Pathophysiology of type 2 diabetes

Type 2 diabetes mellitus is a heterogeneous syndrome characterized by abnormalities in carbohydrate and fat metabolism. The causes of type 2 diabetes are multi-factorial and include both genetic and environmental elements that affect beta-cell function and tissue (muscle, liver, adipose tissue, pancreas) insulin sensitivity. Although there is considerable debate as to the relative contributions of beta-cell dysfunction and reduced insulin sensitivity to the pathogenesis of diabetes, it is generally agreed that both these factors play important roles. However, the mechanisms controlling the interplay of these two impairments are unclear. A number of factors have been suggested as possibly linking insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes. A majority of individuals suffering from type 2 diabetes are obese, with central visceral adiposity. Therefore, the adipose tissue should play a crucial role in the pathogenesis of type 2 diabetes. Although the predominant paradigm used to explain this link is the portal/visceral hypothesis giving a key role in elevated non-esterified fatty acid concentrations, two new emerging paradigms are the ectopic fat storage syndrome (deposition of triglycerides in muscle, liver and pancreatic cells) and the adipose tissue as endocrine organ hypothesis (secretion of various adipocytokins, i.e. leptin, TNF-alpha, resistin, adiponectin, implicated in insulin resistance and possibly beta-cell dysfunction). These two paradigms constitute the framework for the study of the interplay between insulin resistance and beta-cell dysfunction in type 2 diabetes as well as between our obesogenic environment and diabetes risk in the next decade.     

The role of beta-cell dysfunction in the cardiometabolic syndrome

The regulation of blood glucose levels involves a finely tuned relationship between insulin sensitivity, hepatic glucose output, and production of insulin. The cardiometabolic syndrome includes in its definition criteria a disturbance of normal glucose tolerance and implies development of both insulin resistance and beta-cell dysfunction. There is now abundant evidence pointing toward a central role of dysregulation of the beta-cell function and mass in the development of impaired glucose tolerance. Mechanisms implicated in beta-cell dysfunction include genetic abnormalities, prenatal and early postnatal insults, and environmental events along with obesity, dyslipidemia-lipotoxicity, glucotoxicity, oxidative stress, chronic low-grade inflammation, amyloid deposition, and activation of the local renin-angiotensin system. Novel therapeutic characteristics of known medications such as metformin, thiazolidinediones, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and novel medications such as exendin-4 promise encouraging possibilities to battle against the cardiometabolic syndrome and the future development of cardiovascular disease.     

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.     

Serum insulin, insulin resistance, p-cell dysfunction, and gallstone disease among type 2 diabetics in Chinese population： A community-based study in Kinmen, Taiwan

AIM: To explore the association of serum insulin, insulin resistance, and beta-cell dysfunction with gallstone disease (GSD) in type 2 diabetics. METHODS: We used a community-based study conducted between 1991 and 1993 in Kinmen, Taiwan to identify type 2 diabetics. A screening program for GSD was performed in 2001 by a panel of specialists who employed real-time ultrasound sonography to examine the abdominal region after the patient had fasted for at least 8 h. Screening was conducted in 2001 on 848 patients diagnosed with type 2 diabetes. The HOMA method was used to compare the profile differences for insulin resistance (HOMA IR) and beta-cell dysfunction (HOMA beta-cell). RESULTS: We studied 440 type 2 diabetics who attended sonography check-ups. After excluding eight insulin-treated diabetics, the prevalence of GSD among the remaining 432 was 13.9% (26/187) among males and 14.7% (36/245) among females. After adjustment for other GSD-associated risk factors in addition to age and obesity, GSD risk increased among females with levels of serum insulin [4(th) vs 1(st) quartile odds ratios (OR) = 4.46 (95%CI: 1.71-11.66)] and HOMA IR [4(th) vs 1(st) quartile OR = 4.46 (95%CI: 1.71-11.66)]. Better HOMA beta-cell function was significantly related to decreased risk of GSD [4(th) vs 1(st) quartile OR = 0.16 (95%CI: 0.03-1.70)]. Among males, age and central obesity were the most significant risk factors for GSD. No association of GSD with serum insulin, HOMA IR, and HOMA beta-cell was observed among males. CONCLUSION: Serum insulin, insulin resistance, and beta-cell dysfunction are risk factors for GSD in females, but not males with type 2 diabetes.     

糖尿病前期人群的特点及演变

本研究对北京地区中老年人群共2344例进行流行病学调查,行75 g口服葡萄糖耐量试验,并进行随访研究.分析显示单纯空腹血糖受损者主要是肝脏胰岛素抵抗和基础状态的胰岛β细胞功能受损;单纯糖耐量减低者的肌肉胰岛素抵抗较重,糖负荷后胰岛β细胞功能受损较重;糖尿病前期阶段,全天平均血糖,日内、日间血糖漂移幅度较正常人增加;糖调节受损与胰岛β细胞功能及胰岛素抵抗的改善具有一致性;基线时合并的代谢异常项目越少,代谢异常改善越明显,对于糖调节受损逆转并维持正常血糖越有益;对糖调节受损人群进行综合强化干预治疗可显著降低糖尿病发生率,且疗效优于国内外单药干预研究;腰围及收缩压的增加、胰岛β细胞功能的恶化是糖调节受损进展为糖尿病的重要影响因素.     

