Role of protein tyrosine phosphatase-1B in diabetes and obesity

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is reaching epidemic proportions in industrialized countries. Obesity is a major factor in this disease, since about 75% of obese individuals will develop type 2 diabetes. There is an urgent need to develop new therapies for these diseases. Recently, the protein tyrosine phosphatase PTP-1B has been shown to be a negative regulator of the insulin signaling pathway, suggesting that inhibitors of this enzyme may be beneficial in the treatment of type 2 diabetes. Mice lacking PTP-1B are resistant to both diabetes and obesity.     

2型糖尿病患者血脂与胰岛素原等相关指标检测结果的分析

目的分析2型糖尿病患者血脂与胰岛素原等相关指标检测结果,同时讨论改善患者相关临床指标的手段。方法2013年2月至2015年2月该院57例2型糖尿病患者按照胰岛素原水平,分为研究组(≥15.6mIU/L,29例)及对照组(15.6mIU/L,28例),均予以口服葡萄糖治疗,同时分析血脂指标与血清真胰岛素、胰岛素原及稳态胰岛素评估模型胰岛素抵抗指数的相关性。结果胰岛素原、血清真胰岛素、餐后2h胰岛素原、餐后2h血清真胰岛素、稳态胰岛素评估模型胰岛素抵抗指数都与载脂蛋白B/载脂蛋白A1比值有相关关系。结论 2型糖尿病患者的胰岛素原升高,载脂蛋白B/载脂蛋白A1比值也会随之升高。     

新诊断2型糖尿病患者外周血单个核细胞蛋白酪氨酸磷酸酶1B的表达

目的探讨蛋白酪氨酸磷酸酶1B（proteintyrosinephosphatase1B,PTPIB）在新诊断的2型糖尿病患者外周血单个核细胞（peripheralbloodmononuclearcell,PBMC）中的表达水平及意义。方法采用实时荧光定量PCR法检测20例新诊断2型糖尿病患者（糖尿病组）和20例血糖正常者（对照组）PBMC中PTPIBmRNA的表达,分析其与体质量指数（bodymassindex,BMI）、空腹血糖（fastingplasmaglucose,FPG）、空腹胰岛素（fastinginsulin,FINS）、稳态模型的胰岛素抵抗指数（homeostasismodelassessmentofinsulinresistance,HOMA—IR）、血脂的相关性。结果糖尿病组PBMC中PTPIBmRNA水平（1．05±0．19）明显高于对照组（0．53±0．17）（P〈0．01）,且PTPIBmRNA表达与BMI、FPG、FINS、HOMA—IR、三酰甘油和总胆固醇呈正相关（r=0．58,r=0．78,r=0．55,r=0．73,r=0．68,r=0．59,P均〈O．01）。结论PTPIB在新诊断2型糖尿病患者PBMC中表达较血糖正常者增加,其高表达与新诊断2型糖尿病胰岛素抵抗相关。     

Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors

Known treatments of type 2 diabetes mellitus have limitations such as weight gain, and hypoglycaemias. A new perspective is the use of incretin hormones and incretin enhancers. Incretins are defined as being responsible for the higher insulin release after an oral glucose load compared to an intravenous glucose load. The delicate balance of glucose homeostasis, in which incretin hormones are involved, is disturbed in type 2 diabetes mellitus. The incretin GLP-1 helps to maintain glucose homeostasis through stimulation of insulin secretion and inhibition of glucagon release in a glucose-dependent manner. This is associated with reductions in body weight, and no risk of hypoglycaemias. When classical oral agents have failed to maintain adequate glycaemic control, incretin mimetics may be of particular value for obese patients and those who have little control over meal sizes. Exenatide was marketed as a GLP-1 analogue and longer acting incretin mimetics such as liraglutide, albiglutide and others have the same pharmacological profile.In addition to incretin mimetics incretin enhancers which inhibit/delay degradation of incretins were developed: so-called DPP-4 inhibitors such as sitagliptin and vildagliptin are approved in Europe. Their differences from incretin mimetics include: oral bioavailability, less side effects with overdose, no direct CNS effects (nausea and vomiting) and no effect on weight. In rodent models of diabetes, but not yet in humans, GLP-1 receptor agonists and DPP-4 inhibitors increase islet mass and preserve β-cell function.Incretin mimetics and enhancers expand type 2 diabetes treatment, are still not first line therapy and it is discussed if they are to be prophylactically used.     

