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

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

Statins, which are functionally known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) inhibitors, are lipid-lowering compounds widely prescribed in patients with cardiovascular diseases (CVD). Several biological and therapeutic functions have been attributed to statins, including neuroprotection, antioxidation, anti-inflammation, and anticancer effects. Pharmacological characteristics of statins have been attributed to their involvement in the modulation of several cellular signaling pathways. Over the past few years, the therapeutic role of statins has partially been attributed to the induction of autophagy, which is critical in maintaining cellular homeostasis and accounts for the removal of unfavorable cells or specific organelles within cells. Dysregulated mechanisms of the autophagy pathway have been attributed to the etiopathogenesis of various disorders, including neurodegenerative disorders, malignancies, infections, and even aging. Autophagy functions as a double-edged sword during tumor metastasis. On the one hand, it plays a role in inhibiting metastasis through restricting necrosis of tumor cells, suppressing the infiltration of the inflammatory cell to the tumor niche, and generating the release of mediators that induce potent immune responses against tumor cells. On the other hand, autophagy has also been associated with promoting tumor metastasis. Several anticancer medications which are aimed at inducing autophagy in the tumor cells are related to statins. This review article discusses the implications of statins in the induction of autophagy and, hence, the treatment of various disorders

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

HDL-Associated Proteins in Subjects with Polycystic Ovary Syndrome: A Proteomic Study

INTRODUCTION: Serum lipoproteins, with the exception of high-density lipoprotein cholesterol (HDL-C), are increased in polycystic ovary syndrome (PCOS) and their levels may reflect the associated obesity and insulin resistance, but the nature of this association is not fully explained. Therefore, proteomic analysis of key proteins in lipoprotein metabolism was performed. METHODS: In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls without PCOS). Somalogic proteomic analysis was undertaken for the following 19 proteins involved in lipoprotein, and particularly HDL, metabolism: alpha-1-antichymotrypsin; alpha-1-antitrypsin; apolipoproteins A-1, B, D, E, E2, E3, E4, L1, and M; clusterin; complement C3; hemopexin; heparin cofactor II; kininogen-1; serum amyloid A-1; amyloid beta A-4; and paraoxonase-1. RESULTS: The levels of apolipoprotein E were higher in PCOS (p = 0.012). However, the other isoforms of ApoE, ApoE2, E3, and E4, did not differ when compared with controls. ApoM was lower in PCOS (p = 0.000002). Complement C3 was higher in PCOS (p = 0.037), as was heparin cofactor II (HCFII) (p = 0.0004). The levels of the other proteins associated with lipoprotein metabolism did not differ between PCOS and controls. CONCLUSIONS: These data contribute to the concern of the deleterious dyslipidemia found in PCOS, with the novel combination reported here of higher levels of ApoE, C3 and HCFII together with lower ApoM. The dysregulation of these proteins could circumvent the protective effect of HDL-C and contribute to a more atherogenic profile that may increase cardiovascular risk

High density lipoprotein-associated proteins in non-obese women with and without polycystic ovary syndrome

Introduction: Dyslipidemia frequently occurs in women with polycystic ovary syndrome (PCOS), but it is unclear whether dyslipidemia is due to obesity and insulin resistance (IR) or is inherent to PCOS. To address this, proteomic analysis of proteins important in lipid metabolism, particularly for high-density lipoprotein cholesterol (HDL-C), was performed in non-obese, non-insulin resistant PCOS women compared to matched controls. Methods: Weight and aged-matched non-obese subjects with PCOS (n=24) and without IR were compared with control women (n=24). 19 proteins were measured by Somalogic proteomic analysis: alpha-1-antichymotrypsin, alpha-1-antitrypsin, apolipoproteins A-1, B, D, E, E2, E3, E4, L1, M, clusterin, complement C3, hemopexin, heparin cofactor-II (HCFII), kininogen-1, serum amyloid A-1, amyloid beta A-4 and paraoxonase-1. Results: Women with PCOS had a higher free androgen index (FAI) (p0.05). The triglyceride:HDL-cholesterol ratio was elevated (p=0.03) in PCOS. Alpha-1-antitrypsin levels were lower (p0.05). However, in PCOS, alpha-1-antichymotrypsin correlated negatively with BMI (r=-0.40, p<0.04) and HOMA-IR (r=-0.42, p<0.03), apoM correlated positively with CRP (r=0.36, p<0.04) and HCFII correlated negatively with BMI (r=-0.34, p<0.04). Conclusion: In PCOS subjects, when obesity, IR and inflammation confounders were absent, alpha-1-antitrypsin was lower and complement C3 was higher than in non-PCOS women, suggesting increased cardiovascular risk; however, subsequent obesity related IR/inflammation likely stimulates other HDL-associated protein abnormalities, thus increasing cardiovascular risk further

Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis

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