Current Diabetes Reviews - Volume 9, Issue 5, 2013

Advanced glycation end products (AGEs) are synthesized via the non enzymaticglycation and oxidation of proteins, lipids and nucleic acids. The production of AGEs is particularly enhanced in chronic hyperglycemia, as in diabetes mellitus (DM). The formation of irreversible AGEs affects the tissues by compromising the physiologic and mechanical functions, as a result of defective constitution of the extracellular matrix (ECM) components. Periodontitis is an inflammatory disease of microbial origin, resulting in devastation of the tooth supporting apparatus. This disease condition has severe implicationsin subjects with DM, since the tooth supporting tissuescontain ECM targeted by AGE. There is miniscule literature regarding the contribution of AGE to periodontal disease in patients with DM. The purpose of this review is to address the prejudicial role of AGEs in relation to various tissue components. This paper is an attempt to elucidatethe possible link of AGEs between periodontitis and DM. The exploration of novel therapeutic strategies to target AGEs for the treatment of periodontitis in DM subjects is certainly intriguing.

Psychotropic drugs, like antipsychotics and antidepressants, are often associated with metabolic side effects such as weight gain and an increased risk of the development of diabetes and an atherogenic lipid profile. These adverse effects not only bear a high cardiovascular risk and lead to higher morbidity and mortality, but are an additional burden to mentally ill patients and can be a decisive factor for the compliance and, consequently, the success of the therapy. Second generation antipsychotics (SGAs), in particular, clozapine and olanzapine, lead to significant weight gain and impair glucose metabolism. Despite the availability of newer SGAs, such as aripiprazole, which are considered to be less prone to cause metabolic side effects, olanzapine is still one of the most prescribed SGAs worldwide. Antidepressant drugs may also induce weight again and diabetes even though the literature is contradictory, probably due to different receptor affinities. This review aims to provide an overview of the metabolic side effects caused by commonly used psychotropic drugs and give insight into underlying mechanisms.

Type 2 diabetes mellitus (T2DM) accounts for 90%–95% of all diabetes cases. The overarching goal in caring for patients with T2DM is to prevent microvascular and macrovascular complications with glycemic control. Several studies such as UKPDS, DCCT, and EDIC have been performed to evaluate the effects of glucose control on tissue complications in patients with diabetes. In recent diabetes trials including ACCORD, ADVANCE, VADT, BARI 2D, and ORIGIN, intensive glucose control did not prevent macrovascular complications in older patients with long-standing diabetes with either cardiovascular disease or risk factors for cardiovascular disease. In fact, intensive therapy was associated with increased mortality in the ACCORD trial. Although no clear macrovascular benefit was seen in these trials, analyses of earlier studies in younger patients with type 1 and type 2 diabetes have suggested a significant benefit of intensive glycemic control in patients with a shorter duration of diabetes and less vasculopathy. In the UKPDS, the incidence of microvascular disease, particularly retinopathy, was reduced significantly with intensive glucose control, but in the more recent trials (ACCORD, ADVANCE, VADT, ORIGIN) the benefit was relatively modest and limited to reduced proteinuria. Perhaps the most important message from the above trials is to optimize control of cardiovascular risk factors. Although the goal HbA1c to prevent microvascular and macrovascular complications, per the American Diabetes Association, is less than 7%, hypoglycemia should be avoided as it can increase the risk for severe cardiovascular events.

Up to 50% of patients with hepatocellular carcinoma (HCC) have the so-called “cryptogenic cirrhosis.” Most of them are affected by at least one of the condition characterizing the metabolic syndrome, as obesity or diabetes. Recent observations found that type-2 diabetes mellitus (DM) confers a three-fold risk of HCC. Main molecular feature of the conditions of metabolic syndrome is insulin resistance, i.e. the reduced sensitivity to insulin action and, as consequence, increased secretion of this hormone. Insulin resistance and hyperinsulinemia influence hepatocarcinogenesis via several molecular pathways, such as phosphatase and tensin homolog (PTEN)/P13K/Akt and MAPK kinase (MAPKK). Diabetes also seems to influence negatively the prognosis and the clinical course of HCC patients, independently from the cause of the underlying cirrhosis. It’s well known that insulin-sensitizing drugs may reduce the incidence of HCC. Metformin activates 5-adenosine monophosphate-activated protein kinase (AMPK), that has growth inhibition effects on human cancer cell lines via inhibition of its downstream target mammalian target of rapamycin (mTOR), and decreases the expression of Livin, a protein involved in both cell proliferation and survivalexpressed at high level in neoplastic cell. Also thiazolidinediones seem to prevent tumor formation in the liver via the inhibition of peroxisome proliferatoractivated receptor gamma-independent regulation of nucleophosmin. More debated is the role of sulfonylureas in decreasing HCC incidence in diabetic patients. Further investigations are needed to define reliable indications to therapy and surveillance in patients with diabetes or insulin resistance.