Oral agents in the management of type 2 diabetes mellitus

Despite exhaustive efforts to better manage patients with type 2 diabetes mellitus (formerly known as non-insulin-dependent diabetes mellitus), attempts at maintaining near normal blood glucose levels in these patients remains unsatisfactory. This continues to pose a real challenge to physicians as the prevalence of this disease in the United States continues to rise. Type 2 diabetes is defined as a syndrome characterized by insulin deficiency, insulin resistance and increased hepatic glucose output. Medications used to treat type 2 diabetes are designed to correct one or more of these metabolic abnormalities. Currently, there are five distinct classes of hypoglycemic agents available, each class displaying unique pharmacologic properties. These classes are the sulfonylureas, meglitinides, biguanides, thiazolidinediones and alpha-glucosidase inhibitors. In patients for whom diet and exercise do not provide adequate glucose control, therapy with a single oral agent can be tried. When choosing an agent, it is prudent to consider both patient- and drug-specific characteristics. If adequate blood glucose control is not attained using a single oral agent, a combination of agents with different mechanisms of action may have additive therapeutic effects and result in better glycemic control.     

A new approach to glucose control in type 2 diabetes: the role of kidney sodium-glucose co-transporter 2 inhibition

Hyperglycemia is a defining characteristic of type 2 diabetes mellitus and is a major risk factor associated with the development of many microvascular complications. There are numerous therapies currently available to treat hyperglycemia, but glycemic control rates remain poor. One potential reason is the decline in ?-cell function over time, which decreases the effectiveness of therapies that rely on insulin action. The kidney occupies a central position in the control of glucose homeostasis by its role in gluconeogenesis and by regulating glucose excretion. Under normal conditions, glucose filtered by the kidney is virtually totally reabsorbed in the proximal tubule by the sodium-glucose co-transporter 2 (SGLT2). Inhibition of SGLT2 is an attractive, insulin-independent target for increasing glucose excretion in the setting of hyperglycemia. A number of SGLT2 inhibitors have been synthesized, and results from preclinical studies have shown that they increase glucose excretion and normalize plasma glucose in diabetic models. Initial clinical data are promising and suggest that SGLT2 inhibitors may be a new therapeutic option for treating type 2 diabetes mellitus.     

Unresolved bereavement

Abstract

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive β-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.     

Sodium-glucose co-transporter-2 inhibitor-associated euglycemic diabetic ketoacidosis that prompted the diagnosis of fulminant type-1 diabetes: A case report

BACKGROUNDFulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of islet β cells. It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies. Diabetic ketoacidosis with normal blood glucose levels has been reported during sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy.CASE SUMMARYThe patient was a 43-year-old woman that consulted a medical practitioner for malaise, thirst, and vomiting. Blood analysis showed high blood glucose levels (428 mg/dL), a mild increase of hemoglobin A1c (6.6%), and increased ketone bodies in urine. The patient was diagnosed with type 2 diabetes mellitus. The patient was initially treated with insulin, which was subsequently changed to an oral SGLT2 inhibitor. Antibodies to glutamic acid decarboxylase were negative. Four days after receiving oral SGLT2 inhibitor, she consulted at Mie University Hospital, complaining of fatigue and vomiting. Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels. The endogenous insulin secretion was markedly low, and the serum levels of islet-related autoantibodies were undetectable. We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis. The patient''s general condition improved after therapy with intravenous insulin and withdrawal of oral medication. She was discharged on day 14 with an indication of multiple daily insulin therapy.CONCLUSIONThis patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels. This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.     

The effects of pharmacologic agents for type 2 diabetes mellitus on body weight

Type 2 diabetes mellitus and obesity share a pathogenic relationship, and both have rapidly increased in prevalence over the past decade. This review evaluates the effects of antidiabetes therapies on weight and glycemic control in the type 2 diabetes mellitus population. A PubMed search was conducted to identify randomized controlled trials that reported the weight effects of antidiabetes treatments. The search focused on the newer incretin-based therapies, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Antiobesity drugs and treatment options potentially available to patients with type 2 diabetes mellitus, including bariatric surgery, were also examined. Most of the established antidiabetes therapies (eg, sulfonylureas, thiazolidinediones) promote weight gain, thereby exacerbating insulin resistance and glucose intolerance. Dipeptidyl peptidase-4 inhibitors exhibit a weight-neutral profi le, however, and GLP-1 receptor agonists (eg, exenatide, liraglutide) have achieved signifi cant body weight reductions in spite of improved glycemic control, which is often accompanied by weight gain. Antiobesity drugs, such as orlistat and sibutramine, are effective weight-lowering agents in patients with type 2 diabetes mellitus, but safety and tolerability concerns may limit their use. Bariatric surgery in obese patients is associated with improved glycemic values and decreased mortality. Clinical evidence substantiating the weight-neutral effects of DPP-4 inhibitors and the weight-loss effects of GLP-1 agonists is promising, offering an expansion of therapeutic options for overweight and obese patients with type 2 diabetes mellitus. Evidence on the clinical utility of antiobesity drugs is more equivocal, and more data are needed to evaluate the safety and tolerability of these agents.     

Hypoglycemic Potential of Current and Emerging Pharmacotherapies in Type 2 Diabetes Mellitus

Abstract

Intensive glycemic control can reduce the risk of microvascular complications in patients with type 2 diabetes mellitus (T2DM). However, hypoglycemia induced by diabetes medications is recognized as a major limiting factor in the attainment of glycemic goals. Mild hypoglycemia is relatively common in patients with T2DM, and the prevalence of severe hypoglycemia increases with insulin treatment and can approach the prevalence seen in patients with type 1 diabetes. Mild hypoglycemia and the fear of hypoglycemia can have a substantial impact on the physical, mental, social, and economic well–being of patients with T2DM. Severe hypoglycemia is more serious and may be associated with an increased risk of dementia, cardiovascular events, and death. Insulin and insulin secretagogue therapies (eg, sulfonylureas and meglitinides) are the major causes of hypoglycemia in patients with T2DM. Other diabetes drugs, such as metformin, when used as monotherapy, have a low risk of hypoglycemia. Emerging experimental therapies, such as activators of the free fatty acid receptor 1, G protein–coupled receptor 119 agonists, glucokinase activators, inhibitors of 11β-hydroxysteroid dehydrogenase type 1, and sodium–glucose co–transporter 2 inhibitors, some of which have mechanisms of action consistent with a potential low risk of hypoglycemia, may help patients with T2DM achieve improved glycemic control.     

Gycemic control, mealtime glucose excursions, and diabetic complications in type 2 diabetes mellitus

Type 2 diabetes mellitus is a heterogeneous disorder characterized by 2 pathogenic defects, impaired insulin secretion and insulin resistance. The resultant hyperglycemia causes microvascular and macrovascular complications that increase morbidity and mortality in patients with diabetes mellitus. Optimum glycemic control in patients with type 1 and type 2 diabetes mellitus prevents the development of microvascular disease and, to a lesser extent, macrovascular disease. Prandial hyperglycemia may be an independent risk factor for the development of diabetic complications. This article reviews the pathophysiologic mechanisms of glucose metabolism and describes the results of epidemiological and interventional studies that have demonstrated the association of acute and chronic hyperglycemia with the development of diabetic complications. The American Diabetes Association has defined diagnostic and treatment goals for diabetes mellitus, striving to achieve near-normal glycemic control to delay or prevent the development of diabetic complications. A number of oral antidiabetic agents and insulins are currently available for the treatment of type 2 diabetes mellitus in the United States. These agents target fasting and postmeal plasma glucose levels to improve glycemic control. Alone or in combination, these agents have enhanced the clinical approaches to treating diabetes mellitus.     

Exenatide upregulates gene expression of glucagon‐like peptide‐1 receptor and nerve growth factor in streptozotocin/nicotinamide‐induced diabetic mice

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that has modulating effects on insulin release. GLP‐1 and receptors for GLP‐1 are widely expressed throughout the body including the brain. The expression of GLP‐1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP‐1 receptor stimulation enhances glucose‐dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose‐derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP‐1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP‐1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 μg/kg, s.c., twice daily for 2 weeks) on GLP‐1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ–NA)‐induced diabetic mice were assessed by quantitative real‐time polymerase chain reaction (RT‐PCR). The results of this study revealed that hippocampal gene expression of GLP‐1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP‐1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP‐1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA‐induced diabetes.     

Epidemiology of elderly diabetes mellitus in Japan

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and post challenge hyperglycemia in the older population. Diabetes in the elderly is not a single entity, but a heterogeneous group of conditions. A further 9% may have undetected/asymptomatic hyperglycemia. Several studies have also shown that fasting blood glucose rises with age (about 1-2 mg/dl/decade) and postprandial glucose by about 15 mg/dl/decade, leading to a mild glucose intolerance. Age-related glucose intolerance in humans is often accompanied by insulin resistance. The relative contribution of decreased insulin secretion vs. increased insulin resistance to the pathogenesis of type 2 diabetes mellitus has been the subject of long-standing controversy.     

Raising the bar in research ethics

Abstract

Type 2 diabetes mellitus and obesity share a pathogenic relationship, and both have rapidly increased in prevalence over the past decade. This review evaluates the effects of antidiabetes therapies on weight and glycemic control in the type 2 diabetes mellitus population. A PubMed search was conducted to identify randomized controlled trials that reported the weight effects of antidiabetes treatments. The search focused on the newer in cretin-based therapies, including dipeptidy1 peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Antiobesity drugs and treatment options potentially available to patients with type 2 diabetes mellitus, including bariatric surgery, were also examined. Most of the established antidiabetes therapies (eg, sulfonylureas, thiazolidinediones) promote weight gain, thereby exacerbating insulin resistance and glucose intolerance. Dipeptidy1 peptidase-4 inhibitors exhibit a weight-neutral profile, however, and GLP-1 receptor agonists (eg, exenatide, liraglutide) have achieved significant body weight reductions in spite of improved glycemic control, which is often accompanied by weight gain. Antiobesity drugs, such as or listat and sibutramine, are effective weight-lowering agents in patients with type 2 diabetes mellitus, but safety and tolerability concerns may limit their use. Bariatric surgery in obese patients is associated with improved glycemic values and decreased mortality. Clinical evidence substantiating the weight-neutral effects of DPP-4 inhibitors and the weight-loss effects of GLP-1 agonists is promising, offering an expansion of therapeutic options for overweight and obese patients with type 2 diabetes mellitus. Evidence on the clinical utility of antiobesity drugs is more equivocal, and more data are needed to evaluate the safety and tolerability of these agents.     

胰岛素泵与传统注射胰岛素治疗2型糖尿病的临床比较

糖尿病(DM)是一组以慢性高血糖为特征的代谢性疾病,长期的高血糖与DM晚期并发症显著相关,采取胰岛素泵强化治疗可以更好地控制血糖,防治各种并发症的发生、发展。胰岛素泵是目前对DM患者进行强化治疗的有效手段之一,为观察其疗效和安全性,我们应用胰岛素泵治疗2型DM患者38例,并     

妊娠糖尿病患者分娩后胰岛素抵抗及胰岛B细胞功能状态变化研究

目的 了解妊娠糖尿病患者分娩后6周糖耐量异常发生情况,探讨胰岛素抵抗及胰岛 B 细胞功能状态改变在妊娠糖尿病患者分娩后糖耐量异常发生中的作用。方法 选择69例既往诊断为妊娠糖尿病患者,于分娩6周后对所有患者进行口服葡萄糖耐量试验（OGTT）,根据试验结果分为糖耐量减低（IGT）组和糖耐量正常（NGT）组。胰岛素抵抗用胰岛素抵抗指数（HOMA-IR）和胰岛素敏感指数（ISI）表示,胰岛 B 细胞功能状态用第一时相胰岛素分泌量表示,比较观察两组患者的基线资料、胰岛素抵抗及胰岛 B 细胞功能状态变化情况。结果 OGTT 试验结果显示,69例患者中 NGT 组38例,IGT 组31例。IGT 组 HOMA-IR 显著高于 NGT 组,ISI、第一时相 INS 显著低于 NGT组,差异有统计学意义（P ＜0．05）;两组患者第二时相 INS 比较差异无统计学意义（P ＞0．05）。结论 胰岛素抵抗及胰岛 B 细胞功能缺陷可能在妊娠糖尿病患者分娩后糖耐量异常发生中起一定作用,值得进一步深入研究。     

