Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders.

OBJECTIVE -Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucoseand lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone.RESEARCH DESIGN AND METHODS -We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n ϭ 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n ϭ 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals.RESULTS -Triglyceride levels were reduced by 51.9 Ϯ 7.8 mg/dl with pioglitazone, but were increased by 13.1 Ϯ 7.8 mg/dl with rosiglitazone (P Ͻ 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 Ϯ 0.5 vs. 2.4 Ϯ 0.5 mg/dl; P Ͻ 0.001) and the increase in LDL cholesterol was less (12.3 Ϯ 1.6 vs. 21.3 Ϯ 1.6 mg/dl; P Ͻ 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P Ͻ 0.001). LDL particle size increased more with pioglitazone (P ϭ 0.005).CONCLUSIONS -Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size. Diabetes Care 28:1547-1554, 2005T wo core metabolic defects contribute to the development of type 2 diabetes: relative insulin insufficiency and insulin resistance. Approximately 92% of patients with type 2 diabetes demonstrate insulin resistance (1). Even in the absence of overt hyperglycemia, insulin resistance is associated with a cluster of abnormalities that increase the risk for cardiovascular disease (CVD), including dyslipidemia, increased expression of inflammatory markers, activation of procoagulants, hemodynamic changes, and endothelial dysfunction (2,3).The dyslipidemia associated with insulin resistance and type 2 diabetes is characterized by elevated triglycerides and decreased HDL cholesterol (4 -6). Although LDL cholesterol may not be elevated in type 2 diabetes, an increase in the proportion of small, dense, and potentially more atherogenic LDL cholesterol particles is observed (7). In addition to LDL cholesterol, elevated triglyceride levels and reduced HDL cholesterol levels are both risk factors for coronary heart disease (CHD) (8 -11). Compared with nondiabetic individuals, patients with type 2 diabetes have a two-to fourfold high...

Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA

Subjects with NASH have significantly higher systemic levels of lipid peroxidation products and this could indicate an increased risk of cardiovascular disease. More studies are needed to evaluate this possibility.