胰岛素生成,胰岛素分泌及2型糖尿病:问题的核心在于β细胞

近年来,有人将2型糖尿病(T2DM)定义为由胰岛素抵抗引起的一种疾病,作为代谢综合征的一部分。胰岛素抵抗确实存在于T2DM,但同时也以同样程度存在于许多并无糖尿病的人群中,这些人可有或无代谢综合征。因而单独胰岛素抵抗不可能是T2DM的决定性致病因素。T2DM从其最早的阶段包括糖耐量受损(IGT)及空腹血糖受损(IFG),甚或在可测出的这些血糖变化之前的“糖尿病前期”就出现胰岛素释放动力学的障碍;其主要特征是对葡萄糖反应的胰岛素释放第一相丧失,随之而来的是逐渐加重的第二相胰岛素和总胰岛素分泌的受损。第一相胰岛素反应丧失的后果为肝脏未能迅速胰岛素化,延迟了对肝葡萄糖输出的抑制,从而引起餐后高血糖。在某些研究中,确已发现T2DM时β细胞量总体的减少,但并非所有研究中都有此同样结果,故对此尚须进一步证实。现已明确,糖尿病易发人群的β细胞的分泌适应能力是有限的,在胰岛素抵抗或热量负荷对胰岛素释放要求增加时,就难以胜任。此外,即使轻度的高血糖也会严重影响胰岛素的分泌并减少胰岛素原的合成,从而使代谢所需的胰岛素进一步减少。转录因子PDX-1在此损伤过程中起关键作用。因而,及早并有效地将T2DM血糖控制于接近正常水平至关重要,尤其是对胰岛素一相分泌的恢复更是如此。     

Autoimmunity, insulin resistance and Beta cell function in subjects with low body weight type 2 diabetes mellitus

In developing countries like India, the majority of Type 2 diabetics are non-obese, and many are "lean" with a body mass index (BMI) below 18.5. This type is referred to as "Low Body Weight Type 2 DM" (LB Type 2 DM). LB Type 2 DM are confused with Type 1 DM or late autoimmune diabetes in adults (LADA) due to their high blood glucose levels and early insulin-requiring state. We assessed pancreatic islet cell autoimmunity by using both glutamic acid decarboxylase 65 antibody (GADA) and anti-IA(2) antibody estimation in 23 patients with LB Type 2 DM and 10 age-matched normal weight (NW) Type 2 DM. Fasting blood glucose (FBG) and 2 hr postchallenge blood glucose (PGBG2) were significantly higher in LB (p < 0.05), while mean values of fasting insulin (24.47 +/- 73.15 muIU/mL vs. 13.4 +/- 16.54 muIU/mL, p > 0.7) and fasting C-peptide (180.81 +/- 357.08 pM/mL vs. 279.83 +/- 281.38 pM/mL, p > 0.5) in LB and NW respectively were not statistically different. All 23 LB and 10 NW subjects were GADA negative while IA(2) positivity was found in 1/23 and 1/10 cases, respectively. LB Type 2 DM revealed good beta cell function with homeostasis model assessment beta cells (HOMAB) values of 57.41 +/- 153.18 as compared to 44.74 +/- 56.24 (p > -0.2) in NW Type 2 DM. Insulin resistance as assessed by homeostasis model assessment insulin resistant (HOMA IR) was 13.50 +/- 42.83 and 5.68 +/- 6.90 (p > 0.6) in LB and NW Type 2 DM, respectively, suggesting that LB Type 2 DM are a phenotypic variant of Type 2 DM.     

Relationships among insulin resistance, type 2 diabetes, essential hypertension, and cardiovascular disease: similarities and differences

Insulin resistance plays a major role in the pathogenesis and clinical course of patients with type 2 diabetes (2DM) and essential hypertension. However, the syndromes differ in prevalence of insulin resistance, and associated insulin secretory response. Essentially all patients with type 2 diabetes are insulin resistant, whereas only approximately 50% of those with essential hypertension are insulin resistant. Furthermore, 2DM develops when the pancreatic β-cell can no longer maintain the degree of compensatory hyperinsulinemia needed to prevent hyperglycemia. In contrast, the compensatory hyperinsulinemia that prevents most insulin resistant individuals from developing 2DM acts on normally insulin sensitive tissues in a manner that predisposes to the development of essential hypertension. This review will discuss these similarities and differences in some detail, as well as exploring the relationship among insulin resistance and related metabolic abnormalities in the pathogenesis of cardiovascular disease in patients with 2DM and essential hypertension.     

