Programmed disorders of β‐cell development and function as one cause for type 2 diabetes? The GK rat paradigm

Now that the reduction in beta-mass has been clearly established in humans with type 2 diabetes mellitus (T2DM) 1-4, the debate focuses on the possible mechanisms responsible for decreased beta-cell number and impaired beta-cell function and their multifactorial etiology. Appropriate inbred rodent models are essential tools for identification of genes and environmental factors that increase the risk of abnormal beta-cell function and of T2DM. The information available in the Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous T2DM, are reviewed in such a perspective. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of three pathogenic players: (1) several independent loci containing genes causing impaired insulin secretion; (2) gestational metabolic impairment inducing a programming of endocrine pancreas (decreased beta-cell neogenesis) which is transmitted to the next generation; and (3) secondary (acquired) loss of beta-cell differentiation due to chronic exposure to hyperglycemia (glucotoxicity). An important message is that the 'heritable' determinants of T2DM are not simply dependant on genetic factors, but probably involve transgenerational epigenetic responses.     

Pancreatic beta-cell mass in European subjects with type 2 diabetes

Decreases in both beta-cell function and number can contribute to insulin deficiency in type 2 diabetes. Here, we quantified the beta-cell mass in pancreas obtained at autopsy of 57 type 2 diabetic (T2D) and 52 non-diabetic subjects of European origin. Sections from the body and tail were immunostained for insulin. The beta-cell mass was calculated from the volume density of beta-cells (measured by point-counting methods) and the weight of the pancreas. The pancreatic insulin concentration was measured in some of the subjects. beta-cell mass increased only slightly with body mass index (BMI). After matching for BMI, the beta-cell mass was 41% (BMI < 25) and 38% (BMI 26-40) lower in T2D compared with non-diabetic subjects, and neither gender nor type of treatment influenced these differences. beta-cell mass did not correlate with age at diagnosis but decreased with duration of clinical diabetes (24 and 54% lower than controls in subjects with <5 and >15 years of overt diabetes respectively). Pancreatic insulin concentration was 30% lower in patients. In conclusion, the average beta-cell mass is about 39% lower in T2D subjects compared with matched controls. Its decrease with duration of the disease could be a consequence of diabetes that, with further impairment of insulin secretion, contributes to the progressive deterioration of glucose homeostasis. We do not believe that the small difference in beta-cell mass observed within 5 years of onset could cause diabetes in the absence of beta-cell dysfunction.     

Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence

Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.     

Anatomical versus functional beta-cell mass in experimental diabetes

The ability of pancreatic beta-cell mass to vary according to insulin requirements is an important component of optimal long-term control of glucose homeostasis. It is generally assumed that alteration of this property largely contributes to the impairment of insulin secretion in type 2 diabetes. However, data in humans are scarce and it is impossible to correlate beta-cell mass and function with the various stages of the disease. Thus, the importance of animal models is obvious. In rodents, increased beta-cell mass associated with an increase in the function of individual beta-cells contributes to the adaptation of the insulin response to insulin resistance in late pregnancy and in obesity. A reduction in beta-cell mass always corresponds to an alteration in insulin secretory capacity of islet tissue (Zucker diabetic fatty and Goto-Kakisaki rats, db/db mice). During regenerative processes following experimental reduction of beta-cell mass [partial pancreatectomy, streptozocin (STZ) injection], beta-cell mass increase is not associated with a corresponding improvement of beta-cell function, thus indicating that regenerative beta-cells did not achieve functional maturity. The main lesson from experimental diabetes is therefore that beta-cell mass cannot always predict functional capacity of the beta-cell tissue and that the functional beta-cell mass rather than the anatomical beta-cell mass must be taken into account at all times.     

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.     

Glucose counterregulation in Type 2 diabetes mellitus.

Glucose counterregulatory failure and hypoglycaemia unawareness frequently complicate treatment of Type 1 diabetes mellitus, especially when aiming for intensive metabolic control. Since tight metabolic control reduces microvascular long-term complications in Type 2 diabetes mellitus, the integrity of glucose counterregulation in Type 2 diabetic patients is important. Using a Medline search, we identified 12 studies in which counterregulatory responses to insulin-induced hypoglycaemia were compared between Type 2 diabetic patients and appropriate controls. A review of these studies showed that some patients with Type 2 diabetes mellitus develop mild counterregulatory dysfunction and reduced awareness of insulin-induced hypoglycaemia. Some studies suggested an association between counterregulatory impairment and intensity of metabolic control. We speculate that the relatively low frequency of (severe) hypoglycaemic events in Type 2 diabetes may explain why glucose counterregulation remains unaffected in most patients. We hypothesize that residual beta-cell reserve and insulin resistance provide protection against severe hypoglycaemia and limit impaired counterregulation. Diabet. Med. 18, 519-527 (2001)     

Mechanisms of protective effects induced by blockade of the renin-angiotensin system: novel role of the pancreatic islet angiotensin-generating system in Type 2 diabetes.

Large clinical trials have shown that inhibition of the renin-angiotensin system (RAS) can delay and/or prevent the onset of Type 2 diabetes mellitus (T2DM) in high-risk individuals, such as those with hypertension or chronic heart failure. Moreover, a meta-analysis of these randomized clinical studies concluded that the mean weighted relative risk of development of T2DM was reduced by 25% in those patients treated with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors. In spite of these firm clinical data, the mechanistic pathways mediating the protective activity of RAS blockade have yet to be resolved. Of particular interest is the recently identified local pancreatic RAS and, perhaps more importantly, the finding that it is up-regulated in animal models of T2DM. This putative local RAS may regulate pancreatic islet blood flow, oxygen tension, and islet (pro)insulin biosynthesis. It might also mediate the generation of reactive oxygen species, thereby causing oxidative stress-induced pancreatic beta-cell apoptosis and fibrosis. Moreover, findings that RAS blockade improved beta-cell secretory function and cell mass in experimental animal models of Type 2 diabetes indicate that inhibition of RAS activation may play a pivotal role in protecting islet cell function, and furthermore may prevent the development of overt T2DM. Such data supporting the involvement of the local pancreatic RAS in islet function, as well as a causal relationship between RAS activation and T2DM, and RAS induced beta-cell dysfunction, mandate further investigation into the role of RAS in the pathogenesis of the progressive islet impairment observed in patients with T2DM.     

Does interference with the renin–angiotensin system protect against diabetes? Evidence and mechanisms

Agents interfering with the renin-angiotensin system (RAS) were consistently shown to lower the incidence of type 2 diabetes mellitus (T2DM), as compared to other antihypertensive drugs, in hypertensive high-risk populations. The mechanisms underlying this protective effect of RAS blockade using angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on glucose metabolism are not fully understood. In this article, we will review the evidence from randomized controlled trials and discuss the proposed mechanisms as to how RAS interference may delay the onset of T2DM. In particular, as T2DM is characterized by β-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in β-cell function and insulin sensitivity.     

Effects of glucocorticoids and exercise on pancreatic β-cell function and diabetes development

Peripheral insulin resistance and pancreatic β‐cell dysfunction are hallmark characteristics of type 2 diabetes mellitus (T2DM). Several contributing factors have been proposed to promote these two defects in individuals with T2DM, including physical inactivity and chronic exposure to various psychosocial factors that increase the body's exposure to glucocorticoids, the main stress hormones in humans. Initially, β‐cells have been shown to adapt to these stimuli, a phenomenon known as β‐cell ‘compensation’. However, long‐term exposure to these physiologic and psychological stressors induces islet failure. Interestingly, glucocorticoids stimulate β‐cell mass growth in parallel with promoting severe insulin resistance, the former being an important adaptive response to the latter. The direct relationship between glucocorticoids and β‐cell dysfunction remains a controversial area of research. Elevations in circulating and/or tissue specific glucocorticoids have been associated with the development of obesity and T2DM in human and rodent models; however, the progression from insulin resistance to overt T2DM is highly disputed with respect to the in vivo and in vitro effects of glucocorticoids. Paradoxically, both intermittent physical stress and regular exercise alleviate insulin resistance and help to preserve β‐cell mass, potentially by lowering glucocorticoid levels. Recent studies have begun to examine the mechanisms of intermittent and chronic glucocorticoid exposure and regular exercise in altering β‐cell function. This review highlights recent discoveries on the physiological regulation of β‐cells and diabetes development in conditions of elevated glucocorticoids, regular exercise and intermittent stress. Copyright © 2012 John Wiley & Sons, Ltd.     

