Current Diabetes Reviews - Volume 1, Issue 3, 2005

Genetic and environmental determinants play critical roles in insulin resistance and b-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index (DI). Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes and atherosclerotic cardiovascular disease. There is increasing evidence that variation in glucose homeostasis reflects genetic control better than that of commonly used surrogate measures (fasting glucose or fasting insulin). Further, recent linkage scans have identified regions in the human genome that may contain loci that contribute to variation in glucose homeostasis phenotypes. Thus, the prospects are encouraging for positional cloning of genes contributing to glucose homeostasis and providing insight into the nature of the metabolic syndrome and diabetes. Ultimately, knowledge of the genetic basis of glucose homeostasis will facilitate the development of more directed therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.

The prevalence of obesity continues to increase throughout the world in an analogous way to that of type 2 diabetes mellitus (T2DM). Excess adiposity and accompanying insulin resistance is frequently associated to the development of cardiovascular disease. The circulating hormone resistin, which is produced mainly by adipocytes and appears to be increased in obesity and inflammation, seems to play a role in this association. Some studies indicate that T2DM patients have increased circulating concentrations of resistin, although these results need further confirmation. Increased resistin concentrations have been described in patients with severe inflammatory disease. However, the precise physiological role of resistin in the pathogenesis and perpetuation of inflammation remains unclear. Resistin exerts direct effects to promote the activation of endothelial cells inducing the release of endothelin-1, increasing the expression of adhesion molecules and chemokines, and potentiating the effect of the CD40 ligand. The present review summarizes recent advances in understanding the physiology of resistin and analyzes the involvement of this hormone in inflammation and cardiovascular disease.

Diabetes is a highly prevalent chronic and debilitating condition that is associated with significant morbidity, mortality, and increased health care costs. Depression is also highly prevalent and is a leading cause of disability, work place absenteeism, lost productivity, and increased use of health care resources. There is evidence that persons with diabetes are twice as likely to have depression as persons without diabetes and that ∼30% of persons with diabetes have clinically relevant depression. Comorbid depression is strongly associated with adverse health outcomes in persons with diabetes including poor glycemic control, increased risk of complications, decreased adherence to medications, decreased adherence to dietary recommendations, and increased health care costs. This article reviews the epidemiology of depression, the effect of depression on diabetes self-management behavior and diabetes-specific outcomes, potential pathways (mediators and moderators) for these effects, and effective treatment strategies for depression in individuals with type 2 diabetes.

Chronic complications of diabetes mellitus represent a major cause of morbidity and mortality among those affected and have an enormous impact on society as a whole. Although these complications manifest as a number of clinically distinct syndromes, the pathology underlying them may be very similar, if not identical. Endothelial dysfunction leading to microcirculatory insufficiency and functional ischemia of tissues are proposed to play a pivotal role in the process of their development and progression. Diabetic complications affecting the nervous system occur not infrequently and may have disastrous consequences. This article reviews diabetic complications affecting central and peripheral nervous systems, focusing on similarities in their underlying microvascular pathology and discussing aspects of potentially successful therapeutic interventions. In addition, the article draws a parallel between microvascular dysfunction observed in persons with overt diabetes and those at risk for it.

The aim of this project was to develop evidence-based guidelines regarding psychosocial aspects of diabetes mellitus in an effort to help the clinician bridge the gap between research and practice. Recommendations address the following topics: patient education, behavioural medicine, and psychiatric disorders of particular relevance to diabetes: depression, anxiety disorders, eating disorders, and dependence on alcohol and nicotine. The present guidelines were developed through an interdisciplinary process of consensus according to the specifications of evidence-based medicine and are recognized by the German Diabetes Association and the German College for Psychosomatic Medicine as their official guidelines.

This paper reviews emerging interventions from the recent clinical literature that demonstrate the potential for effectiveness in the therapy of the diverse forms of diabetic neuropathy. Diabetic sensorimotor polyneuropathy is the primary focus of this review given that it is the most common form of diabetic neuropathy. For this condition, several promising disease-modifying drugs - including inhibitors of the aldose reductase and protein kinase C metabolic pathways - are currently in phase III development. Additional pharmacological agents with an indication to relieve painful symptoms of diabetic neuropathy have been approved by regulatory agencies in the past year. Therapies for other forms of diabetic neuropathy are discussed briefly: For example, evidence exists to suggest that immunomodulation may be effective for diabetic lumbosacral plexoradiculoneuropathy ('diabetic amyotrophy'), and is effective in diabetic patients with chronic inflammatory demyelinating polyneuropathy regardless of the coexistence of diabetic sensorimotor polyneuropathy. Furthermore, strategies for the management of autonomic neuropathies are itemized. As a whole, current evidence suggests that diabetic neuropathy should not be dismissed as an untreatable disorder, and physicians need to focus on the accurate diagnosis of this complication in order to subsequently offer appropriate therapy to patients.