Beta cell function in insulin-treated non-insulin-dependent diabetic patients

Non--insulin-dependent diabetes mellitus (NIDDM) patients, 94 in number, who were treated with insulin for various reasons for periods ranging from 2 to 10 years, were investigated to study the effect of long-term insulin therapy and also the effect of anti-insulin antibodies on the beta cell function. Insulin antibody titer and the stimulated C-peptide (CP) did not correlate with the duration of insulin therapy, dose of insulin, or the severity of hyperglycemia. The antibody titers were low in 45%, moderate in 10%, and high in 45%; no correlation was found between the antibody titers and the CP values. Satisfactory control of hyperglycemia was obtained in 54 patients after change of treatment to oral hypoglycaemic agents (OHA). The other 40 patients required continued insulin therapy. The initial CP values were similar in both the groups before initiating the new therapeutic patterns. Those who responded to OHA showed improved CP values on follow-up. The beta cell response to exogenous insulin is heterogeneous in NIDDM patients. In many patients, adequate preservation of beta cell function is present even after long-term insulin therapy. Many of them respond to OHA. Insulin antibodies do not influence the secretory status of the beta cells in NIDDM patients.     

Role of islet amyloid in type 2 diabetes mellitus: consequence or cause?

Type 2 diabetes mellitus (DM2) is characterized metabolically by defects in both insulin secretion and insulin action, resulting in hyperglycemia. Histopathologically, DM2 is characterized by depositions of protein in the pancreatic islets. This 'islet amyloid' is present in >90% of patients with DM2, as well as in monkeys and cats with DM2. The pathogenesis of DM2 is heterogeneous and multifactorial, although insulin resistance seems to be the predominant initiating factor for development of the disease. In the longer term, an insulin secretion defect is also revealed (referred to as 'beta-cell failure'), resulting in clinically manifest diabetes. Recent data, particularly from transgenic mouse studies, indicate that islet amyloidosis is a diabetogenic factor, which is both consequence (of insulin resistance) and cause (of beta-cell failure) of DM2. Available transgenic mouse models with islet amyloid formation in vivo will provide the opportunity to assess the effectiveness of novel anti-amyloidogenic therapies, for which promising results are emerging.     

Alterations in white matter volume and integrity in obesity and type 2 diabetes

Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.     

甘精胰岛素联合口服降糖药控制空腹及餐后高血糖的研究

目的探讨甘精胰岛素与口服降糖药联用控制空腹及餐后高血糖的疗效。方法将136例单用口服降糖药血糖控制不理想的T2DM患者随机分为A、B两组。A组采用国产甘精胰岛素（长秀霖）,B组采用进口甘精胰岛素（来得时）,两组在用甘精胰岛素的基础上,均分别与二甲双胍和瑞格列奈联用,观察治疗前后FPG、2hPG及HbA1C水平和低血糖的发生率。结果治疗后两周时FPG、2hPG及HbA1C水平与治疗前相比均明显下降,但仍未达标。两组患者在甘精胰岛素和二甲双胍治疗的基础上加用瑞格列奈,治疗后4周时FPG及2hPG水平均已达标,HbA1C水平于治疗2个月时达标。两组治疗后各项指标与治疗前相比均明显下降（P均〈0．01）,两组临床疗效无统计学差异,低血糖发生率分别为4．2％和4．6％,相比无统计学差异（P〉0．05）。结论两种甘精胰岛素分别与二甲双胍和瑞格列奈联用,能较好控制FPG、2hPG及HbA1C水平,低血糖发生率均较低,临床疗效相近。因此,甘精胰岛素与二甲双胍和瑞格列奈联用是控制FPG、2hPG及HbA1C水平的安全有效的治疗方案。     

Clinical importance of assessment of type 2 diabetes mellitus with visceral obesity. A Japanese perspective

Type 2 diabetes mellitus (T2DM) is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. Obesity T2DM has become a serious problem in Japan as in Western countries, with over-eating and physical inactivity. Obese Asians have mild degree of adiposity, compared with Western subjects. Unlike total body fat, body fat distribution, especially excess accumulation of visceral fat, correlates with various diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities, which increase the risk of atherosclerotic cardiovascular disease (ACVD). Obese patients with T2DM have poor glycemic control with disordered eating behaviors, and complications of hypertension and dyslipidemia, leading to ACVD. The major therapies in obese T2DM, hyperinsulinemia and low insulin sensitivity, available for weight loss, especially visceral fat reduction, include caloric restriction, physical activity and behavior modification. On the other hand, the major therapies in non-obese T2DM with insufficient insulin secretion, are insulin-secretory agents and injectable insulin. For clinically meaningful prevention/reduction in the rate of future ACVD in T2DM, it may be important to stratify T2DM subjects into those with and without visceral obesity and design specific management protocols for each group.     

