Current Diabetes Reviews - Volume 9, Issue 3, 2013

The risk of hypoglycemia with anti-hyperglycemic agents is an important limiting factor in the management of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. While hypoglycemia is more common in T1DM, the incidence is high in T2DM patients who use insulin or secretagogues, particularly patients with longer duration of diabetes. The underlying cause of hypoglycemia in diabetes is a complex interaction between hyperinsulinemia and compromised physiologic and behavioral responses to falling glucose levels. Pancreatic dysfunction also causes loss of normal therapeutic response to hypoglycemia—a reduction in circulating insulin (in T2DM only) and an increase in glucagon secretion. In T1DM and advanced T2DM, the third defense against hypoglycemia is increase in adrenomedullary sympathoadrenal epinephrine secretion, which is also compromised, causing the syndrome of defective glucose counterregulation. Diminished increase in epinephrine, also called hypoglycemia-associated autonomic failure (HAAF), is largely responsible for defective glucose counterregulation. HAAF can result in recurrent hypoglycemia and lowering of glycemic threshold that typically triggers sympathoadrenal response to hypoglycemia. This results in hypoglycemia without warning symptoms, or “hypoglycemia unawareness,” which increases the risk of severe hypoglycemia associated with substantial morbidity and mortality. Long-term effects of severe hypoglycemia, aside from causing accidents, may include adverse cardiovascular outcomes and cognitive impairment. To reduce the impact of hypoglycemia, it is important to identify patients at risk and use careful consideration when choosing antidiabetes medications. Newer insulin analogs that more accurately replicate endogenous insulin secretion and incretin therapies that cause glucose-sensitive insulin secretion may ultimately reduce the risk of hypoglycemia.

High clinic blood pressure (BP), male sex, cigarette smoking, dyslipidemia, renal function, anemia and thiazolidenediones (TZD) treatment are known predictors for clinically significant diabetic macula edema (CSDME). This study was performed to identify the most significant risk factors for CSDME in Japanese patients with type 2 diabetes mellitus (T2DM) and retinopathy (DR), using optical coherence tomography (OCT) if necessary, by multiple regression analysis. One of the risk factors was BP in awakening. Seven diabetic Japanese patients with CSDME (group 1) and 124 subjects without CSDME (group 2) with DR on OCT were studied. The durations of T2DM in groups 1 and 2 were 15 ± 10 years and 20 ± 15 years, respectively. There was no significant difference in sex distribution, duration, age, body mass index (BMI), and HbA1c, lipids (TC, LDL, TC/HDL), creatinine and Hb levels, urinary albumin excretion rate, cigarette smoking, and clinic BP between two groups. Morning systolic home BP (MSHBP) and foveal thickness were significantly (p<0.001) greater in group 1 than in group 2, and visual acuity was significantly (p<0.001) lower in group 1 than group 2. The patients in both groups had received various kinds of drugs for hyperglycemia, hypertension and others. There were no significant differences in the prevalence of other variables between two groups. On multiple regression analysis, MSHBP and nephropathy were significantly (p <0.03) positive predictors for CSDME, while BMI had a significantly (p <0.001) negative predictor. Other variables were not significantly correlated to CSDME. Thus, MSHBP is a predictive factor for CSDME that can be added to the previously reported risk factors in patient with T2DM.

Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral β-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (β-site APP Cleaving Enzime 1). Similarly, deposits of Aβ produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies.

Morbidity and mortality from diabetes mellitus (DM) are serious worldwide concerns. By the year 2030, the estimated number of diabetic patients will reach a staggering 439 million worldwide. Diabetes mellitus type 2 (DM2), which involves disturbances in both insulin secretion and resistance, is the most common form of diabetes and affects approximately 5 to 7% of the world's population. When a patient with DM2 cannot regulate his or her blood glucose levels through diet, weight loss, or exercise, oral medications, such as hypoglycemic agents (i.e., sulphonylureas, biguanides, alpha glucosidase inhibitors and thiazolidinediones), are crucial. Here, we discuss some physiological aspects of P2 receptors on pancreatic β-cells, which express a variety of P2 receptor isoforms. These receptors enhance glucose-dependent insulin release. In addition, we speculate on the potential of purinergic compounds as novel or additional treatments for Type 2 Diabetes mellitus.