β-cell dysfunction and apoptosis are recognized as a major cause of insufficient insulin secretion in response to high blood glucose and metabolic demand. As a consequence, type 2 diabetes mellitus (T2DM) is known to occur. Taking into account the etiology of T2DM, to conduct investigational studies directly on human diabetic patients seems to be unsuitable; thereby, various animal models have been established to investigate the pathogenesis of T2DM. Among these models, Goto-Kakizaki (GK) rats have been considered as one of the best non-obese type 2 diabetic animal model. GK rats exhibit valuable characteristic tools that are more or less common and functionally present in human diabetic patients. This animal model is considered appropriate to inspect various pathologic mechanisms of T2DM. Thereby, in our present article, we have comprehensively summarized the information relating the characteristics of abnormalities including a description of assorted mechanisms involved in pathogenesis of T2DM in GK rats. This might help to investigate various aspects of spontaneous T2DM.

Foot problem has been increasingly recognised as a major complication of diabetes, which is associated with a very high mortality and morbidity. Therefore Multi-Disciplinary Foot Clinics (MDFC) have been established all over the world to provide holistic care to these patients. There is a wide variation in the availability of a range of professional skills in the MDFC in different health economy. Therefore the care provided by these MDFC can vary from one place to other. It is very important to measure the outcome of these MDFC so that patients, regulatory authorities and funding bodies can compare them. Traditionally ulcer related outcomes such as the healing rate and the proportion of ulcers healed have been measured in many foot ulcer studies. Similarly the amputation rate is measured to determine the efficacy of diabetic foot management in an area of the health economy. However, these measures do not take into account other important factors such as the functional ability and the quality of life of patients. Therefore patient related outcomes such as the recurrence of ulcer, number of working days lost, the mobility of patient following treatment, survival following first episode of ulceration etc also needs to be measured, which are very important from the patient's perspective. This review looks into various patient related outcomes that can and should be measured to assess the quality of care provided by the MDFC.

The use of natural products is very common among non-industrialized societies because these remedies are more accessible and affordable than modern pharmaceuticals. In developed countries, use of herbal products has recently increased as scientific evidence about their effectiveness has become broadly available. For the past two decades many research articles in the field of ethno-pharmacology have focused on the anti-diabetic effects of some natural products. This dramatic increase of interest was partly due to the fact that type 2 diabetes mellitus (T2DM) was considered as becoming a global epidemic health problem which imposed high cost to national health services around the world. We have no intention to advocate for replacing conventional pharmacotherapy with natural products to prevent and control T2DM. However, the fact that a lack of highly effective drug-therapy with existing synthetic agents and their resulting adverse effects motivated further search into traditional medicine in order to re-evaluate old remedies as well as screening to find new natural entities to be used as anti-diabetic products cannot be ignored. Some recent reports on the natural products with anti-diabetic effects have provided evidence for possible mechanisms of action. Nonetheless, the majority of investigators only speculated on a wide range of possible mechanisms or simply demonstrated an anti-hyperglycemic effect for the crude plant extracts or the isolated compounds of interest. A few reviews with less attention paid to mechanisms of action have been published on medicinal plants and diabetes. This article reviews publications on anti-diabetic natural products that have appeared in PUBMED or other research-related literature found on the Internet (from 1990 to present) to categorize them based on their mechanisms of action. We hope that this communication will be beneficial as a starting point to consider the discussed products for further investigations to identify and develop new remedies with potential alternative or complementary use in controlling T2DM.

Insulin resistance has been associated with the development of type 2 diabetes, obesity, hypertension, dyslipidemia, atherosclerosis, and thus with increased cardiovascular morbidity and mortality. Insulin resistance precedes the onset of type 2 diabetes by many years. Targeting the pathophysiologic defects that characterize the onset of diabetes is more likely to achieve a durable glucose control and to delay disease progression. Incretins are gut-derived peptides that stimulate in a glucose-dependent mechanism insulin secretion and action. Glucose-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors both decrease fasting and postprandial glucose levels. In addition, GLP-1 analogues promote weight loss and exert a favorable effect on several cardiovascular risk factors. Data from human and experimental studies implicate that GLP-1 analogues and to a less extend DPP-4 inhibitors enhance insulin sensitivity. This review summarizes the current knowledge regarding the impact of GLP-1 analogues and DPP-4 inhibitors on insulin resistance.

There have been a lot of discussions concerning the relationship between testosterone serum levels in males and diabetes. Low testosterone is commonly associated with type 2 diabetes and metabolic syndrome. Testosterone therapy alters the body composition in a metabolically favorable manner. In this article we shed some light on the bidirectional relation between hypotestosteronemia and diabetes discussing also the possible mechanisms and the benefit of treatment.

Insulin resistance is closely associated with obesity and type 2 diabetes. Although the mechanisms of insulin resistance are not fully elucidated, recent studies suggest that a complex interaction between inflammation, endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction and autophagy dysregulation plays an important role in insulin resistance. The stress-activated c-Jun N-terminal kinase (JNK) has been increasingly recognized as a central mediator of insulin resistance. JNK mediates many of the effects of stress on insulin resistance through inhibitory phosphorylation of insulin receptor substrate, and suppression of the JNK pathway has been shown to improve insulin resistance and glucose tolerance. Therefore JNK may serve as a crucial link between stress and metabolic diseases as well as a promising therapeutic target. This review focuses on recent findings that support a critical role for JNK in the development of insulin resistance associated with inflammation, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction. JNK regulation of autophagy and its implications in insulin resistance also will be discussed.