Current Diabetes Reviews - Volume 8, Issue 6, 2012

Blood-tissue barriers prevent an uncontrolled exchange of large molecules between adjacent but metabolically separated compartments. There are several known barriers and two of the most important and tightest blood-tissue barriers are the blood-testis barrier (BTB) and the blood-brain barrier (BBB). Under normal conditions these barriers, formed by tight junctions between adjacent cells, control the entry of substances and metabolites. However, hyperglycemia and other diabetes-related complications, such as hypertension, impair the function of these biological barriers with dramatic consequences. Although both, BBB and BTB, are responsible for the maintenance of different biological processes, they have some remarkable similarities not always explored when looking at metabolic-related diseases such as diabetes. These barriers possess their own glucose sensing machinery, suffer a tied hormonal control and have specific mechanisms to counteract hyper- and hypoglycemia. In BBB and BTB the insulin signaling is also distinct from other tissues and organs thus evidencing their importance in protecting against or exacerbating the effects of diabetes on glucose metabolism. The control of glucose and lactate levels in brain and testis highlights the role of these barriers in protecting against peripheral glucose and lactate fluctuations that occur in the diabetic individual. We review the role of BBB and BTB in the control of glucose and metabolic dysfunction caused by diabetes in the brain and seminiferous epithelium. Gaining a better understanding of the molecular mechanisms through which glucose metabolism disrupts BBB and BTB function may highlight new opportunities for the treatment of diabetic complications in brain and male reproductive function.

There is an epidemic in children of metabolic syndrome, obesity, type 2 diabetes and other individual diseases that form the components of metabolic syndrome. Poor diet and low exercise can not explain many facets of the epidemic including the onset in children 6 month of age, the protective effect of obesity on the incidence of type 1 diabetes and the epidemic of type 2 diabetes/metabolic syndrome in grass fed horses. Poor diet and exercise also do not explain the epidemic of type 1 diabetes in children that resembles the epidemic of type 2 diabetes/metabolic syndrome. Several papers have been published to indicate that the epidemics of type 1 and type 2 diabetes/metabolic syndrome in children are linked and are polar opposite responses to iatrogenic inflammation. Several lines of research support this. Data from different races indicates that there is an inverse relationship between developing type 1 diabetes and type 2 diabetes. Races with high risk of developing type 2 diabetes have a decreased risk of developing type 1 diabetes. Data from Italy confirmed an inverse association between obesity and type 1 diabetes. Further studies indicate the inverse relationship between type 1 diabetes and type 2 diabetes/obesity is due to cortisol production. Data indicates those with low cortisol responses have a predilection for type 1 diabetes and other autoimmune disorders following inflammation, while those with high cortisol/ immune suppressive responses develop type 2 diabetes/metabolic syndrome/obesity which resembles a Cushingoid state but are spared in the autoimmune disorders. Japanese children produce much more cortisol following immunization than Caucasian children. The later explains why discontinuation of BCG vaccination was associated with a decrease in type 1 diabetes in European children and a decrease in type 2 diabetes in Japanese children. Both the epidemics of type 1 diabetes and metabolic syndrome correlate with an increase in immunization. Finally, there is a strong mechanism data that macrophage produced interleukin 1, tumor necrosis factor and interleukin 6, which are released following inflammation, causing destruction of insulin secreting islet cells and increase cortisol release, and thus have the ability to cause both type 1 and type 2 diabetes/metabolic syndrome (which resembles a Cushingoid state). The propensity to develop type 1 diabetes or type 2 diabetes/metabolic syndrome depends on the propensity to release of cortisol which correlates with race.

Activation of adenosine A2A receptors (A2AR) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A2AR agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A2AR agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A2AR activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4+CD25+FoxP3+ T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A2AR activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A2AR agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A2AR agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted.

Introduction: Children with type 1 diabetes mellitus (T1DM) have to deal with a complex and demanding daily treatment regime which can have a negative impact on the quality of life (QoL) of these patients. The objective of the present study is to review studies that have compared generic quality of life of children and adolescents with T1DM with that of healthy peers. In addition, we will examine whether QoL differs between boys and girls, and across different developmental stages. Methods: A systematic literature search using PubMed was conducted for the years 2000 through May 2012. 17 studies were eligible for the current review. Effect sizes were computed to estimate the effects of having T1DM on QoL in children and adolescents. Results: Although individual studies reported small to moderate effect sizes on the distinct QoL-domains, the weighted effect sizes across all studies indicated no differences in QoL-domains between children and adolescents with T1DM and healthy controls. However, disease-specific problems were certainly present. Girls with T1DM reported lower generic and disease-specific QoL than boys with T1DM. Relationships between age and generic or disease-specific QoL remained unclear. Conclusions: Although children and adolescents with T1DM have to live with a demanding treatment regime, overall results revealed that their generic QoL is not impaired compared to healthy peers. However, disease-specific QoL problems, including a negative impact of diabetes on daily functioning, and diabetes-related worries were certainly present. Longitudinal research is needed in order to provide tailored care for children of all ages with T1DM.