Amino acid supplementation is gaining acceptance as an important adjuvant therapy in the treatment of diabetes and its associated complications. Numerous studies in the literature report the impaired amino acid metabolism in diabetes and the beneficial effects of amino acids are positively correlated with the increase in plasma levels of those amino acids. Oxidative stress is known to play a major role in diabetic pathophysiology. Sulfur containing compounds are well known in the treatment of oxidative stress induced pathological disorders. Methionine, cysteine, and homocysteine are the three common sulfur containing amino acids. In addition, taurine, a sulfonic acid containing an amino group (amino sulfonic acid), is found in substantial amounts in mammalian tissues. Both experimental and clinical studies reported the modulatory effects of cysteine, N-acetyl cysteine, or compounds having cysteine moiety in the regulation of insulin secretion and plasma glucose levels. Taurine supplementation has been found to prevent the onset of diabetes mellitus in experimental models of both insulin dependent and insulin independent pathways. Recent reports suggest that the beneficial role of cysteine or taurine is mediated via their ability in reducing glycooxidation and preventing the generation of intracellular reactive intermediates. Studies with methionine or S-adinosyl methionine has been shown to increase mitochondrial DNA density in skeletal muscle, improve insulin sensitivity and prevent body weight gain. Homocysteine, on the other hand, is an emerging risk factor for cardiovascular disease and diabetic patients have higher levels of this sulfur containing amino acid. Supplementation with cysteine or taurine, however, was found to be effective in reducing plasma homocysteine levels. This review will discuss the role of sulfur containing amino acids in the regulation of hyperglycemia and in the development of its associated pathological dysfunctions.

The worldwide epidemic scale of diabetes mellitus has been underestimated for a long time. Currently every 10 seconds one patient dies of diabetes-related pathologies. Given the high risk and prevalence of secondary complications as well as individual predisposition to target organ injury, diabetes is one of the major risk factors for various organ and tissue dysfunctions including nerves. The present review outlines the role of Rho Kinase (ROCK) in various diabetic indications: diabetic neuropathy, erectile dysfunction, cardiomyopathy, sexual dysfunction, nephropathy, cardiomyopathy, retinopathy, cerebro-vascular disease and cystopathy. We found that ROCK is involved in various pathophysiological mechanisms, leading to a number of unique diabetic complications. Recent studies have indicated an increasing interest in the use of ROCK inhibitors like Y-27632, H1152 and fasudil not only for the treatment of diabetic neuropathy, but also for the treatment of sexual dysfunction, cardiomyopathy and other diabetic complications. The pathophysiological mechanism has been extensively analyzed and the current status of ROCK inhibitors has been discussed in the review.

Diabetic patients can be affected by a wide range of peripheral nerve disorders, the rarer of which are often poorly recognised and understood. “Insulin neuritis” or “treatment induced neuropathy” is a reversible disorder characterised by acute severe distal limb pain, peripheral nerve fibre damage and autonomic dysfunction, preceded by a period of rapid glycaemic control. The condition has been reported in both type 1 and type 2 diabetics treated with insulin or oral hypoglycaemic agents who typically have a history of poor glycaemic control. Pathogenesis of the condition and its associated pain is poorly understood, with proposed mechanisms including endoneurial ischaemia, hypoglycaemic microvascular neuronal damage and regenerating nerve firing. Pain can affect other areas including the trunk and abdomen, or be more generalised. “Diabetic neuropathic cachexia” is a rare disorder associated with poor diabetic control that presents with large amounts of unintentional weight loss associated with an acute symmetrical painful peripheral neuropathy without weakness. Pain is characteristically burning in nature with predominant lower limb involvement and allodynia. The disorder can also affect type 1 and type 2 diabetics and occur irrespective of the duration of their diabetes. Depression and in males, impotence, appear to be common, although other autonomic features can be present. Typically it has a monophasic course but has been reported to be recurrent. As with insulin neuritis, this condition is reversible over weeks to months after adequate diabetic control. For both disorders, the pain can be treatment resistant despite the use of multiple analgesics.