阿卡波糖与预混人胰岛素联合治疗2型糖尿病42例

目的：观察在预混人胰岛素基础上联合阿卡波糖治疗是否能强化血糖控制并减少胰岛素用量。方法：将84例2型糖尿病人随机分为两组，甲组单用预混人胰岛素治疗，乙组联合预混人胰岛素与阿卡波糖治疗，共观察3个月，分别检测两组治疗前后空腹及餐后2h血糖、糖化血红蛋白，计算观察终点时各患者胰岛素用量及3个月中两组各发生低血糖的总人次，并进行统计学比较。结果：两组治疗后血糖水平、糖化血红蛋白均较治疗前有明显下降；乙组餐后2h血糖及糖化血红蛋白下降较甲组更加明显，且胰岛素用量少于甲组，低血糖发生次数亦减少。结论：在预混人胰岛素基础上联合阿卡波糖能使血糖得到更好的控制并能减少胰岛素用量。     

Tumour necrosis factor-alpha levels in non-diabetic offspring of patients with type 2 diabetes mellitus

Tumour necrosis factor-alpha (TNF-alpha) is considered to be involved in the insulin resistance of type 2 diabetes mellitus. The offspring of patients with type 2 diabetes mellitus are at increased risk of developing diabetes and several metabolic abnormalities, but the underlying defects responsible are not known. We studied serum TNF-alpha levels in 30 healthy non-diabetic offspring of type 2 diabetic parents (group A), and the relationship between TNF-alpha levels and variables associated with insulin resistance and diabetes. For comparison, 30 healthy offspring of non-diabetic parents (group B) were also studied. The median serum concentration of TNF-alpha was significantly higher in group A than in group B, 3.5 pg/ml compared with 2.0 pg/ml, respectively. The individuals of group A also had significantly elevated levels of glycosylated haemoglobin, fasting glucose, glucose 2 h after an oral glucose tolerance test and triglycerides. We conclude that serum TNF-alpha concentration is significantly elevated in non-diabetic offspring of type 2 diabetics and this may predict later impairment of insulin action in these individuals.     

罗格列酮对2型糖尿病患者血浆tPA和PAI1活性的影响

目的:运用胰岛素增敏剂罗格列酮治疗2型糖尿病患者,观察罗格列酮对2型糖尿病患者血浆tPA和PAI1活性水平的影响。方法:48例2型糖尿病患者,口服罗格列酮(文迪雅)4mg/d,共12周,观察治疗前后的血浆tPA和PAI1活性、血糖和胰岛素等,计算胰岛素敏感指数和胰岛素抵抗指数,并将各指标进行分析比较。结果:罗格列酮治疗后2型糖尿病患者血浆tPA活性升高(P<0.05),PAI1活性及PAI1/tPA活性比值降低(P<0.05,P<0.01)。血糖、胰岛素水平降低(均P<0.05);胰岛素敏感指数明显升高(P<0.05);胰岛素抵抗指数降低(P<0.05)。结论:罗格列酮在降低血糖、改善胰岛素抵抗、提高胰岛素敏感指数的同时,能增强糖尿病患者纤溶系统的活性,对心血管起到保护作用。     

Pathogenesis of type 2 diabetes mellitus

This article provides an overview of the pathogenesis of type 2 diabetes mellitus. Discussion begins by describing normal glucose homeostasis and ingestion of a typical meal and then discusses glucose homeostasis in diabetes. Topics covered include insulin secretion in type 2 diabetes mellitus and insulin resistance, the site of insulin resistance, the interaction between insulin sensitivity and secretion, the role of adipocytes in the pathogenesis of type 2 diabetes, cellular mechanisms of insulin resistance including glucose transport and phosphorylation, glycogen and synthesis,glucose and oxidation, glycolysis, and insulin signaling.