Polycystic ovary syndrome (PCOS) is associated with reproductive and metabolic consequences. The review of findings indicate that the long-term reproductive outcomes of women with PCOS are surprisingly similar compared to women with normal ovaries, and that they have an ovarian reserve possibly superior to women with normal ovaries. The typical features of PCOS, specifically the anovulatory cycles tend to normalize over time, but in spite of a decrease over time, free androgen levels remain elevated compared to age-matched control subjects. Women with PCOS diagnosed at young age continue to display reduced insulin sensitivity in the perimenopausal age, independent from phenotypic expression of PCOS, both at diagnosis and at follow-up. Insulin resistance does not seem to deteriorate further, however. Overall, the accumulated data from several European cohort studies of older women with a previous diagnosis of PCOS suggest an increased incidence of type 2 diabetes, increased prevalence of several features of the metabolic syndrome, but no increased incidence of mortality from CVD.

Receptor-interacting protein 140 (RIP140) is best known for its functional role as a wide-spectrum transcriptional co-regulator. It is highly expressed in metabolic tissues including mature adipocyte. In the past decade, molecular biological and biochemical studies revealed extensive and sequential post-translational modifications (PTMs) of RIP140. Some of these PTMs affect RIP140’s sub-cellular distribution and biological activities that contribute to the development and progression of metabolic diseases. The biological activity of RIP140 that translocates to the cytoplasm in adipocytes is to regulate glucose uptake, adiponectin secretion and lipolysis. Accumulation of RIP140 in the cytoplasm promotes adipocyte dysfunctions, and provides a biomarker of early stages of metabolic diseases. Administering compounds that reduce cytoplasmic accumulation of RIP140 in high fat diet-fed animals can ameliorate metabolic dysfunctions, manifested in improving insulin sensitivity and adiponectin secretion, and reducing incidences of hepatic steatosis. This review summarizes studies demonstrating RIP140’s PTMs and biological activities in the cytoplasm of adipocyte, signaling pathways stimulating these PTMs, and a proof-of-concept that targeting cytoplasmic RIP140 can be an effective strategy in managing metabolic diseases.

Our current knowledge on substrate oxidation in skeletal muscle in relation to insulin resistance and type 2 diabetes (T2D) originate mainly from in vivo studies. The oxidative capacity of skeletal muscle is highly influenced by physical activity, ageing, hormonal status, and fiber type composition, rendering it difficult to determine the contribution of heritable factors to the alteration in oxidative metabolism. Cultured human myotubes offer a unique model to distinguish between primary and environmental factors in the etiology of insulin resistance. The objective of this review is to summarise our studies on substrate oxidation in human myotubes established from lean, obese and T2D subjects, especially focusing on whether the increased respiratory quotient seen in T2D subjects is based on primary traits and whether changes in substrate oxidation may have a common explanation. Obtained results add further regulatory mechanism to our understanding of substrate oxidation in human skeletal muscle during normo- an pathophysiological conditions, focusing especially on the governing influence of a primary reduced TCA flux for the diabetic phenotype in skeletal muscle.

Diabetes mellitus (DM) is a disease with constellation of metabolic aberrations resulting in debilitating complications. The prevalence of DM worldwide was 2.8% (171 million people) in 2000 and estimated to be at 4.4% (366 million people) in 2030. DM is a major risk factor for heart, kidney diseases, and lower limb amputations. Emerging in vitro and in vivo data suggest that systemic inflammation plays a role in the pathogenesis of DM complications via innate immune receptors. Toll-like receptors (TLRs) are key innate immune receptors that mediate the inflammatory responses in DM. There are no reviews that collectively summarize and examine the detrimental role of TLRs in the manifestation of DM complications namely heart disease, nephropathy, neuropathy, and wound healing. Thus, in this review, we will provide summaries of the TLR expression and activation and elucidate their role in propagating inflammation seen in DM complications.