Current Diabetes Reviews - Volume 3, Issue 1, 2007

According to the International Diabetes Federation World Atlas the frequency of diabetes is increasing at an alarming rate, with 246 million people worldwide affected, and a projected figure of 380 million by 2025 if the current situation is not rectified. More than 90% of this epidemic is of type 2 diabetes, the causes relating in large part to ageing of the population, diet and obesity, and a sedentary lifestyle. This gives rise to enormous direct and indirect costs for healthcare systems, people with diabetes and their families, and society in general. At no time there has been a greater impetus for research in to the causes and treatment of diabetes and its complications. This issue contains several insightful reviews on aspects of diabetes and metabolic syndrome, and potential therapeutic intervention. Jay and Ren, and Stojanovska et al. examined the role of peroxisome proliferator-activated receptors (PPARs) in insulin resistance and type 2 diabetes, and review results of trials with PPAR agonists on diabetes management. Evidence for reducing the cardiovascular risks of diabetes is considered, particularly in terms of blood pressure control, effects on smooth muscle and endothelial function, and the anti-atherogenic effects of thiazolidinediones. Saraceni and Broderick review the potential benefits of exercise in diabetes, with a particular focus on data from animal models. They consider the actions of exercise to increase myocardial and skeletal muscle glucose homeostasis, increase insulin sensitivity, and improve autonomic nervous system control and vascular endothelium function. The glucagon-like peptide (GLP) signalling system is of current interest in treatment of type 2 diabetes. The review by Salvatore et al. give an overview of the incretin system and examines the therapeutic potential of GLP-1 and small molecule inhibitors of the enzymes that degrade this gut peptide. Fukui et al. consider effects of lowered endogenous androgen levels in men with type 2 diabetes on insulin resistance and atherosclerosis, and discuss the potential clinical implications and side effect profile of androgen replacement therapy in these patients. The renal complications of diabetes are addressed in two specialist reviews. Nordquist and Palm review the important effects of diabetes on renal medulla microcirculation and metabolism. The research that the normally low medullary oxygen tensions are further reduced in diabetes is likely to have great significance for total kidney function. The potential roles of glucose-driven mechanisms such as oxidative stress, polyol pathway activity, protein kinase C and advanced glycation are discussed. It is well established that the angiotensin converting enzyme (ACE) inhibition is renoprotective in diabetes. The review by Lely et al. examines evidence for genetic and environmental factors that increase ACE levels, their role in the pathogenesis of renal damage, and potential relevance to treatment of nephropathy. Capillary occlusion is an early sign of problems in non-proliferative diabetic retinopathy. Chibber and co workers review the evidence for leukocyte entrapment as a cause of capillary non-perfusion in man and experimental models. This is an area of great current interest. The review examines potential endothelial and leukocyte mechanisms, and the therapeutic potential of drug therapy to inhibit leukostasis. A particular novel target identified by these workers is the leukocyte adhesion molecule core 2 GlcNAc-T. These states of the art reviews in this issue of CDR were a pleasure to work with, and I hope readers will find them stimulating and highly informative.

Diabetic retinopathy is one of the most common diabetic complications, and is a major cause of new blindness in the working-age population of developed countries. Progression of vascular abnormalities, including the selective loss of pericytes, formation of acellular capillaries, thickening of the basement membrane, and increased vascular permeability characterizes early nonproliferative diabetic retinopathy (NPDR). Capillary occlusion, as shown on fluorescein angiograms, is also one of the earliest clinically recognizable lesion of NPDR. In response to capillary non-perfusion, there is dilation of neighbouring capillaries, leading to early blood-retinal barrier breakdown, capillary non-perfusion, and endothelial cell injury and death. The resulting ischemia leads to increased production of growth factors, and the development of proliferative diabetic retinopathy (PDR), which is characterized by growth of new vessels and potential severe and irreversible visual loss. The exact pathogenic mechanism by which capillary non-perfusion occurs is still unclear but growing evidence now suggests that increased leukocyte-endothelial cell adhesion and entrapment (retinal leukostasis) in retinal capillaries is an early event associated with areas of vascular non-perfusion and the development of diabetic retinopathy. The leukocytes in diabetic patients are less deformable more activated, and demonstrate increased adhesion to the vascular endothelium. This review summarizes the current literature on the role of leukocytes in the pathogenesis of capillary occlusion, and discusses the potential of leukostasis as a new promising target in the treatment of diabetic retinopathy.