胰岛素强化治疗对初诊2型糖尿病患者胰岛β细胞功能和胰岛素抵抗的影响

目的探讨阶梯式胰岛素强化治疗对初诊2型糖尿病（T2DM）患者胰岛β细胞功能和胰岛素抵抗（IR）的影响及机制。方法初诊T2DM患者61例,进行为期2周的胰岛素强化治疗和后续10周的预混胰岛素治疗,比较治疗前后FPG、2hPG、HbA1c、Fins、2hIns、FC-P、2hC-P、TC、TG、胰岛β细胞分泌指数（HOMA-β）和胰岛素抵抗指数（HOMA-IR）的变化。结果治疗后患者FPG、2hPG、HbA1 c和HOMA-IR显著下降,而Fins、2hIns、FC-P、2hC-P和HOMA-β显著上升。结论对血糖明显升高的初诊T2DM患者,短期胰岛素强化治疗及后续数周预混胰岛素皮下注射治疗可有效控制血糖,明显改善胰岛8细胞功能并减轻IR。     

Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men

Type 2 diabetes mellitus (T2DM) is strongly associated with obesity in most, but not all, ethnic groups, suggesting important ethnic differences in disease susceptibility. Although it is clear that insulin resistance plays a major role in the pathogenesis of T2DM and that insulin resistance is strongly associated with increases in hepatic (HTG) and/or intramyocellular lipid content, little is known about the prevalence of insulin resistance and potential differences in intracellular lipid distribution among healthy, young, lean individuals of different ethnic groups. To examine this question, 482 young, lean, healthy, sedentary, nonsmoking Eastern Asians (n = 49), Asian-Indians (n = 59), Blacks (n = 48), Caucasians (n = 292), and Hispanics (n = 34) underwent an oral glucose tolerance test to assess whole-body insulin sensitivity by an insulin sensitivity index. In addition, intramyocellular lipid and HTG contents were measured by using proton magnetic resonance spectroscopy. The prevalence of insulin resistance, defined as the lower quartile of insulin sensitivity index, was approximately 2- to 3-fold higher in the Asian-Indians compared with all other ethnic groups, and this could entirely be attributed to a 3- to 4-fold increased prevalence of insulin resistance in Asian-Indian men. This increased prevalence of insulin resistance in the Asian-Indian men was associated with an approximately 2-fold increase in HTG content and plasma IL-6 concentrations compared with Caucasian men. These data demonstrate important ethnic and gender differences in the pathogenesis of insulin resistance in Asian-Indian men and have important therapeutic implications for treatment of T2DM and for the development of steatosis-related liver disease in this ethnic group.     

Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance

Leptin, an adipocyte-derived hormone, plays an essential role in the maintenance of normal body weight and energy expenditure, as well as glucose homeostasis. Indeed, leptin-deficient ob/ob mice are obese with profound hyperinsulinemia, insulin resistance, and often hyperglycemia. Interestingly, low doses of exogenous leptin can reverse the hyperinsulinemia and hyperglycemia in these animals without altering body weight. The hyperinsulinemia in ob/ob mice may result directly from the absence of leptin signaling in pancreatic β-cells and, in turn, contribute to both obesity and insulin resistance. Here, we acutely attenuated endogenous leptin signaling in normal mice with a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) to determine the contribution of leptin signaling in the regulation of glucose homeostasis. PEG-MLA was either injected or continuously administered via osmotic minipumps for several days, and various metabolic parameters were assessed. PEG-MLA-treated mice had increased fasting and glucose-stimulated plasma insulin levels, decreased whole-body insulin sensitivity, elevated hepatic glucose production, and impaired insulin-mediated suppression of hepatic glucose production. Moreover, PEG-MLA treatment resulted in increased food intake and increased respiratory quotient without significantly altering energy expenditure or body composition as assessed by the lean:lipid ratio. Our findings indicate that alterations in insulin sensitivity occur before changes in the lean:lipid ratio and energy expenditure during the acute disruption of endogenous leptin signaling.     