The in vivo regulation of pulsatile insulin secretion

The presence of oscillations in peripheral insulin concentrations has sparked a number of studies evaluating the impact of the insulin release pattern on the action of insulin on target organs. These have convincingly shown that equal amounts of insulin presented to target organs have improved action when delivered in a pulsatile manner. In addition, impaired (not absent) pulsatility of insulin secretion has been demonstrated in Type II (non-insulin-dependent) diabetes mellitus, suggesting a possible mechanism to explain impaired insulin action in Type II diabetes. Whereas the regulation of overall insulin secretion has been described in detail, the mechanisms by which this regulation affects the pulsatile insulin secretory pattern, and the relative and absolute contribution of changes in the characteristics of pulsatile insulin release have not been reviewed previously. This review will focus on the importance of the secretory bursts to overall insulin release, and on how insulin secretion is adjusted by changes in these secretory bursts. Detection and quantification of secretory bursts depend on methods, and the methodology involved in studies dealing with pulsatile insulin secretion is described. Finally, data suggest that impaired pulsatile insulin secretion is an early marker for beta-cell dysfunction in Type II diabetes, and the role of early detection of impaired pulsatility to predict diabetes or to examine mechanisms to cause beta-cell dysfunction is mentioned. [Diabetologia (2002) 45: 3–20] Received: 9 November 2000 and in revised form: 26 July 2001     

Crucial role of insulin receptor substrate-2 in compensatory beta-cell hyperplasia in response to high fat diet-induced insulin resistance

In type 2 diabetes, there is a defect in the regulation of functional beta-cell mass to overcome high-fat (HF) diet-induced insulin resistance. Many signals and pathways have been implicated in beta-cell function, proliferation and apoptosis. The co-ordinated regulation of functional beta-cell mass by insulin signalling and glucose metabolism under HF diet-induced insulin-resistant conditions is discussed in this article. Insulin receptor substrate (IRS)-2 is one of the two major substrates for the insulin signalling. Interestingly, IRS-2 is involved in the regulation of beta-cell proliferation, as has been demonstrated using knockout mice models. On the other hand, in an animal model for human type 2 diabetes with impaired insulin secretion because of insufficiency of glucose metabolism, decreased beta-cell proliferation was observed in mice with beta-cell-specific glucokinase haploinsufficiency (Gck(+/) (-)) fed a HF diet without upregulation of IRS-2 in beta-cells, which was reversed by overexpression of IRS-2 in beta-cells. As to the mechanism underlying the upregulation of IRS-2 in beta-cells, glucose metabolism plays an important role independently of insulin, and phosphorylation of cAMP response element-binding protein triggered by calcium-dependent signalling is the critical pathway. Downstream from insulin signalling via IRS-2 in beta-cells, a reduction in FoxO1 nuclear exclusion contributes to the insufficient proliferative response of beta-cells to insulin resistance. These findings suggest that IRS-2 is critical for beta-cell hyperplasia in response to HF diet-induced insulin resistance.     

Involvement of oxidative stress and the JNK pathway in glucose toxicity

The hallmark of type 2 diabetes is pancreatic beta-cell dysfunction and insulin resistance. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance becomes aggravated. Such phenomena are collectively called "glucose toxicity". Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in "glucose toxicity". Activation of the JNK pathway suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Consequently, the JNK pathway plays a crucial role in the progression of pancreatic beta-cell dysfunction and insulin resistance and thus could be a potential therapeutic target for the "glucose toxicity" found in diabetes.     

Serum adiponectin is associated with fasting serum C-peptide in non-obese diabetic patients

Circulating adiponectin (ADP) level in diabetic patients was mainly studied from a viewpoint of insulin action, with little being known about the regulation by pancreatic beta-cell function. We thus investigated the relationship between the serum ADP concentration and pancreatic beta-cell function in non-obese [body mass index (BMI) <30 kg/m(2)] diabetic patients. Serum ADP was measured in 239 type 2 diabetic patients, 61 type 1 diabetic patients and 159 non-obese and non-diabetic subjects with enzyme-linked immunosorbent assay. Serum ADP was analyzed separately by gender. In both males and females, the ADP level increased in conjugation with beta-cell dysfunction, estimated by fasting serum C-peptide, and showed marked increase in type 1 diabetic patients. Multivariate analysis in type 2 diabetic patients showed that the fasting serum C-peptide was extracted as an independent and significantly negative modulator for serum ADP in addition to BMI. The ADP level was not associated with the daily dose of injected insulin in the multivariate analysis using insulin treated patients with types 1 and 2 diabetes. These results indicate that pancreatic beta-cell function is one of a significant negative modulator for the circulating ADP level in non-obese diabetic patients and support the presence of an adipoinsular axis.