Diabetic nephropathy is a major cause of end-stage renal failure (ESRF) in patients with both type 1 and type 2 diabetes. Many factors such as genetic and non-genetic promoters, hypertension, hyperglycemia, accumulation of advanced glycation end products (AGEs), dyslipidemia, albuminuria and proteinuria influence the progression of this desease. It is important to determine pathogenesis and treatment of this disease. However, it is difficult to investigate since human diabetes is a heterogeneous and multifactorial disease. Therefore, most of these mechanisms have been investigated in animal experiments. KK/Ta mice have a clearly different genetic background in terms of body weight, blood glucose, impaired glucose tolerance (IGT), urinary albumin excretion and serum triglyceride than BALB/c mice. Renal lesions of KK/Ta mice closely resemble those in human early diabetic nephropathy. Thus, the KK/Ta mouse may serve as a suitable model for the study of type 2 diabetes and early diabetic nephropathy in humans. We reviewed genetic susceptibility using genome-wide linkage analysis and differential display polymerase chain reaction (DD-PCR) or Northern blot analysis, and treatment of diabetic nephropathy using angiotensin type 1 (AT1) receptor blockers (ARB) or thiazolidinediones (TZDs) in KK/Ta mice.

Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is one likely or potential trigger for biochemical dysfunction leading to the development of diabetic complications. This may be prevented by disposal of excess triosephosphates via the reductive pentosephosphate pathway. This pathway is impaired in experimental and clinical diabetes by mild thiamine deficiency. The expression and activity of the thiamine-dependent enzyme, transketolase - the pacemaking enzyme of the reductive pentosephosphate pathway, is consequently decreased. Correction of thiamine deficiency in experimental diabetes by high dose therapy with thiamine and the thiamine monophosphate prodrug, Benfotiamine, restores disposal of triosephosphates by the reductive pentosephosphate pathway in hyperglycemia. This prevented multiple mechanisms of biochemical dysfunction: activation of protein kinase C, activation of the hexosamine pathway, increased glycation and oxidative stress. Consequently, the development of incipient diabetic nephropathy, neuropathy and retinopathy were prevented. Both thiamine and Benfotiamine produced other remarkable effects in experimental diabetes: marked reversals of increased diuresis and glucosuria without change in glycemic status. High dose thiamine also corrected dyslipidemia in experimental diabetes - normalizing cholesterol and triglycerides. Dysfunction of β-cells and impaired glucose tolerance in thiamine deficiency and suggestion of a link of impaired glucose tolerance with dietary thiamine indicates that thiamine therapy may have a future role in prevention of type 2 diabetes. More immediately, given the emerging multiple benefits of thiamine repletion, even mild thiamine deficiency in diabetes should be avoided and thiamine supplementation to high dose should be considered as adjunct nutritional therapy to prevent dyslipidemia and the development of vascular complications in clinical diabetes.

Only a limited number of treatment options are available for insulin resistance, a major cause of type 2 diabetes (T2D) and the metabolic syndrome. None adequately address the simultaneous defects in lipid and carbohydrate metabolism. Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors that function as ligand-activated transcription factors. The PPAR family, which includes pparα, pparγ, and pparδ, are receptors for fatty acids and their metabolites. Consequently, PPARs play a critical physiological role in the regulation of genes involved in glucose, fatty acid, and cholesterol metabolism. pparα and pparγ also mediate antiinflammatory effects, which likely contribute to their anti-atherogenic activities. A number of PPAR agonist drugs are marketed for the treatment of individual aspects of the metabolic syndrome. Dual agonists that target both pparα and pparγ are being developed in an effort to broaden the activities and beneficial effects of the ligands selective for pparγ. To address the multiple metabolic defects associated with insulin resistance, T2D and the metabolic syndrome, the simultaneous activation of pparα, pparγ, and pparδ by a single compound (i.e. a PPAR pan-agonist) is being pursued. Similar to pparα and pparγ, pparδ plays a significant role in the regulation of genes that control lipid metabolism. Unlike pparγ, pparδ is not adipogenic, and activation of pparδ is associated with an anti-obesity and more insulin-sensitive phenotype. While there are no currently marketed drugs known to target pparδ, pre-clinical studies indicate that pparδ agonists increase energy expenditure and elevate plasma high-density lipoprotein (HDL) cholesterol. Recent studies in rodents and primates suggest that a small molecule targeting all three isoforms of PPAR would provide a significantly improved treatment option.

