Current Diabetes Reviews - Volume 7, Issue 5, 2011

Diabetic retinopathy is associated with hyperglycemia, and there is convincing evidence that oxidative stress (the overproduction of reactive oxygen species (ROS)) measured indirectly in patients, is related to the severity of diabetic complications. Also, reducing such stress by various means, including drugs and reducing hyperglycemia, decreases the rate of development of diabetic retinopathy (DR). It is therefore supposed that oxidative stress causes DR, and the injuries caused by ROS in retinas of diabetic animals (and in human preparations). But the cells first affected in small animal models of DR are found throughout the inner retina, and not specifically associated with small blood vessels until later in the development of retinopathy. We raise the questions A: why in human disease the small retinal blood vessels are so selectively affected B: what are the processes that induce oxidative damage in the retina. There are difficulties in interpretation of experimental results, because there is no metric which relates the degree of damage to the level of ROS, either in clinical or animal experiments and the relative sensitivity of the different methods employed to demonstrate oxidative damage in experiments on tissues is unquantified. It is also important to note that in addition to oxidative stress, hyperglycemia induces several changes including leucostasis, vasoconstriction and a pro-inflammatory state that also causes hypoxia in the retina. The earliest retinal pathology and the earliest biochemical changes appear to begin within 1 week of the time when the animals become diabetic and are provoked by hyperglycemia. These changes include alterations to the appearance of microglia, the formation of Advanced Glycation Endproducts (AGEs), the overproduction of Vascular Endothelial Growth Factor (VEGF) and its mRNA and consequent leakage of capillary endothelial cells. These early pro-inflammatory changes can directly cause hypoxia in the retina and not necessarily via ROS. Experiments on isolated cells indicate that retinal capillaries are less susceptible to hyperglycemia than other retinal cells, but in vivo are selectively damaged, possibly via paracrine changes. This suggests a new concept: although the changes in blood vessels may be a consequence of gradual and cumulative development of oxidative stress, the preceding paracrine and other changes that cause the development of oxidative stress are highly significant to the understanding and treatment of DR. The clinical importance is that about the time that oxidative stress becomes easily demonstrable, the progress of DR is already irreversible. A number of methods of treatment of DR depend upon the relief of retinal hypoxia. If oxidative stress is considered ‘the’ determinant of DR, explanation of such findings solely in terms of oxidative stress would require additional hypotheses.

Context: Owing to the pathogenic role of insulin resistance and beta-cell dysfunction in type 2 diabetes, the clinical manifestation of this disease is extremely complex and is often associated with obesity. In recent years, Roux-en-Y gastric bypass (RYGB) surgery, which was originally developed to treat morbid obesity, has been found to have therapeutic potential for diabetes. However, the underlying mechanisms of the therapeutic application of this technique are not fully known. Objective: This review describes the technique of RYGB, including the advantages and disadvantages of the procedure. The advantages include metabolic improvement, obesity resolution, and reduction in morbidity. The disadvantages include short-term perioperative complications and long-term nutritional disorders. Finally, we provide a review of the possible underlying mechanisms leading to the resolution of type 2 diabetes symptoms after the RYGB procedure. Conclusions: While some complications are found after RYGB, there have also been reports showing a remarkable decrease in mortality, successful weight loss, and resolution of type 2 diabetes. The actual mechanism leading to diabetes resolution remains unknown. Gastric bypass surgery is certainly an effective method to increase remission rate in a subgroup of type 2 diabetes patients with morbid obesity.

A growing body of evidence suggests that oxidative stress plays a key role in the pathogenesis of micro- and macrovascular diabetic complications. The increased oxidative stress in subjects with type 2 diabetes is a consequence of several abnormalities, including hyperglycemia, insulin resistance, hyperinsulinemia, and dyslipidemia, each of which contributes to mitochondrial superoxide overproduction in endothelial cells of large and small vessels as well as the myocardium. The unifying pathophysiological mechanism that underlies diabetic complications could be explained by increased production of reactive oxygen species (ROS) via: (1) the polyol pathway flux, (2) increased formation of advanced glycation end products (AGEs), (3) increased expression of the receptor for AGEs, (4) activation of protein kinase C isoforms, and (5) overactivity of the hexosamine pathway. Furthermore, the effects of oxidative stress in individuals with type 2 diabetes are compounded by the inactivation of two critical anti-atherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Of interest, the results of clinical trials in patients with type 2 diabetes in whom intensive management of all the components of the metabolic syndrome (hyperglycemia, hypercholesterolemia, and essential hypertension) was attempted (with agents that exert a beneficial effect on serum glucose, serum lipid concentrations, and blood pressure, respectively) showed a decrease in adverse cardiovascular end points. The purpose of this review is (1) to examine the mechanisms that link oxidative stress to micro- and macrovascular complications in subjects with type 2 diabetes and (2) to consider the therapeutic opportunities that are presented by currently used therapeutic agents which possess antioxidant properties as well as new potential antioxidant substances.

