Current Diabetes Reviews - Volume 4, Issue 1, 2008

The microvasculature is a key interface between blood and tissues and participates in numerous pathophysiological processes. The heterogeneity of microvascular endothelial cells derived from different organs, suggests that these cells have specialised functions at different anatomical sites. Pancreatic islet microcirculation exhibits distinctive features, with an islet capillary network showing five times higher density than the capillary network of the exocrine counterpart and high permeability. Moreover, the islet microvascular endothelial cells show about 10 times more fenestrations than those of the exocrine tissue. In an interdependent physical and functional relationship with β cells, islet endothelial cells are involved not only in the delivery of oxygen and nutrients to endocrine cells, but induce insulin gene expression during islet development, affect adult β cell function, promote β cell proliferation, and produce a number of vasoactive, angiogenic substances and growth factors. Specific markers of islet microvasculature are α-1 proteinase inhibitor and nephrin, a highly specific barrier protein with adhesion and signalling function. The islet microendothelium also appears to have a role in fine-tuning blood glucose sensing and regulation, and to behave as an active “gatekeeper” in the control of leukocyte recruitment into the islets, adopting an activated phenotype during autoimmune insulitis in type 1 diabetes. This dense vasculature is therefore likely to play a role in the physiology as well as in the disease of the pancreatic islets. In this review we will describe the phenotypic and functional characteristics of islet microendothelium and its possible involvement in type 1 and 2 diabetes, and islet revascularisation in transplantation settings.

Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD). Although the pathogenesis of DN is multifactorial, local inflammatory stress may result from both the metabolic and hemodynamic derangements observed in DN. Inflammatory markers such as Interleukin-18 and Tumor Necrosis Factor (TNF)-α are increased in the serum of patients with diabetes and DN. This occurs at a very early stage of disease, and correlates with the degree of albuminuria. Recent data suggest that standard pharmacologic interventions for DN, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists, may have anti-inflammatory properties that are independent of their hemodynamic effect. Although inflammation is traditionally thought of as a process resulting in macrophage infiltration, current scientific progress has lead to the novel idea that even cells distant from the blood stream, such as podocytes, can produce cytokines and can express molecules that are part of the co-stimulatory pathway. A strong translational research effort is currently aimed at defining the role of such molecules in cells other than lymphocytes and macrophages. Experimental animal models have recently provided evidence that some acute phase markers of inflammation such as intracellular cell adhesion molecule-1 (ICAM-1), TNF-alpha and Monocytes Chemoattractant Protein-1 (MCP-1) may have a causative role in the development of DN. Here, we review the current evidence supporting the role of inflammation in the early phases of clinical and experimental DN. A complete understanding of inflammatory pathways activated in DN may lead to the discovery of earlier and more reliable markers of DN than albuminuria and the identification of novel therapeutic targets.

Insulin release from pancreatic islet β-cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, a novel acylated 28-amino acid peptide isolated from stomach, is the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in stomach. Ghrelin is a potent stimulator of GH release and feeding as well as exhibiting positive cardiovascular effects. In relation to the glucose metabolism, initial studies indicated that low plasma ghrelin levels are associated with elevated fasting insulin levels, insulin resistance, and obesity. It has recently been demonstrated that ghrelin suppresses glucose-induced insulin release via Gαi2 subtype of GTP-binding proteins and delayed outward K+ (Kv) channels, representing a novel signaling mechanism, and that the ghrelin originating from islets regulates insulin release and thereby glycemia. Furthermore, elimination of ghrelin enhances insulin release to prevent or ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the physiological roles of ghrelin in regulating insulin release and glycemia, the insulinostatic mechanisms of ghrelin in islet β-cells, and the potential of ghrelin-GHS-R system as the therapeutic target to treat type 2 diabetes.

Diabetes mellitus (DM) is an established risk factor predisposing to male erectile dysfunction (ED), and it has been calculated that more than 50% of diabetic men develop ED within ten years of diagnosis. It has been suggested that the risk of ED increases with metabolic indices of inadequate diabetes control and with a longer duration of disease. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the pathogenesis of diabetic ED. Coronary and peripheral atherosclerosis are frequent complications of DM and diabetic patients have an increased risk of future cardiovascular events comparable to that of patients with coronary artery disease. The prolonged half-life of tadalafil (17.5 hours) and its prolonged period of responsiveness (36- hours), constitute an ideal pharmacokinetic profile for once-a-day dosing and makes it an ideal candidate for rehabilitative therapy in DM patients, whereas a poor compliance with on-demand schedule is reported. The aim of this review will be to give an update on clinical overall efficacy and safety of tadalafil trials, i.e in diabetic population, and finally provide evidences for redefining the role of chronic treatment in selected group of patients.