Diabetes is on the increase worldwide and greater than 90% are type 2. There are two features to type 2 diabetes: muscle, fat and liver tissues are insulin resistant and β cells lose the ability to secrete insulin. Prior to developing diabetes, however, insulin resistant individuals lose the first-phase insulin secretion response. Transgenic mice lacking insulin receptors in their β cells have no first-phase response. Primary cultures of mouse islets pre-exposed to anti-insulin do not exhibit a first-phase insulin secretion response. That is, β cells, like muscle, fat, and liver, are an insulin sensitive tissue and in the presence of insulin resistance (type 2 diabetes), in the absence of insulin receptors (transgenic mice lacking β cell insulin receptors), or in the absence of constitutively secreted insulin (anti-insulin treatment), β cells are unable to respond properly to post-prandial glucose. The purpose of this report is to review our understanding of the glucose-stimulus response and of insulin signaling, and to suggest why the latter may be necessary for the former to proceed.

Triglyceride accumulation in skeletal muscle is increased in subjects with insulin resistance. Increased intracellular lipolysis from stored triglyceride may induce insulin resistance in skeletal muscle by activating the glucosefatty acid cycle. However, inconsistent with this hypothesis, intracellular lipolysis from skeletal muscle is decreased in high fat-fed, insulin resistant rats. Therefore, it is suggested that an increase in triglyceride accumulation is the result of decreased mitochondrial fatty acid oxidation in the cells. As evidence, fenofibrate (a PPARα activator), rosiglitazone (a PPARγ activator) and alpha-lipoic acid completely prevented the development of diabetes in obese diabetes-prone rats. All three drugs increased fatty acid oxidation and decreased triglyceride accumulation in skeletal muscle. Administration of ALA activated AMPK and increased fatty acid oxidation. It is suggested that decreased fatty acid oxidation in skeletal muscle is one of the major factors leading to an accumulation of lipid metabolites and insulin resistance.

Diagnosis of Gestational Diabetes Mellitus (GDM) requires at least two or more values to be abnormal on the 3 h - 100 g oral glucose tolerance test: but how to care for pregnant women with only one abnormal glucose value remains a point of discussion. In fact, although a large number of studies on this argument exist, the clinical significance of "one abnormal value" has yet to be clarified. Our review of previous studies and personal experience on prevalence, metabolic findings and maternal-fetal outcome suggests this pregnancy induced carbohydrate intolerance is a continuum with GDM, associated with an increased incidence of materno-fetal complications. For this reason we believe that it should be diagnosed, monitored and treated.

Helicobacter pylori [H. pylori], one of the most common chronic infections worldwide, is the main etiologic agent of gastritis, peptic ulcer and gastric cancer. Patients with diabetes mellitus are often affected by chronic infections. Many studies have evaluated the prevalence of H. pylori infection in diabetic patients and the possible role of this condition in their metabolic control. Some studies found a higher prevalence of the infection in diabetic patients and a reduced glycaemic control, while others did not support any correlation between metabolic control and H. pylori infection. There are only a few studies on the eradication rate of H. pylori in diabetic patients. Most of these papers concluded that standard antibiotic therapy allows a significantly lower H. pylori eradication rate than is observed in control groups matched for sex and age. Changes in the microvasculature of the stomach with a possible reduction of antibiotic absorption, the presence of gastroparesis and the frequent use of antibiotics for recurrent bacterial infections with the development of resistant strains could be some of the mechanisms underlying this phenomenon. A quadruple therapy may be used as the second line approach with a good eradication rate, even if an antibiotic selected according to a specific H. pylori antibiogram is considered the gold standard in these patients. As regards the gastrointestinal symptoms of H. pylori infected individuals, many studies showed that they are as frequent in patients with type 1 diabetes as in the general population. The incidence of H. pylori recurrence after 12 months follow-up is significantly higher in type 1 diabetic subjects when compared to controls. Reduced lymphocyte activity, neutrophil dysfunction with failure of chemiotaxis and a possible reservoir of H. pylori in dental plaque may explain the higher rate of re-infection in these patients.