Current Diabetes Reviews - Volume 4, Issue 2, 2008

Contrary to its historical epithet as a lifestyle disorder, obesity is now widely recognized as having a neurobiological basis. This progress is due to our knowledge not only about energy homoeostatic pathways within the central nervous system (CNS), but also about the role of peripheral peptide hormones acting upon the CNS. These hormones include long-term adiposity signals, such as leptin, that inform the CNS primarily of changes in the body's overall fat and energy reserves, and short-term signals such as amylin, peptide YY (PYY) and ghrelin, that primarily reflect changes in the immediate nutritive state (energy intake). The limited weight loss effects achieved with current monotherapy approaches to obesity have been attributed, at least in part, to the redundancies and potent counter-regulatory responses within the neurohormonal feedback loop governing energy balance. Recently, we reported that combinations of amylin, leptin and PYY3-36 resulted in additive and/or synergistic interactions and caused marked weight loss in the diet-induced obese rat model, which to date has reasonably predicted the clinical effects of several hormones in obese humans. If confirmed in ongoing translational clinical research studies, these findings may provide a physiological rationale for a novel, integrated neurohormonal approach to pharmacotherapy for obesity.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Advanced glycation end products [AGEs] seem to play an important role for the development and/or progression of CVD mainly through induction of oxidative stress and inflammation. AGEs are a heterogenous group of molecules formed by the nonenzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. Recent studies suggest that in addition to those endogenously formed, diet constitutes an important exogenous source of AGEs. Diet-derived AGEs contribute to the whole body AGE pool and the AGE-related pathology. Recent in vitro and in vivo studies revealed significant correlations between diet-derived AGEs and several risk factors and/or markers of CVD, suggesting the dietary AGEs restriction as a promising therapeutic intervention.

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive β-cell dysfunction as well as abnormalities in pancreatic α-cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in β-cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon-like peptide-1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Type 1 diabetes (T1D) is an autoimmune disease resulting from pancreatic beta-cells destruction, often appearing on a genetic ground susceptibility under the influence of one or more environmental factors. Multiplex families studies, using genetic markers allowed the identification of various genes, including HLA, insulin, SUMO-4 and CTLA-4 all being linked with different degrees to disease risk. The MIF gene was also suggested, although its role has yet to be established on family or twin studies. The difference in susceptibility among T1D patients suggest the development of the disease as resulting from the interaction between genetic and environmental factors. This review emphasizes the importance of identifying the genes that have a direct impact on the autoimmune process, while recalling the different strategies that are followed. The style of writing should appeal to those with strong interests in molecular biology with an equal balance of immunology and molecular epidemiology.

Objective: To evaluate the lipoprotein profiles, triglycerides and glycemia along with the abdominal fat to explore the risk factors associated with non-diabetic state to IGF, IGT and Type-2 diabetes in Canadian population. Methods: We examined 780 subjects using the ADA and WHO criteria to classify them into groups based on (1) normal glucose tolerance with FBS <6.0 and 2hBS <7.0 mmol/l), (2) IFG; FPG ≥6.1 mmol/l but 2hBS >7.8-11.1 mmol/l; (3) combined IFG/IGT (FPG ≥7.0 mmol/l and 2hBS >11.1 mmol/l). We compared the three groups for glycemia, insulin secretion and insulin sensitivity based on their WHR, abdominal and visceral fat measurements. Results: The subjects with higher 2 hrs glucose levels 5.2 for NGT vs. 9.1 for IGT and 13.4 mmol/l for NIDDM, p<0.001, apo C-III level (12.8 (DM) vs. 8.9 mg/dl (normal), p<0.001), waist to hip ratio (0.91 (IGT) vs. 0.89 (Normal), p<0.01) and abdominal fat and were found to be highly insulin resistant. Conclusions: The higher apolipoproteins levels, BMI and abdominal and visceral fat accompanied by poor glycemia were shown to be associated strongly with the metabolic abnormalities. These factors led to the worsening of insulin secretory dysfunction and insulin resistance and were strong predictors of diabetes. Abbreviations: 2hBS, 2-hour blood sugar, • FBS, fasting blood glucose, •NGT, normal glucose tolerance, • IFG, impaired fasting glucose, • IGT, impaired glucose tolerance, • MS, metabolic syndrome, • IR, insulin resistance • ISI, insulin sensitivity index • OGTT, oral glucose tolerance test • WHR, waist-to-hip ratio, • BMI, body mass index, • VFA, visceral fat area, • SFA, subcutaneous fat area, • WHO, World Health Organization.

In healthy individuals, the ability of the pancreatic islets to sense and respond appropriately to changes in plasma glucose levels maintains plasma glucose levels within a narrow range despite broad fluctuations in nutrient intake and variable “demand” for insulin imposed by changes in insulin sensitivity. This ability of the pancreatic islets is lost in type 2 diabetes (T2DM). For studies on the pathophysiology of T2DM, methods for analyzing islet function are therefore required. Many methods of varying degrees of complexity have been developed and used to measure pancreatic β-cell function in humans and to characterize the defects existing in patients with T2DM or precursors thereof (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]). Significant, although perhaps less progress has been made toward development of methods to characterize α-cell function. This work presents an overview of clinical measures of islet function, from simple static measures such as HOMA-β to the more complex dynamic measures such as those utilizing stepped hyperglycemic clamps and acute administration of arginine to obtain more detailed information regarding the interaction of glucose and non-glucose secretagogues. We emphazise the need for accurate measures of α-cell function, and we discuss the strengths and limitations of the various methods, highlighting the many aspects of both α- and β-cell function that become impaired during development of T2DM.

The incidence of Type 1 diabetes has been increasing at a rate too rapid to be due to changes in genetic risk. Instead changes in environmental factors are the likely culprit. The endoplasmic reticulum (ER) plays an important role in the production of newly synthesized proteins and interference with these processes leads to ER stress. The insulinproducing beta cells are particularly prone to ER stress as a result of their heavy engagement in insulin production. Increasing evidence suggests ER stress is central to initiation and progression of Type 1 diabetes. An early environmental exposure, such as toxins and viral infections, can impart a significant physiological load on beta cells to initiate abnormal processing of proinsulin, ER stress and insulin secretory defects. Release of altered proinsulin from the beta cells early in life may trigger autoimmunity in those with genetic susceptibility leading to cytokine-induced nitric oxide production and so exacerbating ER stress in beta cells, ultimately leading to apoptosis of beta cells and diabetes. Here we suggest that ER stress is an inherent cause of beta cell dysfunction and environmental factors, in particular dietary toxins derived from Streptomyces in infected root vegetables, can impart additional stress that aggravates beta cell death and progression to diabetes. Furthermore, we propose that the increasing incidence of Type 1 diabetes may be accounted for by increased dietary exposure to ER-stress-inducing Streptomyces toxins.