Insulin secretion and action in different stages of glucose tolerance in Asian Indians.

AIMS: To evaluate the sequence of changes in insulin secretion and action in different stages of glucose tolerance and the effect of obesity on insulin profile in South Indian adults. Blood samples from 260 consecutive cases with no known history of diabetes were collected. Plasma insulin levels were measured during a 75-g oral glucose tolerance test. Insulin resistance (IR) was calculated, using the homeostasis model assessment (HOMA). An index of insulin secretion was derived as the ratio of incremental insulin at 30 min divided by 30 minute plasma glucose (delta I/G). RESULTS: Normoglycaemia was present in 164, impaired glucose tolerance (IGT) in 60 and diabetes in 36 subjects. Fasting and 2 h insulin secretion showed bell shaped curves with increasing plasma glucose. The peak values corresponded to the cut-off values used for the diagnosis of clinical diabetes. IR was higher in obese than in nonobese, nondiabetic subjects but the effect of obesity on IR was not found in subjects with diabetes. IGT was associated with higher IR, but not with evidence of a beta-cell defect. CONCLUSIONS: Evaluation of insulin resistance and beta-cell function in different stages of glucose tolerance indicate that insulin resistance is manifested in the early stage of glucose intolerance in South Indians, i.e. IGT. A beta-cell defect was mostly found in people with diabetes. The beta-cell defect is more common in diabetes among the nonobese.     

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。     

Cell therapy for type 2 diabetes: is it desirable and can we get it?

The functional mass of beta-cells is decreased in type 2 diabetes. Replacing missing beta-cells or triggering their regeneration may thus allow for improved treatment of type 2 diabetes, to the extent that this is combined with therapy for improved insulin sensitivity. Although progress has been made in deriving beta-cell-like cells from stem or precursor cells in vitro, these cannot yet be obtained in sufficient quantities or well enough differentiated to envisage their therapeutic use in beta-cell replacement therapy. Likewise, our very limited understanding of beta-cell regeneration in adult man does not yet allow for development of a valid strategy for kick-starting such a process in individuals with type 2 diabetes, whether by bona fide neogenesis or self-replication of existing beta-cells. Regardless of how beta-cell mass is restored in type 2 diabetes, it will be important to prevent any renewed decrease thereafter. Current understanding suggests that islet inflammation as well as signals from (insulin-resistant/inflamed) adipose tissue and skeletal muscle contribute towards decreased beta-cell mass in type 2 diabetes. It will likely be important to protect newly formed or implanted beta-cells from these negative influences to ensure their long-term survival.     

Associations between smoking and beta-cell function in a non-hypertensive and non-diabetic population. Skaraborg Hypertension and Diabetes Project.

AIMS: An increased risk for Type 2 diabetes in male and female smokers has been associated with insulin resistance. However, this might also be the result of an adverse effect on the beta-cell. The aim of the present study was to examine the association between smoking and beta-cell function. METHODS: A community-based, cross-sectional observation study. In 1994, a randomized age-stratified sample of men and women aged > or = 40 years in the city of Skara, Sweden, were invited to a survey of cardiovascular risk factors. In all, 1,109 subjects participated (80%). After the exclusion of subjects with known hypertension or diabetes mellitus, 874 subjects remained to explore. Samples were drawn after an overnight fast. Lifestyle (smoking, physical activity, alcohol consumption) was assessed using a questionnaire. Insulin resistance and insulin secretion were estimated using the homeostasis model assessment (HOMA). RESULTS: Cigarette smoking men (n = 101) had a lower HOMA beta-cell value (58.1), than never-smokers (n = 158, beta-cell value 90.1, P < 0.001). The difference remained with adjustments for age, body mass index, daily alcohol intake and physical exercise habits: 25.9 (95% confidence interval (CI) 9.7-38.8, P = 0.003). Correspondingly, in men the HOMA beta-cell value was lower in current smokers than in ex-smokers (difference 24.3, 95% CI 11.1-35.2, P < 0.001). In women, no significant difference appeared in beta-cell function vs. different smoking status. There was no association between smoking status and insulin resistance. CONCLUSIONS: At least in men, smoking may interfere with beta-cell function. The prevention of Type 2 diabetes should include strategies to stop smoking.     