In the present review, we discuss the sorting mechanism of peptide hormones and the biogenesis mechanism of secretory granules in view of the significance of the high cholesterol composition of secretory granule membranes. Peptide hormones and graninfamily proteins are sorted to immature budding granules at the trans-Golgi network in neuroendocrine cells. Two models have been proposed for granule protein sorting: “aggregation-mediated sorting” and “receptor-mediated sorting”. In the aggregation-mediated sorting model, granin-family proteins such as chromogranin A and B form aggregates with peptide hormones in weakly acidic, high calcium milieu of the budding granules. Chromogranins have a disulfide loop at their N-terminal at which they bind to the budding granular membrane, and bring hormones to the granules. In the receptor-mediated sorting model, carboxypeptidase E and/or secretogranin III function as a sorting receptor for peptide hormones. They bind peptide hormones, such as proopiomelanocortin, and have a high-cholesterolbinding domain. Since secretory granule membranes contain high levels of cholesterol, peptide hormones are brought to the secretory granules by these receptors. Although the two models have been conflicting, we suggest that both are cooperative and compensating each other for the sorting of peptide hormones and the biogenesis of secretory granules.

Microalbuminuria is the earliest detectable clinical abnormality in diabetic glomerulopathy. On a molecular level, metabolic pathways activated by hyperglycemia, glycated proteins, hemodynamic factors, and oxidative stress are key players in the genesis of diabetic kidney disease. A variety of growth factors and cytokines are then induced through complex signal transduction pathways. Transforming growth factor-beta 1 (TGF-β1) has emerged as an important downstream mediator for the development of renal hypertrophy and the accumulation of mesangial extracellular matrix components, but there is limited evidence to support its role in the development of albuminuria. The loss of proteoglycans in the glomerular basement membrane (GBM) has been recently questioned as causative of the albuminuria, and current research has focused on the podocyte as a central target for the effects of the metabolic milieu in the development and progression of diabetic albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is increased in diabetic kidney disease, is perhaps a major mediator of the increased protein filtration. Decreased podocyte number and/or density as a result of apoptosis or detachment, GBM thickening with altered matrix composition, and a reduction in nephrin protein in the slit diaphragm with podocyte foot process effacement, all comprise the principal features of diabetic podocytopathy that clinically manifests as albuminuria and proteinuria. Many of these events are mediated by angiotensin II whose local concentration is stimulated by high glucose, mechanical stretch, and proteinuria itself. Angiotensin II in turn stimulates podocyte-derived VEGF, suppresses nephrin expression, and induces TGF-β1 leading to podocyte apoptosis and fostering the development of glomerulosclerosis. Proteinuria can then induce in tubular cells a genetic program leading to tubulointerstitial inflammation, fibrosis and tubular atrophy. Besides direct effects of albuminuria on tubular cells, pathophysiological changes in the ultrafiltration barrier lead to an increased tubular filtration of various growth factors (TGF-β1, insulin-like growth factor I) that may further alter the function of tubular cells. Moreover, angiotensin II also stimulates uptake of ultrafiltered proteins into tubular cells and enhances the production of proinflammatory and profibrotic cytokines within the cells. Migration of macrophages and other inflammatory cells into the tubulointerstitium occurs. Increased synthesis and decreased turnover of extracellular matrix proteins in tubular cells and interstitial fibroblasts contribute to interstitial fibrosis. In addition, under locally high concentrations of angiotensin II and TGF-β1, tubular cells may change their phenotype and become fibroblasts by a process called epithelial to mesenchymal transition (EMT) which contributes to interstitial fibrosis and tubular atrophy because of vanishing epithelia cells. An alternative explanation for the development of albuminuria in diabetic nephropathy that involves primarily an abnormality in tubular handling of ultrafiltered proteins has also been suggested, but these changes are not necessarily exclusive of the altered properties of glomerular ultrafiltration barrier.

