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.

Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.

OBJECTIVE -To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -A total of 23 diabetic patients (age 30 -70 years, BMI Ͻ 36 kg/m2 ) who were being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n ϭ 11) or pioglitazone (45 mg/day) (n ϭ 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT); and hepatic and peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU ⅐ min Ϫ1 ⅐ m -2 ) clamp performed with 3-[ 3 H]glucose and indirect calorimetry. HbA 1c was measured monthly throughout the study period.RESULTS -After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 Ϯ 15 to 135 Ϯ 11 mg/dl, P Ͻ 0.01), mean plasma glucose during OGTT (293 Ϯ 12 to 225 Ϯ 14 mg/dl, P Ͻ 0.01), and HbA 1c (8.9 Ϯ 0.3 to 7.2 Ϯ 0.5%, P Ͻ 0.01) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 Ϯ 39 to 478 Ϯ 49 Eq/l, P Ͻ 0.01) and mean plasma FFA during OGTT (485 Ϯ 30 to 347 Ϯ 33 Eq/l, P Ͻ 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose production (EGP) and FPG were strongly correlated (r ϭ 0.67, P Ͻ 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P Ͻ 0.05), whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P Ͻ 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGTT was strongly related to the change in total body glucose disposal during the second insulin clamp step.CONCLUSIONS -These results suggest that pioglitazone therapy in type 2 diabetic patients decreases fasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin. Diabetes Care 24:710 -719, 2001T ype 2 diabetes is characterized by defects in both insulin secretion and insulin sensitivity (1,2). The insulin resistance is established early in the natural history of type 2 diabetes (1-3), but with time there is a progressive failure of ␤-cell function (1,4,5). Based on the pathophysiology of type 2 diabetes, combination therapy with an insulin secretagogue and an insulin sensitizer provides a rational therapeutic approach to reduce blood glucose levels in poorly controlled type 2 diabetic patients (6). Such an approach has been used successfully with sulfonylureas and metformin (7).Recently, a new class of insulinsensitizing agents, the thiazolidinediones, was introduced for the treatment of type 2 diabetic patients (8). Troglitazone, the first thiazolidinedione introduced into the U.S. market, has been...

The effect of pioglitazone (PIO) on plasma adiponectin concentration, endogenous glucose production (EGP), and hepatic fat content (HFC) was studied in 11 type 2 diabetic patients (age, 52 ؎ 2 yr; body mass index, 29.6 ؎ 1.1 kg/m 2 ; HbA 1c , 7.8 ؎ 0.4%). HFC (magnetic resonance spectroscopy) and basal plasma adiponectin concentration were quantitated before and after PIO (45 mg/d) for 16 wk. Subjects received a 3-h euglycemic insulin (100 mU/m 2 ⅐min) clamp combined with 3-[ 3 H] glucose infusion to determine rates of EGP and tissue glucose disappearance (Rd) before and after PIO. PIO reduced fasting plasma glucose (10.0 ؎ 0.7 to 7.2 ؎ 0.6 mmol/liter, P < 0.01) and HbA 1c (7.8 ؎ 0.4 to 6.5 ؎ 0.3%, P < 0.01) despite increased body weight (83.0 ؎ 3.0 to 86.4 ؎ 3.0 kg, P < 0.01). PIO improved Rd (6.6 ؎ 0.6 vs. 5.2 ؎ 0.5 mg/kg⅐min, P < 0.005) and reduced EGP (0.23 ؎ 0.04 to 0.05 ؎ 0.02 mg/kg⅐min, P < 0.01) during the 3-h insulin clamp. After PIO treatment, HFC decreased from 21.3 ؎ 4.2 to 11.0 ؎ 2.4% (P < 0.01), and plasma adiponectin increased from 7 ؎ 1 to 21 ؎ 2 g/ml (P < 0.0001). Plasma adiponectin concentration correlated negatively with HFC (r ‫؍‬ ؊0.60, P < 0.05) and EGP (r ‫؍‬ ؊0.80, P < 0.004) and positively with Rd before (r ‫؍‬ 0.68, P < 0.02) pioglitazone treatment; similar correlations were observed between plasma adiponectin levels and HFC (r ‫؍‬ ؊0.65, P < 0.03) and Rd after (r ‫؍‬ 0.70, P ‫؍‬ 0.01) pioglitazone treatment. EGP was almost completely suppressed after pioglitazone treatment; taken collectively, plasma adiponectin concentration, before and after pioglitazone treatment, still correlated negatively with EGP during the insulin clamp (r ‫؍‬ ؊0.65, P < 0.001). In conclusion, PIO treatment in type 2 diabetes causes a 3-fold increase in plasma adiponectin concentration. The increase in plasma adiponectin is strongly associated with a decrease in hepatic fat content and improvements in hepatic and peripheral insulin sensitivity. The increase in plasma adiponectin concentration after thiazolidinedione therapy may play an important role in reversing the abnormality in hepatic fat mobilization and the hepatic/muscle insulin resistance in patients with type 2 diabetes. (J Clin Endocrinol Metab 89: 200 -206, 2004)

