Molecular mechanisms of trehalose in modulating glucose homeostasis in diabetes

Diabetes mellitus is the most prevalent metabolic disorder contributing to significant morbidity and mortality in humans. Many preventative and therapeutic agents have been developed for normalizing glycemic profile in patients with diabetes. In addition to various pharmacologic strategies, many non-pharmacological agents have also been suggested to improve glycemic control in patients with diabetes. Trehalose is a naturally occurring disaccharide which is not synthesized in human but is widely used in food industries. Some studies have provided evidence indicating that it can potentially modulate glucose metabolism and help to stabilize glucose homeostasis in patients with diabetes. Studies have shown that trehalose can significantly modulate insulin sensitivity via at least 7 molecular pathways leading to better control of hyperglycemia. In the current study, we concluded about possible anti-hyperglycemic effects of trehalose suggesting trehalose as a potentially potent non-pharmacological agent for the management of diabetes

Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues

The effect of C-peptide on diabetic nephropathy: A review of molecular mechanisms

C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu

Obesity and Insulin Resistance: A Review of Molecular Interactions

The prevalence of insulin resistance and diabetes mellitus is rising globally in epidemic proportions. Diabetes and its complications contribute to significant morbidity and mortality. An increase in sedentary lifestyle and consumption of a more energydense diet increased the incidence of obesity which is a significant risk factor for type 2 diabetes. Obesity acts as a potent upstream event that promotes molecular mechanisms involved in insulin resistance and diabetes mellitus. However, the exact molecular mechanisms between obesity and diabetes are not clearly understood. In the current study, we have reviewed the molecular interactions between obesity and type 2 diabetes

Anti-inflammatory potentials of incretin-based therapies used in the management of diabetes

GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase 4 inhibitors (DPP-4i) are two classes of antidiabetic agents used in the management of diabetes based on incretin hormones. There is emerging evidence that they have anti-inflammatory effects. Since most long-term complications of diabetes have a background of chronic inflammation, these agents may be beneficial against diabetic complications not only due to their hypoglycemic potential but also via their anti-inflammatory effects. However, the exact molecular mechanisms by which GLP-1RAs and DPP-4i exert their anti-inflammatory effects are not clearly understood. In this review, we discuss the potential molecular pathways by which these incretin-based therapies exert their anti-inflammatory effects

Incretin-based therapies and renin-angiotensin system: Looking for new therapeutic potentials in the diabetic milieu

Incretin-based therapies include pharmacologic agents such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors which exert potent anti-hyperglycemic effects in the diabetic milieu. They are also shown to have extra-pancreatic effects. Renin-angiotensin system is part of the endocrine system which is widely distributed in the body and is closely involved in water and electrolyte homeostasis as well as renal and cardiovascular functions. Hence the renin-angiotensin system is the main target for treating patients with various renal and cardiovascular disorders. There is growing evidence that incretins have modulatory effects on renin-angiotensin system activity; thereby, can be promising therapeutic agents for the management of renal and cardiovascular disorders. But the exact molecular interactions between incretins and renin-angiotensin system are not clearly understood. In this current study, we have reviewed the possible molecular mechanisms by which incretins modulate renin-angiotensin system activity

Molecular mechanisms by which SGLT2 inhibitors can induce insulin sensitivity in diabetic milieu: A mechanistic review

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are a relatively newer class of anti-hyperglycemic medications that reduce blood glucose by inhibition of renal glucose re-uptake, thereby increasing urinary glucose excretion. Although glycosuria is the primary mechanism of action of these agents, there is some evidence suggesting they can reduce insulin resistance and induce peripheral insulin sensitivity. Identifying the molecular mechanisms by which these medications improve glucose homeostasis can help us to develop newer forms of SGLT2i with lesser side effects. We have reviewed the molecular mechanisms and signaling pathways by which SGLT2i therapy improve insulin sensitivity and ameliorates insulin resistance

The major molecular mechanisms mediating the renoprotective effects of SGLT2 inhibitors: An update

Abstract The incidence of diabetes mellitus, as well as its complications, is rapidly growing. Diabetic nephropathy is one of the most prevalent disorders induced by chronic uncontrolled hyperglycemia and is accompanied by a reduction in renal sufficiency with microstructural tissue damage in the kidneys. Many therapeutic protocols have been designed to address the treatment and prevention of diabetic nephropathy. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a newly introduced class of glucose-lowering agents that reduce blood glucose by inhibition of urinary glucose reabsorption in renal proximal tubules and so induce glycosuria. Also, these hypoglycemic agents may provide protective effects in different tissues such as cardiovascular, brain, and kidneys. In recent years, accumulating evidence has indicated that SGLT2i possess potent renal protective properties in the setting of diabetes. In the current study, we present the latest findings regarding the renoprotective effects of SGLT2 inhibition and discuss the molecular mechanisms involved

MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress

MicroRNAs (miRs) are small non-coding pieces of RNA that are involved in a variety of physiologic processes such as apoptosis, cell proliferation, cell differentiation, cell cycle and cell survival. These multifunctional nucleotides are also capable of preventing oxidative damages by modulating antioxidant defense systems in a variety of milieu, such as in diabetes. Although the exact molecular mechanisms by which miRs modulate the antioxidant defense elements are unclear, some evidence suggests that they may exert these effects via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intracellular mechanism is crucial in the maintenance of the physiologic redox balance by regulating the expression and activity of various cellular antioxidative defense elements and thereby plays a pivotal role in the development of oxidative stress. Any impairment in the Nrf2 signaling pathway may result in oxidative damage-dependent complications such as various diabetic complications, neurological disorders and cancer. In the current review, we discuss the modulatory effects of miRs on the Nrf2 signaling pathway, which can potentially be novel therapeutic targets

The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials