[方法]按65mg／kg体重一次性腹腔内注射（ip）STZ制备糖尿病大鼠模型,随机分成糖尿病治疗组和糖尿病对照组。治疗组分别按每日250、500、1500mg／kg灌胃壳寡糖水溶液,正常对照组、阴性对照组按体重灌胃等体积蒸馏水（10ml／k）,阳性对照组按每日200mg／k灌胃二甲双胍水溶液,连续60d,每10d测1次餐后2h血糖值。60d后对肝脏等脏器称重,计算器官系数。蒽酮试剂法测定肝、肌糖原含量。肝脏、骨骼肌PAS染色,做病理组织学检查。[结果]不同剂量的壳寡糖均能不同程度改善糖尿病大鼠的体重减轻、多饮、多食等症状,降低餐后2h血糖值。中、高剂量组的降糖效果优于低剂量组。PAS染色显示,壳寡糖各组肝索排列整齐,脂变程度低,骨骼肌和肝组织糖原比模型组明显增多。[结论]壳寡糖可以减少肝、肌糖原分解,减轻肝脏、肌肉组织的胰岛素抵抗,使血糖浓度下降。     

Regulation of fasted blood glucose by resistin

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.     

Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant

Insulin-dependent diabetes mellitus (IDDM) is caused by a specific loss of the insulin-producing beta cells from pancreatic Langerhans islets. It has been proposed that aberrant expression of major histocompatibility complex (MHC) class II molecules on these cells could be a triggering factor for their autoimmune destruction. This proposal was tested in transgenic mice that express allogeneic or syngeneic class II molecules on the surface of islet cells at a level comparable with that normally found on resting B lymphocytes. These animals do not develop diabetes, nor is lymphocyte infiltration of the islets observed. This immunological inactivity does not result from tolerance to the "foreign" class II molecules.     

Underexpression of beta cell high Km glucose transporters in noninsulin-dependent diabetes

The role of defective glucose transport in the pathogenesis of noninsulin-dependent diabetes (NIDDM) was examined in Zucker diabetic fatty rats, a model of NIDDM. As in human NIDDM, insulin secretion was unresponsive to 20 mM glucose. Uptake of 3-O-methylglucose by islet cells was less than 19% of controls. The beta cell glucose transporter (GLUT-2) immunoreactivity and amount of GLUT-2 messenger RNA were profoundly reduced. Whenever fewer than 60% of beta cells were GLUT-2-positive, the response to glucose was absent and hyperglycemia exceeded 11 mM plasma glucose. We conclude that in NIDDM underexpression of GLUT-2 messenger RNA lowers high Km glucose transport in beta cells, and thereby impairs glucose-stimulated insulin secretion and prevents correction of hyperglycemia.     

Localization of the pancreatic beta cell glucose transporter to specific plasma membrane domains

Immunocytochemical techniques revealed that the "liver-type" glucose transporter is present in the insulin-producing beta cells of rat pancreatic islets but not in other islet endocrine cells. Ultrastructural analysis of the transporter by the protein A-gold technique showed that it is restricted to certain domains of the plasma membrane, its density being sixfold higher in microvilli facing adjacent endocrine cells than in the flat regions of the plasma membrane. These results support a possible role for this glucose transporter in glucose sensing by beta cells and provide evidence that these cells are polarized.     

蜂胶对糖尿病SD大鼠的影响

测定和比较了蜂胶醇提液(EEP)和蜂胶水提液(WSP)对糖尿病SD大鼠的影响. 结果表明,EEP和WSP均能降低糖尿病SD大鼠的空腹血糖(FBG)、糖化血红蛋白(HBAlc)、果糖胺(FRU)、甘油三酯(TG)、总胆固醇(TC)、肌酐(CREA)、尿素氮(BUN)、尿酸(UA)、丙二醛(MDA)水平,减少总蛋白(TP)和白蛋白(ALB)的消耗,降低肾重与体重的比值. 表明蜂胶能够改善糖尿病SD大鼠的糖、脂肪、蛋白质代谢,减少糖尿病肾病的危害.