Current Diabetes Reviews - Volume 1, Issue 2, 2005

Type 2 diabetes mellitus and the closely related metabolic syndrome markedly increase the risk of cardiovascular disease a major contributor is the dyslipidemia. Recent studies and new national guidelines suggest these very high risk patients with cardiovascular disease achieve optional low density lipoprotein cholesterol (LDL-C) level of less than 70mg/dl. In addition there may be no threshold to begin therapeutic lifestyle change and pharmacologic therapy to reduce LDL-C by 30-40%. Although randomized controlled trials with statins indicate that LDL reduction clearly reduces cardiovascular risk in these patients, the typical dyslipidemia of type 2 diabetes mellitus is also characterized by low high density lipoprotein cholesterol (HDL-C) levels, increased triglyceride-rich lipoproteins and small dense LDL, as well as increased postprandial lipemia. The later lipoproteins increase non-HDL-C levels. In order to address these abnormalities it may be necessary to utilize combined approaches with a fibrate or nicotinic acid, or other agents with statins to help reduce risk beyond statins. In addition, supervised, therapeutic life-style change is often underutilized therapy in patients with established coronary artery disease. This review will focus on maximizing the treatment of dyslipidemia in type 2 diabetes and the metabolic syndrome and discuss the evidence based studies and new developments in the management in these very high risk patients.

There are four definitions of the metabolic syndrome that have been recommended by the World Health Organization (WHO), the European Group for Study of Insulin Resistance (EGIR), the National Cholesterol Education Program Expert Panel (NCEP), and the American Association of Clinical Endocrinologists (AACE) separately since 1998. The prevalence of the metabolic syndrome reported from different studies has varied widely, mainly because of differences in the definitions of the syndrome and in the characteristics of the populations studied. Prospective studies on the relationship between the metabolic syndrome and cardiovascular risk are still scanty. Results from several studies including a large population-based Italian study, the Framingham Offspring Study, the Botnia Study, the Kuopio Ischemic Heart Disease Study, the National Health and Nutrition Examination Survey II Mortality Study, the San Antonio Heart Study, and the DECODE study have shown that the presence of metabolic syndrome using different definitions is associated with a significantly increased risk of total mortality and cardiovascular morbidity and mortality.

The metabolic syndrome is known to increase cardiovascular morbidity and precede the development of type 2 diabetes. Even before the appearance of hyperglycemia, the components of the metabolic syndrome play a crucial role in the pathogenesis of the macrovascular complications. Thus, the recognition and treatment of the metabolic syndrome may be a strategy to prevent the most likely cause of death (i.e. cardiovascular events) in cases that eventually develop type 2 diabetes. In this review, controversial issues regarding the treatment of the two main components of the metabolic syndrome (i.e dyslipidemia and arterial hypertension) are discussed. Several disparities in the current NCEP-ATPIII recommendations, when applied to patients with the metabolic syndrome, are pointed out. In population-based studies, the number of individuals with the metabolic syndrome who would need LDL cholesterol lowering treatment following these guidelines is remarkably low compared to subjects belonging to the same risk strata (10 year risk 10-20%). Subjects with the metabolic syndrome do not fall into the same risk category, resulting in differing LDL-C targets. Also, the Framingham tables underestimate the cardiovascular risk associated with the metabolic syndrome; hence fewer cases qualify for drug therapy. In addition, LDL-C underestimates the number of atherogenic particles and is therefore not the ideal target for these patients. The selection of antihypertensive medication in the metabolic syndrome is also controversial. Thus, there is sufficient evidence for a review of the current management of the metabolic syndrome as part of a strategy to prevent the macrovascular complications in type 2 diabetes.

Altered platelet function reported in diabetic patients appears to be involved in the pathogenesis of diabetic vascular complications. However until recently, the role of platelets in progression of spontaneous atherosclerosis remained questionable. The original version of the response to injury hypothesis, where deposited platelets at denuded endothelium play key roles in the spontaneous development of atherosclerosis, has been modified dramatically over the past three decades; atherogenesis is now considered a chronic inflammatory process in which monocytes and T cells play central roles. Recently however, evidence has been accumulated that activated platelet contributes to progression of atherosclerosis in apo E-deficient mice. Activated platelets aggregate with leukocytes, release proinflammatory cytokines, chemokines and growth regulatory molecules, resulting in endothelial activation, leukocyte recruitment and altered smooth muscle cell function. Indeed, it has been shown that activated platelets, and their aggregates with leukocytes are found in the circulation of patients with coronary artery diseases. We have recently shown that circulating P-selectin positive platelets, which are higher in diabetic patients than non-diabetic subjects, are significantly and positively associated with carotid atherosclerosis in the large-scale human studies. This review will focus on altered platelet function in diabetic patients, and its implications in the progression of atherosclerosis.

Type 2 (non-insulin-dependent) diabetes mellitus afflicts millions of people worldwide and is one of the main causes of morbidity and mortality. Current therapeutic agents to treat Type 2 diabetes are insufficient and thus, newer approaches are desperately needed. Type 2 diabetes is manifested by progressive metabolic impairments in tissues such as skeletal muscle, adipose tissue and liver, such that these tissues become less responsive to insulin. Skeletal muscle is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions, and is a major site of insulin resistance in Type 2 diabetic patients. At the cellular level, glucose transport into skeletal muscle is the rate-limiting step for whole body glucose uptake and a primary site of insulin resistance in Type 2 diabetes. Thus, skeletal muscle is a key insulin target tissue that harbours intrinsic defects that impinges upon whole body glucose homeostasis. Here, we review the current knowledge of signalling events that regulate glucose transport in human skeletal muscle.