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous glucose production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 ؎ 2 years, BMI 29.4 ؎ 1.1 kg/m 2 , HbA 1c 7.8 ؎ 0.4%). Hepatic fat content (magnetic resonance spectroscopy) and SGU (oral glucose load-insulin clamp technique) were quantitated before and after pioglitazone (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic insulin (100 mU ⅐ m ؊2 ⅐ min ؊1 ) clamp, and a 75-g oral glucose load was ingested 3 h after starting the insulin clamp. Following glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4 h after glucose ingestion from the ingested glucose load. 3-[ 3 H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of EGP and glucose disappearance (R d ). Pioglitazone reduced fasting plasma glucose (10.0 ؎ 0.7 to 7.5 ؎ 0.6 mmol/l, P < 0.001) and HbA 1c (7.8 ؎ 0.4 to 6.7 ؎ 0.3%, P < 0.001) despite increased body weight (83 ؎ 3 to 86 ؎ 3 kg, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, pioglitazone improved R d (6.9 ؎ 0.5 vs. 5.2 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.001) and insulinmediated suppression of EGP (0.21 ؎ 0.04 to 0.06 ؎ 0.02 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.01). Following pioglitazone treatment, hepatic fat content decreased from 19.6 ؎ 3.6 to 10.4 ؎ 2.1%, (P < 0.005), and SGU increased from 33.0 ؎ 2.8 to 46.2 ؎ 5.1% (P < 0.005). Pioglitazone treatment in type 2 diabetes 1) decreases hepatic fat content and improves insulin-mediated suppression of EGP and 2) augments splanchnic and peripheral tissue glucose uptake. Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes. Diabetes 52:1364 -1370, 2003 T he splanchnic tissues play a pivotal role in the maintenance of normal glucose homeostasis (1). Hyperglycemia, plasma free fatty acid (FFA) concentration, and route of glucose administration all exert independent effects on splanchnic glucose uptake (SGU). When glucose is administered intravenously, the resultant hyperglycemia enhances SGU in proportion to the increase in plasma glucose concentration such that the splanchnic glucose clearance remains unchanged (2,3). This mass-action effect of hyperglycemia to augment SGU is dependent upon maintained portal insulin levels (2-5,8). Insulin per se does not increase SGU (2,5). Studies by DeFronzo and colleagues (3,5) in humans and by Cherrington and colleagues (6,7) in dogs have shown that the gastrointestinal/portal route of glucose administration has a specific enhancing effect on SGU. Thus, following glucose ingestion, the fractional, as well as absolute rate of glucose uptake by the splanchnic tissues is significantly greater than the combined effects of hyperinsulinemia plus hyperglycemia created...