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Cefalu WT, Rood J, Pinsonat P, Qin J, Sereda O, Levitan L, et al. processes in other glucokinase-expressing cells via GKA-mediated increase in the affinity of glucokinase for glucose and its maximal catalytic rate.[27] GKAs mediate their antidiabetic effects via generalized enhancement of -cell function and through fasting restricted changes in glucose turnover. Piragliatin, a GKA, has shown an acute glucose-lowering action in patients with moderate type 2 diabetes.[28] An experimental GKA molecule ZYGK1 showed promising efficacy in controlling both fasting and non-fasting blood glucose.[29] The side effects although rare of GKAs are hypoglycemia, fatty liver, and hyperlipidemia. Dual PPAR agonists Inhibition of PPAR -agonists (Fibrates) lowers plasma triglycerides and VLDL particles and increases HDL cholesterol while PPAR -agonists (thiazolidinediones) influence free fatty acid flux and reduce insulin resistance and blood glucose levels. The PPAR / dual agonism addresses both insulin resistance (the inability of tissues to utilize insulin efficiently for the uptake of glucose) and key aspects of the dyslipidemia that contribute to the high risk of cardiovascular disease (CVD) in diabetics. They have documented heightened insulin sensitivity and are known to improve inflammation, vascular function, and vascular remodeling.[30] Aleglitazar, a new balanced dual PPAR / agonist, reduces hyperglycemia and improves the levels of HbA1C, HDL-C, LDL, and triglycerides with minimal PPAR-related adverse effects.[31,32] In models, aleglitazar strongly decreased the multiple aspects of SJ 172550 the inflamed phenotype of human adipocyte/macrophage co-culture system compared to pioglitazone and fenofibrate suggesting its contribution to prevent progression of adipose dysfunction and insulin resistance, SJ 172550 and increased cardiovascular risk.[33] Although muraglitazar a similar molecule showed efficacy as an add-on therapy for poorly controlled diabetics, extra incidence of death, major adverse cardiovascular events (MI, stroke, TIA), and heart failure were noted with it and hence withdrawn.[34] Monoclonal antibodies To induce immune tolerance via monoclonal antibodies has been tried as a way to prevent and effectively treat diabetes. Otelixizumab, an anti-CD3 monoclonal antibody, is known to stimulate C-peptide levels and reduce insulin requirement in type 1 diabetes.[35] Similarly studies with teplizumab are also reassuring.[36] Other monoclonal antibodies such as anti-CD20,[37] anti-CTGF,[38] anti-IL-1,[39] have shown promising results and are yet to be approved. Dopamine-2 receptor agonist Timed bromocriptine (centrally-acting dopamine D2 receptor agonist) is usually believed to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial says in insulin-resistant patients. Its use as monotherapy and in combination with other OHAs is usually shown to reduce HbA1c, plasma triglyceride, and FFA concentrations in type 2 diabetic patients.[40] Side effects include nausea, fatigue, vomiting, headache, dizziness, orthostatic hypotension, and syncope, the latter two upon initiation or dose escalation. Others Chromium (Cr) may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 diabetes mellitus impartial of its effects on weight or hepatic glucose production.[41] Clinical response to Cr is usually more likely in insulin-resistant type 2 diabetics with elevated fasting glucose and A1C levels. It also has anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFB, Akt, and Glut-2 and increased IRS-1 gene activation.[42] Sodium tungstate is known to preserve the pancreatic -cell function in diabetics and normalize the activity of sucrase and SJ 172550 SGLT1 in the brush-border CITED2 membrane of enterocytes.[43] A combination of hyperglycemia-independent pathways are postulated to explain its antidiabetic effects.[44] Vanadium is known to mimic most effects of insulin on the main target tissues of the hormone and it is shown to induce a sustained fall in blood glucose levels in insulin-deficient diabetic rats, and improve glucose homeostasis in obese, insulin-resistant diabetic rodents ( em in vivo /em ). It has shown antidiabetic effects in phase II trials[45] although another study showed no such benefits.[46] Proxyfan, a central histamine H3 receptor ligand, is shown to significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.[47] Aspartame, guargum, and glucomannan have all displayed notable benefits in glycemic control either singly or as combinations. Experimental research A new molecule SR 1664 which is a potent binder to the nuclear receptor PPAR shows that blockage of cyclin-dependent kinase 5 (Cdk5)’s action on PPAR is a viable therapeutic approach for development of antidiabetic brokers. It also exhibited fewer side effects, such as weight gain or increased plasma volume, compared to rosiglitazone.[48] Systemic administration of toll-like receptor (TLR) ligands can suppress autoimmune responses (autoimmune diabetes) which reinforces the hypothesis that TLR stimulation can recapitulate the.