Current Diabetes Reviews - Volume 7, Issue 4, 2011

Kidney transplantation is being performed more frequently for individuals with end stage renal disease (ESRD) due to improved survival and quality of life compared to long-term dialysis. Though rates decrease after transplant, cardiovascular disease (CVD) remains the most common cause of death after kidney transplant. New-onset diabetes after transplant (NODAT), a common complication following kidney transplantation, and pre-transplant diabetes both significantly increase the risk for CVD. Several other risk factors for CVD in kidney transplant recipients have been identified; however, optimal therapy for controlling the risk factors of CVD after kidney transplantation, including NODAT and pretransplant diabetes, is not well defined. In the following review we will discuss the role of traditional and non-traditional risk factors in CVD after kidney transplant and the mechanisms involved therein. We will also examine the current literature regarding treatment of these risk factors for the prevention of CVD. Finally, we will review the current recommendations for pre- and post-transplant cardiovascular evaluation and management.

IGF-I is structurally related to proinsulin and when administered to human subjects it enhances insulin sensitivity. However because of its growth promoting properties and its relationship to growth hormone, it has been proposed as a etiologic factor in the development of diabetic complications. This review discusses recently published data regarding the ability of hyperglycemia to sensitize cells that are capable of dedifferentiating to the growth promoting effects of IGF-I. Under normoglycemic conditions vascular smooth muscle and endothelial cells are cystostatic and stimulation of the IGFI receptor activates the adaptor protein IRS-1 which leads to PI-3 kinase pathway activation. Following exposure to hyperglycemia these cell types undergo a signaling switch whereby an entirely different mechanism is utilized to activate both the PI-3 and the MAP kinase pathways. This leads to increased cell proliferation and migration. This molecular mechanism involves the coordinate regulation of signaling molecules and scaffolding proteins. Activation of this alternative signaling mechanism is directly linked to the stimulation of pathophysiologic processes that are involved in the pathogenesis of both diabetic retinopathy and atherosclerosis. Inhibition of activation of these intermediates has been shown to attenuate glucose induced pathophysiologic changes and results in the inhibition of both atherosclerotic lesion progression and diabetic retinopathy. In summary, hyperglycemia induces a signaling switch in vascular endothelial and smooth muscle cells that results in enhanced sensitivity to the growth promoting effects of IGF-I. This may be an important variable for determining the progression of atherosclerosis in poorly controlled diabetes and in the development of retinopathy.

Systematic screening for diabetic retinopathy using retinal photography has been shown to reduce the incidence of blindness among people with diabetes. The implementation of diabetic retinopathy screening programmes faces several challenges. Consequently, methods for improving the efficiency of screening are being sought, one of which is the automation of image grading involving detection of images with either disease or of inadequate quality using computer software. This review aims to bring together the available evidence that is suitable for making a judgement about whether automated grading systems could be used effectively in diabetic retinopathy screening. To do this, it focuses on studies made by the few centres who have presented results of tests of automated grading software on large sets of patients or screening episodes. It also considers economic model analyses and papers describing the effectiveness of manual grading in order that the effect of replacing stages of manual grading by automated grading can be judged. In conclusion, the review shows that there is sufficient evidence to suggest that automated grading, operating as a disease / no disease grader, is safe and could reduce the workload of manual grading in diabetic retinopathy screening.

Regular moderate-intensity exercise is strongly recommended for its beneficial effects in all people. In patients with type 1 diabetes, however, the exercise-associated glycemic imbalances remain an unresolved clinical challenge. Current guidelines require an in-depth understanding of the glycemic responses to exercise and each patient has to discover, by trial-and-error, his/her own strategy, several attempts being usually required to gain sufficient experience. Consequently, fear of hypoglycemia remains the strongest barrier to physical activity. This paper explores the potential strategies that may be employed to minimize the risk of exercise related glycemic imbalances. Moreover, a newly developed algorithm (ECRES, Exercise Carbohydrate Requirement Estimating Software) is described, which estimates on a patientand situation-specific basis the glucose supplement required by the patient to maintain safe blood glucose levels. The algorithm was tested on 27 patients who performed three 1-hr constant intensity walks (each starting at a different time interval following insulin injection). Results showed that in 70.4% of the trials, independent of the time of day, the algorithm provided a satisfactory estimate of the carbohydrates needed by patients to complete the exercise with a glucose level within safe thresholds (i.e. 3.9 - 10 mmol·L-1). Despite the algorithm requires further experimental testing to be applied by the majority of patients, these results indicate its potential usefulness as a tool for preventing immediate exerciseinduced glycemic imbalances (i.e. during exercise) in type 1 diabetic patients, in particular for spontaneous activities not planned in advance, thus allowing all insulin-dependent patients to safely enjoy the benefits of exercise.

