Effects of insulin and oral anti‐diabetic agents on glucose metabolism, vascular dysfunction and skeletal muscle inflammation in type 2 diabetic subjects

Abstract

Background To test potential differences between the actions of anti-diabetic medications, we examined the effects of oral hypoglycemic agents versus insulin glargine-apidra therapy in T2DM. Methods T2DM subjects were randomized to either OHA (pioglitazone, metformin, glipizide, n=9) or IT (n=12) for 6 months. Carotid intimal media thickness (CIMT), vascular reactivity [FMD] (% change in brachial arterial diameter [BD] post-ischemia), and sublingual nitrate [SLN] were measured with ultrasonography. Euglycemic hyperinsulinemic (80 mU/m2) clamp with [3]-3H-glucose and muscle biopsies were performed. Results FPG (∼257 to ∼124, OHA ∼256 to ∼142 mg/dl, IT) and HgbA1C (∼10.3 to ∼6.4%, OHA; ∼10.7 to ∼7.1%, IT), improved comparably. EGP (∼2.1 to ∼1.7, OHA; ∼2.3 to ∼2.0, IT) and EGP suppression by insulin (∼0.4 to ∼0.3, OHA; ∼0.5 to ∼0.7 mg/kg.min, IT) was different. Total glucose disposal [TGD/I) × 100] increased in OHA (∼5.2 to ∼8.1, p=0.03), but not in IT (∼6.0 to ∼5.4 mg/kg.min/μU/ml × 100). OHA reduced CIMT (∼0.080 to ∼0.068, p<0.05), whereas IT did not (∼0.075 to ∼0.072 cm). After SLN, BD increased in OHA (∼8.7 to ∼18.2%), but not in IT (∼11.2 to ∼15.0), [p<0.02]. Except for plasma adiponectin (∼7 to ∼15, OHA vs. ∼6 to ∼10, IT), changes in inflammatory markers in the circulation and in muscle (IκBα, SOD2 & MCP1, p-ERK and JNK) were equivalent. Conclusions OHA and IT achieved adequate glycemic control and the effects on circulating and muscle inflammatory biomarkers were similar, but only OHA improved insulin sensitivity, vascular function and CIMT. These findings in a small sample suggest that the use of OHA provide additional benefits to patients with T2DM.

Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes

“…Metformin has been reported to decrease hepatic glucose production, thereby activating AMPK, reducing fatty liver, and decreasing microvascular and macrovascular complications associated with type 2 diabetes (40). Several studies also have suggested additional benefits of metformin beyond hypoglycemic effects, including improvement of vascular function, regulation of vaspin levels and ovary function in polycystic ovary syndrome, adjuvant treatment for cancer, and disease prevention in prediabetic populations (41–43). The anti-inflammatory effect of metformin also was demonstrated in neutrophils and acute lung injury mediated by mitochondrial complex I inhibition (44).…”

Effect of Insulin Glargine and n-3FA on Carotid Intima-Media Thickness in People With Dysglycemia at High Risk for Cardiovascular Events

“…Several studies confirmed the presence of increased CIMT in people with type 2 diabetes or prediabetes (37). However, there are only a few small, and therefore not reliable, intervention trials with insulin on atherosclerosis progression (38,39). Clinical CV end point trials conducted prior to ORIGIN also fail to provide clear answers regarding the impact of exogenous insulin on CV events.…”

The vascular endothelium in diabetes—a therapeutic target?

“…Demonstrating improvement in vascular function with reductions in glucose is more difficult, because of confounding effects of most glucose-lowering therapies independent of benefits via glucose lowering. For example, glucose reductions with insulin therapy have been shown to improve endothelial function, but these benefits cannot be cleanly attributed to the glucose lowering effect alone [30,31]. Even therapies that modulate glucose concentrations independent of direct effects on beta cell function or insulin sensitivity in peripheral tissues can produce secondary improvements in these parameters, as will be discussed below.…”