Glucagon-like peptide-1 (GLP-1) may contribute to the decreased incretin effect characterizing type 2 diabetes. Multiple actions other than insulin secretion stimulation give to GLP-1 a highly desirable profile for an antidiabetic agent. To overcome the need for continuous infusion of the native compound, which is rapidly degraded by dimetyl peptidil peptidase-IV (DPP-IV), analogues with low affinity for this protease have been developed. A second major strategy is represented by DPP-IV inhibitors that act to increase endogenous GLP-1. On the basis of the promising results in clinical trials, the incretin-based therapy may offer an useful option for diabetes management.

Age-related decline in serum testosterone and dehydroepiandrosterone sulfate concentrations occur in men. Low concentrations of these endogenous androgens have been linked with insulin resistance, which is an important upstream driver for metabolic abnormalities such as hyperglycemia, hypertension, or hyperlipidemia, and increased cardiovascular risk. Moreover, men with diabetes have significantly less circulating androgen than nondiabetic men. Here, we summarize how androgen affects insulin resistance and atherosclerosis in men with type 2 diabetes. Low serum concentrations of endogenous androgens are associated with visceral fat accumulation. Androgen deprivation by castration to treat prostate cancer increases insulin resistance, while testosterone administration in type 2 diabetic men with androgen deficiency improves glucose homeostasis and decreases visceral fat, in addition to alleviating symptoms of androgen deficiency including erectile dysfunction. Androgen correlates inversely with severity of atherosclerosis and has beneficial effects upon vascular reactivity, inflammatory cytokine, adhesion molecules, insulin resistance, serum lipids, and hemostatic factors. Because men with type 2 diabetes have relative hypogonadism, testosterone supplementation could decrease both insulin resistance and atherosclerosis.

Type 2 diabetes mellitus, a global epidemic, is largely attributed to metabolic syndrome and its clustering of cardiovascular risk factors including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The two primary approaches to optimally control risk factors associated with metabolic syndrome are lifestyle changes and medications. Although many pharmacological targets have been identified, clinical management of cardiovascular risk factors associated with metabolic syndrome and type 2 diabetes is still dismal. Recent evidence suggests premises of the peroxisome proliferator-activated receptor (PPAR) ligands in the combat against type 2 diabetes and metabolic syndrome including obesity and insulin resistance. Three subtypes of the PPAR nuclear fatty acid receptors have been identified:α, β/δ and γ . PPARα is believed to participate in fatty acid uptake (β- and ω-oxidation) mainly in the liver and heart. PPARβ/δ is involved in fatty acid oxidation in muscle. PPARγ is highly expressed in fat to facilitate glucose and lipid uptake, stimulate glucose oxidation, decrease free fatty acid level and ameliorate insulin resistance. Synthetic ligands for PPARα and γsuch as fibric acid and thiazolidinediones have been used in patients with type 2 diabetes and pre-diabetic insulin resistance with significantly improved HbA(1c) and glucose levels. In addition, nonhypoglycemic effects may be elicited by PPAR agonists or dual agonists including improved lipid metabolism, blood pressure control and endothelial function, as well as suppressed atherosclerotic plaque formation and coagulation. However, issues of safety and clinical indication remain undetermined for use of PPAR agonists for the incidence of heart disease in metabolic syndrome and type 2 diabetes.

The renin-angiotensin aldosterone system (RAAS) is well-established to be involved in diabetic nephropathy. Several abnormalities in the RAAS have been described in diabetes mellitus, including an abnormal aldosterone to renin ratio, elevated angiotensin I-converting enzyme (ACE) levels, and altered angiotensin II sensitivity. Whereas the renoprotective properties of ACE-inhibition in diabetic nephropathy have been demonstrated more than a decade ago, somewhat surprisingly, the role of ACE-activity in the pathogenesis of diabetic nephropathy is not well established. This paper addresses the possible functional impact of genetic and environmental increased in ACE activity in the pathogenesis of diabetic renal damage, in the context of the various other abnormalities in the RAAS in diabetes. Human and experimental data on circulating and tissue ACE in diabetes are reviewed, as well as the associations of ACE with angiotensin I conversion, with pathophysiological responses, and with renal end organ damage. New data from our laboratory provide evidence for interaction between genetical regulation of ACE activity by the ACE (I/D) genotype and diabetes as an environmental factor. Moreover, for functional effects of the elevated ACE activity in terms of increased conversion of angiotensin I to angiotensin II. The effects of enhanced generation of angiotensin II are modulated by the angiotensin II-subtype I receptor (AT1R). Altered AT1R sensitivity has been reported in diabetes that may further modulate the eventual effects of elevated ACE. Epidemiological data on the association of genetically elevated ACE activity with diabetic nephropathy provide support for a pathogenetic role of elevated ACE activity in diabetic nephropathy. Together, the data suggest that differences in ACE expression and activity, resulting from both genetic and environmental factors and their interaction can modulate the pathogenesis of diabetic nephropathy. Unravelling the nature of this interaction, with focus on modifiable environmental factors, may help to ameliorate the risk for nephropathy in diabetes.

Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanisms mediating the negative influence of hyperglycemia on renal function are unclear, although several hypotheses have been postulated. Cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through polyol pathway and pentose phosphate shunt, formation of advanced glycation end-products and activation of protein kinase C and NADPH oxidase. However, the renal effects in vivo of each and every one of these mechanisms are less clear, although recent studies have shown several major alterations predominantly in the renal medulla as a result of sustained hyperglycemia. Already during normal conditions, the renal medulla has a remarkably low oxygen tension (PO2) and a high degree of non-oxygen dependent energy metabolism. Alterations in either blood perfusion or oxygen delivery to the medullary region will have significant effects on both regional metabolism and total kidney function. Recently, sustained hyperglycemia has been shown to induce a pronounced reduction in preferentially renal medullary PO2. This review will present the current knowledge of diabetes-induced alterations in renal medullary metabolism and function, but also discuss future targets for prevention of diabetic nephropathy.

The thiazolidinediones (TZDs) rosiglitazone (ROS) and pioglitazone (PIO) are insulin-sensitising agents widely used to treat patients with type 2 diabetes mellitus (T2DM). Thiazolidinediones significantly improve glycaemic control in diabetics by reduced fasting glucose, insulin and glycated haemoglobin and they delay the progression of insulin resistance/impaired glucose tolerance into T2DM. It is well recognized that adequate glycaemic control and subsequent amelioration of hyperinsulinaemia and hyperglycaemia can delay the onset of vascular complications. TZDs, however, also have a number of anti-atherogenic effects independent of their influences on glucose and insulin metabolism. They improve lipid profiles, lower blood pressure, have anti-inflammatory properties, improve endothelial function and increase large artery compliance in patients with type 2 diabetes mellitus. When compared to rosiglitazone, pioglitazone has more favourable effects on the lipid profiles of patients with T2DM. The disease preventive actions of TZDs may be the result of their agonistic effects on peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that regulate the expression of numerous genes and affect metabolism and vascular parameters. Thiazolidinediones, provide an effective treatment for populations with insulin resistance which is at high risk of developing cardiovascular disease. This paper discusses the differences between ROS and PIO and explores their antiatherogenic effects with particular focus on post-menopausal women with type 2 diabetes mellitus.

The experimental literature of the foregoing decade has furnished an assemblage of mechanisms explaining the metabolic perturbations and overall decline in cardiac performance implicated in the pathogenesis of diabetes mellitus. Particularly, the experimentally-induced diabetic rat model has been indispensable in the examination of diabetic cardiomyopathy, an entity distinctly separable from atherosclerosis, hypertension, coronary artery disease and valvular dysfunction, yet convincingly attributable to the increase in cardiac-associated mortality commonly observed in the diabetic patient. The widespread epidemic of diabetes mellitus in developed societies has elicited considerable attention and the role of exercise as an adjuvant therapy in diabetes management has been increasingly emphasized. However, the evidence endorsing the beneficial attributes of exercise in the diabetic state is indeterminate despite markedly observed increases in myocardial and skeletal muscle glucose homeostasis, endothelial and autonomic function, insulin sensitivity and amelioration of diabetes pathogenesis. As evidenced by review of the experimental literature, a mild to moderately intense exercise regime may be a reliably implicated insulin-sensitizing therapy for the experimentally-diabetic rat model as well as the human diabetic patient. Notably, the cardio-protective and metabolic benefits of aerobic exercise are seemingly more pronounced in those individuals most susceptible to diabetes progression.