Beta-cell preservation: a potential role for thiazolidinediones to improve clinical care in Type 2 diabetes.

Type 2 diabetes is caused by progressively increasing insulin resistance coupled with deteriorating beta-cell function, and there is a growing body of evidence to suggest that both of these defects precede hyperglycaemia by many years. Several studies have demonstrated the importance of maintaining beta-cell function in patients with Type 2 diabetes. This review explores parameters used to indicate beta-cell dysfunction, in Type 2 diabetes and in individuals with a predisposition to the disease. A genetic element undoubtedly underlies beta-cell dysfunction; however, a number of modifiable components are also associated with beta-cell deterioration, such as chronic hyperglycaemia and elevated free fatty acids. There is also evidence for a link between pro-inflammatory cytokines and impairment of insulin-signalling pathways in the beta-cell, and the potential role of islet amyloid deposition in beta-cell deterioration continues to be a subject for debate. The thiazolidinediones are a class of agents that have demonstrated clinical improvements in indices of beta-cell dysfunction and have the potential to improve beta-cell function. Data are accumulating to show that this therapeutic group offers a number of advantages over traditionally employed oral agents, and these data demonstrate the growing importance of thiazolidinediones in Type 2 diabetes management.     

Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus

In the natural history of type 2 diabetes (T2DM), individuals progress from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to overt T2DM and this progression has been demonstrated in populations of diverse ethnic background. It is widely recognised that both insulin resistance and beta-cell dysfunction are important in the pathogenesis of glucose intolerance. In populations with a high prevalence of T2DM, insulin resistance is well established long before the development of any impairment in glucose homeostasis, particularly in subjects with ectopic fat accumulation. However, as long as the beta cell is able to secrete sufficient amounts of insulin to offset the severity of insulin resistance, glucose tolerance remains normal. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of NGT and interruption of this crosstalk between the beta cell and peripheral tissues results in the progressive deterioration of glucose homeostasis. In this paper the role of beta-cell function is reviewed, as well as the role of ectopic fat accumulation and insulin resistance in the development of type 2 diabetes.     

Association between smoking, insulin resistance and beta-cell function in a North-western First Nation.

AIMS: Aboriginal peoples have a high prevalence of smoking and are at major risk for diabetes. The role of insulin resistance vs. compromised beta-cell function in the link between smoking and glycaemic disease is not clear. This study tested whether relations between insulin resistance and beta-cell function differ between current smokers, former smokers and non-smokers, and if having diabetes modifies smoking-related effects. METHODS: A community-based diabetes screening initiative was mounted for a North-western First Nation (Interior Salishan) in rural British Columbia, Canada. Respondents were on-reserve Aboriginal people (n=156), all adults 18+ years. Glycaemic status was determined by oral glucose tolerance test. Fasting values for glucose and insulin were used to estimate beta-cell function and insulin resistance by homeostasis model assessment (HOMA). Analyses adjusted for age, sex, alcohol intake, education, body mass index and physical activity. RESULTS: For normoglycaemic persons (n=119) current smokers relative to non-smokers had high beta-cell values [difference (95% confidence interval) 19.5 (17.1, 21.9)], while former smokers had low beta-cell values [difference -22.8 (-20.3, -25.3)] (P<0.0001). For diabetic persons (n=37) differences were of equivalent direction but greater magnitude (P<0.0001). Insulin resistance was for normoglycaemic persons highest for current smokers, and for diabetic persons lowest for current smokers (P=0.021). CONCLUSIONS: Former smoking is associated with low beta-cell function, and current smoking with high beta-cell function, independent of diabetes in the North-western First Nation surveyed. Associations between smoking and insulin resistance vary according to glycaemic status. Smoking may have diametric acute and post-cessation effects on beta-cell function and insulin resistance.     

Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 in hibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.