Insulin resistance and decreased insulin response to glucose in lean type 2 diabetics

In an attempt to determine the mechanism of decreased glucose tolerance in lean type 2 diabetics, glucose turnover in such subjects and controls was studied under basal conditions and during hyperglycemia induced by intravenous administration of glucose. The diabetics had decreased intravenous glucose tolerance and a fasting plasma glucose of 6-8 mM (108-144 mg/dl). Glucose was infused for 2 hr at 2 mg/kg per min in the controls (n = 16) and diabetics (n = 9). Furthermore, 11 healthy subjects were infused also with glucose at 4 mg/kg per min to match the glycemia of the diabetics. Glucose production, utilization, and metabolic clearance were assessed by the primed constant tracer infusion technique. In the basal state, diabetics showed normal plasma insulin, C peptide, and glucagon concentrations. Their increased basal plasma glucose levels were associated with normal rates of glucose production and utilization, but the metabolic glucose clearance was 21% lower than in the controls (P < 0.001), indicating decreased sensitivity to insulin. During infusion of glucose at 2 mg/kg per min, the hyperglycemia attained in the diabetics (170 mg/dl) was higher than that in controls (115 mg/dl) but comparable to that of the controls exposed to the higher glucose load. With the lower glucose load, metabolic clearance rate decreased more markedly in diabetics, again suggesting insulin resistance. This was further substantiated by the fact that, at the same insulin levels, glucose utilization did not increase more in the diabetics than in the controls, although the glycemia reached was considerably higher in the diabetics. With the lower glucose load, glucose production was suppressed to the same degree in the controls and diabetics, although the attained glycemia was much more marked in the latter. Because both insulin and hyperglycemia can suppress glucose production, some defect in the regulation of glucose production of the diabetics is also indicated. The insulin and C peptide levels were much higher in the controls than in the diabetics at the same levels of glycemia, demonstrating the inadequacy of insulin response to glycemia of the diabetics. Glucagon concentration was equally suppressed in all groups. In conclusion, impaired glucose tolerance of mild type 2 diabetics resulted both from inadequate insulin response and from decreased sensitivity to insulin. The insulin resistance could mainly be ascribed to inadequate glucose uptake, but a defect in glucose-induced suppression of glucose production may also have contributed.     

Beta-cell function, insulin sensitivity, and glucose tolerance in obese diabetic and nondiabetic adolescents and young adults

CONTEXT: Type 2 diabetes mellitus (T2DM) is estimated to account for 10-45% of incident pediatric diabetes cases. OBJECTIVE: Our objective was to characterize the metabolic defects underlying T2DM in adolescents and young adults. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of islet function and insulin sensitivity in 16 adolescents with T2DM and 13 obese (OB) and 13 lean (LN) age-matched nondiabetic subjects at a University Medical Center. INTERVENTION: We provided oral and iv glucose tolerance tests. MAIN OUTCOME MEASURES: We measured insulin and glucagon levels, insulin sensitivity, acute insulin responses to iv glucose, and the ratio of proinsulin to immunoreactive insulin. RESULTS: The diabetic subjects had elevated fasting insulin levels and significantly reduced insulin sensitivity (P < 0.05). The acute insulin response to iv glucose was comparable in the T2DM and LN groups (P < 0.05 for the OB vs. LN and T2DM), but insulin secretion adjusted for insulin resistance, the disposition index, was severely impaired in the diabetic subjects (P < 0.05 for the T2DM vs. LN and OB). The ratio of proinsulin to immunoreactive insulin did not differ among the three groups in the basal or stimulated state. Plasma glucagon levels were comparable before and after ingestion of glucose. CONCLUSIONS: These findings demonstrate that diabetic adolescents have significant insulin resistance, even compared with subjects of similar obesity and body fatness, and impaired insulin secretion relative to their degree of insulin resistance. However, the adolescent diabetic subjects retained a first-phase insulin response to glucose that was comparable to lean controls and did not have hyperproinsulinemia or hyperglucagonemia.     

Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats

The aim of this study was to investigate the effects of melatonin on glucose homeostasis in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n=30) and lean littermates (ZL) (n=30) were used. At 6wk of age, both lean and fatty animals were subdivided into three groups, each composed of ten rats: naive (N), vehicle treated (V), and melatonin treated (M) (10mg/kg/day) for 6wk. Vehicle and melatonin were added to the drinking water. ZDF rats developed DM (fasting hyperglycemia, 460±39.8mg/dL; HbA(1) c 8.3±0.5%) with both insulin resistance (HOMA-IR 9.28±0.9 versus 1.2±0.1 in ZL) and decreased β-cell function (HOMA1-%B) by 75%, compared with ZL rats. Melatonin reduced fasting hyperglycemia by 18.6% (P<0.05) and HbA(1) c by 11% (P<0.05) in ZDF rats. Also, melatonin lowered insulinemia by 15.9% (P<0.05) and HOMA-IR by 31% (P<0.01) and increased HOMA1-%B by 14.4% (P<0.05). In addition, melatonin decreased hyperleptinemia by 34% (P<0.001) and raised hypoadiponectinemia by 40% (P<0.001) in ZDF rats. Moreover, melatonin reduced serum free fatty acid levels by 13.5% (P<0.05). These data demonstrate that oral melatonin administration ameliorates glucose homeostasis in young ZDF rats by improving both insulin action and β-cell function. These observations have implications on melatonin's possible use as a new pharmacologic therapy for improving glucose homeostasis and of obesity-related T2DM, in young subjects.     

