Effects of Rosiglitazone and Metformin on Liver Fat Content, Hepatic Insulin Resistance, Insulin Clearance, and Gene Expression in Adipose Tissue in Patients With Type 2 Diabetes

Abstract

Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 ؎ 3 years, fasting plasma glucose 152 ؎ 9 mg/dl, BMI 30.6 ؎ 0.8 kg/m 2 ) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA 1c , insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 ؎ 4 vs. 82 ؎ 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 ؎ 3 vs. 7 ؎ 1%, 0 vs. 16 weeks, P ‫؍‬ 0.003) but not by metformin (13 ؎ 3 to 14 ؎ 3%, NS). Rosiglitazone (16 ؎ 2 vs. 20 ؎ 1 ml ⅐ kg ؊1 ⅐ min ؊1, P ‫؍‬ 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r ‫؍‬ ؊0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-␥, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.

Associations of adiponectin with metabolic and vascular risk parameters in the British Regional Heart Study reveal stronger links to insulin resistance-related than to coronory heart disease risk-related parameters

“…In line with this notion, evidence of a link between adiponectin and directly measured endothelial dysfunction is inconsistent, [6][7][8]53 whereas other data support a link between elevations in adiponectin and reduced liver fat. 54 The inverse correlation between adiponectin and ALT in this study supports to some extent this latter possibility. Associations of adiponectin with metabolic and vascular risk parameters SG Wannamethee et al…”

“…Moreover, a marked rise in adiponectin by glitazones has been directly correlated with a reduction in hepatic fat accumulation. 54 Thus adiponectin's action to reduce hepatic fat by enhancing fatty acid oxidation, may partially explain its inverse association to parameters such as ALT, triglyceride, CRP and, as discussed above, t-PA (via reduced hepatic PAI-1 synthesis).…”

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

“…These results could be due to metformin's weak antisteatogenic effect and no increase in adiponectin. 15 The latter, together with the absence of improvement of steatosis, have since been confirmed. 13 Therefore, there are no convincing data favoring the efficacy of metformin in NASH.…”

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…Plasma AD levels are reduced in obese humans [22], the offspring of diabetic parents [23] and patients with type 2 diabetes [22] and are increased two-to threefold following thiazolidinedione treatment [24]. We [25] and others [19] have previously reported that PPAR-γ (thiazolidinedione) treatment causes a threefold increase in plasma AD concentration, which is closely related to the decrease in hepatic fat content and enhanced hepatic and peripheral insulin sensitivity in type 2 diabetic patients. Injection of recombinant AD in mice enhances adenosine 5′-monophosphate-activated protein kinase (AMPK) activity, increases fatty acid oxidation and reduces triacylglycerol content in muscle, improves muscle sensitivity to insulin and decreases basal hepatic glucose output [26,27].…”

“…thiazolidinediones) exert their metabolic effects by binding to the PPAR-γ receptor, which is located primarily on the adipocytes [15]. Previous studies from our laboratory [16,17] and others [18,19] have demonstrated that thiazolidinedione (PPAR-γ agonists) treatment in patients with type 2 diabetes mellitus is associated with a reduction in plasma NEFA levels and NEFA turnover, a shift in fat distribution from visceral and hepatic to subcutaneous depots, improved hepatic and peripheral (muscle) insulin sensitivity and enhanced insulin signalling. Of note, positive relationships between increased hepatic fat content and various measures of insulin resistance have been observed in humans, independently of BMI [16,20].…”