Diabetes Mellitus (DM), a state of chronic hyperglycemia, is a major cause of serious micro and macrovascular diseases, affecting, therefore, nearly every system in the body. Growing evidence indicates that oxidative stress is increased in diabetes due to overproduction of reactive oxygen species (ROS) and decreased efficiency of antioxidant defences, a process that starts very early and worsens over the course of the disease. During the development of diabetes, oxidation of lipids, proteins and DNA increase with time. Mitochondrial DNA mutations have also been reported in diabetic tissues, suggesting oxidative stress-related mitochondrial damage. Diabetes- related oxidative stress may also be the trigger for many alterations on sexual function, which can also include decreased testicular mitochondrial function. Although sexual disorders have been extensively studied in diabetic men, possible changes in the sexual function of diabetic women have only recently received attention. The prevalence of sexual dysfunction in diabetic men approaches 50%, whereas in diabetic women it seems to be slightly lower. Testicular dysfunction, impotence, decreased fertility potential and retrograde ejaculations are conditions that have been described in diabetic males. Diabetes is also the most common cause of erectile dysfunction in men. Poor semen quality has also been reported in diabetic men, including decreased sperm motility and concentration, abnormal morphology and increased seminal plasma abnormalities. In addition, diabetic men may have decreased serum testosterone due to impaired Leydig cell function. Among diabetic women neuropathy, vascular impairment and psychological complaints have been implicated in the pathogenesis of decreased libido, low arousability, decreased vaginal lubrication, orgasmic dysfunction, and dyspareunia. An association between the production of excess radical oxygen species and disturbed embryogenesis in diabetic pregnancies has also been suggested. In fact, maternal diabetes during pregnancy is associated with an increased risk of complications in the offspring, such as altered fetal growth, polyhydramnios, fetal loss and congenital malformations. In addition, hypocalemia and reduced bone mineral content are found in neonates of diabetic mothers. Abnormalities in gametogenesis and sexual function have also been documented in animal models for both types of Diabetes, which thus constitute an important research tool to both study the effects of the disease, and to test novel therapeutical interventions. Because sexuality and fertility are important aspects in the lives of individuals and couples, and considering that over 124 million individuals worldwide suffer from Diabetes, this review highlights the impact of Diabetes and associated oxidative stress on sexual function.

The prevalence of diabetes and its complications is increasing worldwide. Among the microvascular complications, diabetic nephropathy is the most frequent cause of end-stage renal disease. Although angiotensin-converting-enzyme inhibitors have been cited as the first line of therapy for the management of microalbuminuria, the rate of remission from microalbuminuria to normoalbuminuria has been lower than the expected. Furthermore, due to the elevated frequency of side effects of the rennin-angiotensin blockers new approaches for the treatment of microalbuminuria are needed. Pentoxifylline, a xanthine derivate drug with hemorheologic properties and primarily indicated for the therapy of disturbances of blood fluidity, is also an antagonist of adenosine 2 receptors and have antiinflammatory and immunomodulatory effects, properties that promote beneficial changes in the blood flow conditions and kidney function. Current evidence shows that the short-term use of pentoxifylline has low side-effects, reduces both proteinuria and microalbuminuria in subjects with diabetes, and is as effective as captopril in the reduction of microalbuminuria in non-hypertensive type 2 diabetic patients. Although this data suggests that pentoxifylline could be useful for preventing the development of end-stage renal disease is necessary to conduct long-term studies to evaluate the role of pentoxifylline in the treatment of diabetic nephropathy and the prevention of chronic renal failure. In this article, we review the clinical evidence that show the efficacy of pentoxifylline in the management of microalbuminuria in diabetic patients.

Type 2 diabetes is reaching epidemic proportions throughout the world, which has major health implications as such patients have considerably increased risk of coronary heart disease (CHD). The renin-angiotensin-aldosterone system (RAAS) is involved in a wide range of adverse effects that contribute to the pathogenesis of CHD in diabetic patients, including vascular haemodynamic regulation, oxidative stress and hypertrophy of vascular cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. In diabetic patients ACE inhibitors and ARBs both effectively lower blood pressure, particularly in combination with low-dose thiazide diuretics, and may be considered first line therapies in the treatment of diabetic hypertension. Additionally they have important renoprotective actions independent of their blood pressure-lowering action, which is of particular benefit in diabetic patients, who are at increased risk of developing nephropathy. ARBs are generally well tolerated, but ACE inhibitor therapy is associated with some side effects such as cough and both may result in hyperkalaemia. Blockade of the RAAS with these agents appears to play an important role not only in protecting from renal disease, but it may also help to reduce morbidity and mortality from certain vascular diseases in diabetic patients.