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor to complete pivotal phase III trials, which have demonstrated its superiority to its competitors based on its low therapeutic dose, long-lasting inhibition of DPP-4 activity and a good safety/tolerability profile. One of the unique characteristics of linagliptin is its primarily non-renal route of excretion. The drug has recently been approved by the US Food and Drug Administration and has been portrayed as a promising treatment option for patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.

The impact of bariatric surgery on insulin sensitivity and glucose tolerance has refocused interest in the role of gut-derived factors in the regulation of insulin secretion and action. The incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, including augmentation of glucose-stimulated insulin secretion (GSIS), actions that promote the cellular assimilation and storage of dietary glucose and lipid as liver and skeletal muscle glycogen and adipocyte triacylglycerol (TAG) respectively. Similarly, increased delivery of fatty acids (FA) acutely augments GSIS, and the resultant enhancement of GSIS facilitates FA storage as adipocyte TAG. Leptin secretion from white adipocytes curbs appetite to limit dietary nutrient intake and adipocyte TAG storage and, potentially, GSIS, thereby curtailing insulin-dependent TAG storage. On fasting, GSIS is curbed, an effect the mechanism of which is even now incompletely understood, but which may reflect augmented β-cell FA oxidation. The orexigen ghrelin, systemic concentrations of which increase with fasting, exerts enigmatic effects on GSIS, in that acylated ghrelin and unacylated ghrelin exert opposing effects on GSIS, whereas acylated ghrelin and unacylated ghrelin share protective effects on islet survival. This review will build on these emerging studies to evaluate the roles of the incretins, leptin, lipids and acylated and unacylated ghrelin in modulating islet function and survival during feasting and fasting.

As a therapy for type I diabetes, islet transplantation provides clear benefits in terms of increased insulinindependence and a reduced risk of hypoglycemia. However, a critical shortage of donor pancreata means that few can benefit from this approach. The ex vivo expansion of human β-cells prior to transplantation could ameliorate this problem, however, attempts to grow large numbers of β-cells that retain their native phenotype have thus far failed. Recent lineage tracing studies suggest that this problem is due to the inherent tendency of cultured human β-cells to undergo a process reminiscent of epithelial-to-mesenchymal transition (EMT). EMT describes a highly complex process that culminates in a loss of epithelial cell polarity, severance of intercellular adhesive junctions and the acquisition of a highly motile mesenchymal phenotype. Interestingly, recent evidence suggests that a transient EMT-like process may also contribute to the delamination of endocrine progenitors and subsequent islet neogenesis. The inherent susceptibility of cultured human β-cells to EMT, and the potential involvement of this process during islet neogenesis, raises important questions as to how this process is triggered and subsequently regulated. The primary purpose of this review is to describe those factors, pathways or processes that are complicit in inducing or regulating the mesenchymal transition of human β-cells. This includes addressing the role of the extracellular matrix, the contribution of select signaling pathways, and the regulatory function of microRNAs. We propose that manipulation of these cues and pathways offers the greatest potential for restoring β-cell function after ex vivo expansion.

Patients with type 2 diabetes (T2DM) have a two- to three-fold increased risk for Alzheimer's disease (AD), the most common form of dementia. Vascular complications might explain partially the increased incidence of neurodegeneration in patients with T2DM. Alternatively, neuronal resistance for insulin/insulin-like growth factor-1 (IGF- 1) might represent a molecular link between T2DM and AD, characterizing AD as “brain-type diabetes”. According to this hypothesis, brains from AD patients showed substantially downregulated expression of the Insulin receptor (IR), the IGF-1 receptor (IGF-1R), and the insulin receptor substrate (IRS) proteins. Similar changes in insulin/IGF-1 signaling (IIS) have been described in animals fed a high fat diet and human T2DM, suggesting that decreased IIS might be involved in the pathogenesis of both T2DM and AD. In contrast, type 2 diabetic patients suffering from AD accumulate less β-amyloid (Aβ) compared to non-diabetic AD patients raising the question, whether the changes in IIS are cause, consequence, or compensatory counterregulation to neurodegeneration. Recent data in C. elegans showed that reducing IIS decreases Aβ toxicity. This effect is accomplished via two transcription factors downstream of IIS, DAF-16 and HSF- 1: The first detoxification path leads to degradation of the toxic misassemblies and is mediated via HSF-1. The second mechanism mediates the formation of low toxic, high molecular weight aggregates from highly toxic small molecular weight aggregates regulated by DAF-16 suggesting that Insulin/IGF-1 transmitted signals influence Aβ proteotoxicity. The current review discusses possible implications of recent findings in humans and model organisms for the understanding and possible therapeutic approaches of diabetes associated dementia.