A large and increasing number of people in all over the world suffer from obesity, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Attenuation of the heat shock response (HSR), which was originally identified as a cellular defense mechanism, is one of the key factors involved in the deterioration of metabolic abnormalities. On the other hand, activating the HSR increases heat shock protein 72 (HSP72) expression and improves insulin resistance and glucose homeostasis in rodents and humans, possibly by inhibiting the activation of stress kinases such as c-jun terminal kinase (JNK) and inhibitor of kappa B kinase β (IKKβ). These approaches may also reduce inflammatory cytokine production and prevent the onset of atherogenic complications. This review focuses on the physiological effects of HSR in regulating insulin sensitivity and hyperglycemia, and the potential to target the HSR system for the treatment of MS and T2DM, as well as other cellular stress-related diseases.

In adipose tissue, the primary physiological function of insulin is the suppression of lipolysis, the hydrolysis of stored fat. Mechanistically, insulin suppresses lipolysis both in transcriptional and post-transcriptional levels. Insulin signaling acutely inhibits beta-adrenergic signaling by decreasing intracellular cyclic AMP levels and the rate of lipolysis. Insulin also suppresses lipolysis by down-regulating the expression of the rate-limiting lipolytic enzyme, adipose triglyceride lipase or ATGL. In insulin resistance and type 2 diabetes, insulin mediated attenuation of lipolysis is impaired leading to an increased rate of lipolysis and increased release of free fatty acids (FFA) in the circulation. This is one of the potential mechanisms behind the development of hyperlipidemia and subsequent metabolic abnormalities in type 2 diabetes. In this article, we focus on the recent findings that highlight distinct molecular mechanisms by which insulin action is mediated and possible implications of the deregulation of these pathways in the pathophysiological context.

In type 1 diabetes, a failure in the regulation of either innate or acquired immunity may be the cause of autoimmune response. A cell population that may have a regulatory role of the immune response are the Natural Killer T (NKT) cells, which are a population expressing T lymphocyte antigen receptor (TCR), and a common marker for NK cells. A distinctive characteristic in NKT cells is their capacity to produce large amounts of immune-modulating cytokines. A decrease in the number and/or functional incapability of NKT cells is associated with progression of type 1 diabetes and with other self-immune diseases. However, the relevance of such findings is not completely understood. Limitations of the current studies include the existing methods to measure NKT activation and the lack of assessment of the expression of genes affected by NKT action. Nevertheless, the study of NKT cells may be a new clinical approach to detect individuals at risk for having type 1 diabetes. Additional studies are needed to evaluate the clinical value of this new predictive tool.

Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia and vascular complications, leading to significant morbidity and mortality. All forms of diabetes are ultimately related to insufficient functional pancreatic β-cell mass to maintain euglycemia. In this context, the promotion of β-cell survival and function is a fundamental issue of direct relevance to diabetes prevention and treatment. Although first identified as a hematopoietic factor that promotes erythropoiesis and erythrocyte survival, an accumulating body of evidence suggests that erythropoietin (EPO) may also exert cytoprotective effects on non-erythroid tissues, including the brain, kidney, blood vessels, and pancreatic β cells. Recent reports have demonstrated the biological effects of EPO on the pancreatic β cells and its potential preventative and therapeutic role in diabetes. This review will focus on the emerging extra-hematopoietic roles of EPO and its potential protective role in diabetes.