Diabetes and obesity are characterised by an impairment in mitochondrial function resulting in a decrease in glucose and fatty acid oxidation, respiration and an increase in intramuscular triglycerides (IMTG's) and insulin resistance. Peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1α (PGC-1α) is a nuclear transcriptional coactivator which regulates several important metabolic processes including, mitochondrial biogenesis, adaptive thermogenesis, respiration, insulin secretion and gluconeogenesis. In addition, PGC-1α has been shown to increase the percentage of oxidative type I muscle fibres, with the latter responsible for the majority of insulin stimulated glucose uptake. PGC-1α also co-activates PPAR's α, β/δ and γ which are important transcription factors of genes regulating lipid and glucose metabolism. Exercise causes mitochondrial biogenesis, improves skeletal muscle fatty acid oxidation capacity and insulin sensitivity, therefore making it an important intervention for the treatment of insulin resistance. The expression of PGC-1α mRNA is reduced in diabetic subjects, however, it is rapidly induced in response to interventions which signal alterations in metabolic requirements, such as exercise. Because of the important role of PGC-1α in the control of energy metabolism and insulin sensitivity, it is seen as a candidate factor in the etiology of type 2 diabetes and a drug target for its therapeutic treatment.

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are the most common microvascular complications of diabetes. DR is a leading cause of blindness, and DN is a major cause of end-stage renal diseases. Diabetic macular edema (DME) resulting from increased vascular permeability in the retina and retinal neovascularization (NV) represent two major pathological changes in DR and are the primary causes of vision loss in diabetic patients. Previous studies have shown that angiogenic factors such as vascular endothelial growth factor (VEGF) play a key role in the development of DME and retinal NV. Studies in recent years have demonstrated that a number of endogenous angiogenic inhibitors are present in the normal retina and counter act the effect of VEGF in the regulation of angiogenesis and vascular permeability. Decreased levels of angiogenic inhibitors in the vitreous and retina have been found in diabetic patients and diabetic animal models. The decreased levels of angiogenic inhibitors shift the balance between angiogenic factors and angiogenic inhibitors and consequently, lead to the development of DME and retinal NV. Recently, we have found that these angiogenic inhibitors are expressed at high levels in the normal kidney and are down-regulated in diabetes. Moreover, these inhibitors inhibit the activity of VEGF and TGF-β, two major pathogenic factors of DN. Therefore, decreased levels of these angiogenic inhibitors in diabetes may be associated with pathologies of DN. This review will summarize recent progress in these fields and therapeutic approaches to use angiogenic inhibitors for the treatment of diabetic complications.

Excessive cellular proliferation is a major contributor to the pathological changes associated with the secondary complications of diabetes. In particular, hyperglycemia (HG)-induced growth of vascular smooth muscle cells (VSMC) and glomerular mesangial cells (GMC) are characteristic features of the cardiovascular and renal complications of diabetes. VSMC and GMC respond to traditional growth factors, however in diabetes this occurs in the context of an environment, enriched in circulating vasoactive mediators and HG. For example, signaling via the angiotensin II (Ang II) pathway has been implicated in the pathogenesis of diabetic vascular disease. Recent findings indicate that HG and Ang II activate intracellular processes, including the polyol pathway and the generation of reactive oxygen species. These pathways activate the JAK (janus kinase)/STAT (signal transducers and activators of transcription) signaling cascades in both VSMC and GMC. Activation of the latter signaling cascade can stimulate excessive proliferation and growth of these cells, contributing to the accelerated atherosclerosis and nephropathy seen in the diabetic state. This review focuses on key factors in the diabetic microenvironment, in particular the interplay between HG, accumulation of advanced glycation end products and Ang II mediated signaling events both in vitro and in vivo.

Gestational diabetes mellitus (GDM) is carbohydrate intolerance with onset or first recognition in pregnancy. More often than not the intolerance abates between pregnancies but may recur. As well, up to 70% of affected women will manifest type 2 diabetes mellitus within 10 years thereafter. GDM is diagnosed with a glucose challenge at approximately 28 weeks' gestation though there is no universally accepted protocol for the procedure or for interpreting its results. Morbidity increases for both mother and foetus in GDM affected pregnancies. Maternal and early infant morbidity can be ameliorated by returning the maternal glucose economy to within healthy limits. Diet, exercise and, if needed, insulin, are used therapeutically to this end. Beneficial effects later in the affected infant's life are less well established. Thresholds and targets vary from place to place.

Basal bolus insulin dosing (BBD) may be defined as the physiological replacement of basal and bolus insulin to achieve near normal glycemia without hypoglycemia and loss of life quality. Normally, continuous and variable basal insulin release provides partial suppression of hepatic glucose production to maintain euglycemia during the fasting period. With meals, additional insulin is released in a biphasic pattern to further suppress hepatic glucose production and to increase glucose transport into muscle, fat and liver. Newer subcutaneous insulins for bolus and basal mimic near normal secretion. In addition, improvements in continuous subcutaneous insulin infusion pump features such as dual wave insulin delivery allow improved postprandial glycemia. Insulin dosing is done in a three step process. Firstly, the dosage is estimated based on formulas derived from body weight or previous insulin requirements. Secondly, pre-dosing adjustments modify these formulas by considering estimations of insulin sensitivity based on clinical judgment and laboratory evaluations. Lastly, post-dosage adjustments are based on timed, self-monitored, blood glucose determinations assisted by overall average glucose determinations such as hemoglobin A1c. Continuous glucose monitoring systems have provided a more insightful tool for dosage adjustments. Daily consecutive intensive glucose evaluations using a continuous glucose monitoring system and corresponding dosage adjustments may offer an even better tool for insulin dosing selection.