OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Intra-abdominal fat is independently associated with liver fat, whereas subcutaneous fat is not. Liver fat, but not intra-abdominal fat, is independently associated with serum insulin. Men and women with similar amounts of intra-abdominal and liver fat do not exhibit sex differences in markers of insulin resistance (serum insulin, triglycerides, HDL cholesterol and adiponectin).

OBJECTIVEWe previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure.RESEARCH DESIGN AND METHODSSixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI).RESULTSAt 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (−7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and −0.99 ± 0.65, respectively; P = 0.028).CONCLUSIONSEXE and GLAR sustained HbA1c over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.

OBJECTIVE -The purpose of this study was to determine whether type 2 diabetic patients have more liver fat than age-, sex-, and BMI-matched nondiabetic subjects and whether liver enzymes (serum alanine aminotransferase [S-ALT] and serum aspartate aminotransferase) are similarly related to liver fat in type 2 diabetic patients and normal subjects. RESEARCH DESIGN AND METHODS -Seventy type 2 diabetic patients and 70nondiabetic subjects matched for BMI, age, and sex were studied. Liver fat ( 1 H-magnetic resonance spectroscopy), body composition (magnetic resonance imaging), and biochemical markers of insulin resistance were measured.RESULTS -The type 2 diabetic patients had, on average, 80% more liver fat and 16% more intra-abdominal fat than the nondiabetic subjects. The difference in liver fat between the two groups remained statistically significant when adjusted for intra-abdominal fat (P Ͻ 0.05). At any given BMI or waist circumference, the type 2 diabetic patients had more liver fat than the nondiabetic subjects. The difference in liver fat between the groups rose as a function of BMI and waist circumference. Fasting serum insulin (r ϭ 0.55, P Ͻ 0.0001), fasting plasma glucose (r ϭ 0.29, P ϭ 0.0006), A1C (r ϭ 0.34, P Ͻ 0.0001), fasting serum triglycerides (r ϭ 0.36, P Ͻ 0.0001), and fasting serum HDL cholesterol (r ϭ Ϫ0.31, P ϭ 0.0002) correlated with liver fat similarly in both groups. The slopes of the relationships between S-ALT and liver fat were significantly different (P ϭ 0.004). Liver fat content did not differ between the groups at low S-ALT concentrations (10 -20 units/l) but was 70 -200% higher in type 2 diabetic patients compared with control subjects at S-ALT concentrations of 50 -200 units/l. CONCLUSIONS -Type 2 diabetic patients have 80% more liver fat than age-, weight-, and sex-matched nondiabetic subjects. S-ALT underestimates liver fat in type 2 diabetic patients. Diabetes Care 31:165-169, 2008I t has been estimated that ϳ70 -80% of type 2 diabetic patients have nonalcoholic fatty liver disease (1,2). In addition, 9 of 12 prospective epidemiological studies have shown that elevated serum liver enzyme concentrations predict type 2 diabetes independent of obesity (3). These data thus suggest that liver fat content is increased in patients with type 2 diabetes compared with equally obese nondiabetic subjects. To date, only one study has addressed this question (4). In this study, liver fat was measured qualitatively using the liver-to-spleen attenuation ratio (4). Liver fat was increased in type 2 diabetic patients compared with 10 weight-matched normal subjects (4). The small number of normal subjects, however, prevents any firm conclusions from being drawn.Clinically, it would be helpful to have a simple measure of liver fat in patients with type 2 diabetes, as liver fat is closely correlated with insulin requirements (5,6) and may be an important parameter to consider when choosing patients for peroxisome proliferator-activated receptor-␥ agonist therapy (7,8). Serum alanine aminotransfera...