Interventions to improve β-cell mass and function

Diabetes mellitus (T2DM) has become an epidemiologically important disease worldwide and is also becoming a great matter of concern due to the effects associated with it like: high morbidity, elevated health care cost and shortened life span. T2DM is a chronic metabolic disease characterized by insulin resistance as well as β-cell dysfunction. It is widely accepted that in the face of insulin resistance, euglycemia can be maintained by increase in pancreatic β-cell mass and insulin secretion. This compensation is largely due to enhanced secretion of insulin by the β-cell mass, which is present initially, and thereby subsequent increases in β-cell mass provide additional insulin secretion. However, the mechanism by which β-cell anatomical plasticity and functional plasticity for insulin secretion is coordinated and executed in different physiological and pathophysiological states is complex and has been poorly understood. As the incidence of T2DM continues to increase at an alarming rate, it is becoming imperative to shift the research focus towards the β-cell physiology where identification of novel pathways that influence the β-cell proliferation and/or contribute to increase insulin secretion has the potential to lead to new therapies for preventing or delaying onset of disease.     

Type 2 diabetes mellitus in children and adolescents

Over the last decade, there has been an alarming increase of Type 2 diabetes mellitus (T2DM) in youths, concomitant with the rise of obesity in this age group. T2DM is a progressive disease with a gradual increase in insulin resistance associated later with a decline in insulin secretion with fasting hyperglycemia. Prevalence of T2DM in children is mostly linked to some risk factors: obesity and sedentary lifestyle, puberty, membership of ethnic minorities, features of insulin resistance, family history of T2DM, female gender and perinatal factors. Prevention is essential and can be considered a public health approach directed to the general population. Treatment of T2DM in youth is complex and based on different strategies: diet, exercise and pharmacotherapy. An appropriated intervention program must be started early, in order to prevent or retard the progression of the disease and associated comorbidities.     

Secondary failure to oral hypoglycaemic agents in non-obese patients with non-insulin-dependent diabetes is related to reduced insulin release

The frequency of secondary failure to oral hypoglycaemic agents (OHA) in patients with non-insulin dependent diabetes (NIDDM) is still unknown, despite more than 30 years of use of OHA. The term secondary failure should be limited to patients who, despite maximal dosages of OHA and despite full compliance with diet and therapy, are no longer controlled and require insulin to obtain an acceptable glucose metabolism. We evaluated 248 out-patients, either on OHA, or on insulin because of poor metabolic control with OHA, in order to assess duration of treatment with OHA since diagnosis, by means of actuarial curves (Mantel-Cox test). Patients with low relative body weight (RBW less than or equal to 100) experienced secondary failure earlier and more often than obese patients (RBW greater than 120) or overweight (RBW 101-120) patients. In 66 of the above out-patients, 33 OHA-treated and 33 insulin-treated, matched for age at onset and duration of disease, islet-cell-antibodies (ICA) and C-peptide release at fasting, 6 min after i.v. glucagon and post prandially were evaluated. Only among lean and overweight patients, was C-peptide release significantly lower in insulin-treated than in OHA-treated patients; differences disappeared in obese patients. ICA were found in only 7 patients (10.6%). HLA phenotype was different from that of healthy blood donors for the loci HLA B5, B13, CW4, with no differences between OHA-treated and insulin-treated patients. These data indicate that secondary failure is more frequent in lean patients with NIDDM, and is related to reduced insulin release.     

Etiology of Insulin Resistance in Youth with Type 2 Diabetes

Type 2 diabetes (T2DM), historically an adult disease, is now increasingly prevalent in obese youth. Poor diet and increased sedentary behavior contribute to the increasing rates of obesity in youth, yet not all obese children develop T2DM. In general, T2DM is characterized by both insulin resistance (IR) and pancreatic beta-cell insufficiency. In children, IR is related to elevated body mass index (BMI) and pubertal hormones, along with abnormal fat partitioning, elevated free fatty acids, inflammation, and/or mitochondrial dysfunction. Hyperglycemia and T2DM develop when the pancreas cannot match the increased insulin demands resulting from IR. Unique to youth, IR varies with stage of pubertal development, and some children may have resolution of hyperglycemia post-puberty once the IR of puberty resolves. Further understanding of IR, the progression to T2DM in youth, and later outcomes as adults will help direct future therapies and interventions for youth at risk.