Acute elevations in free fatty acids (FFAs) stimulate insulin secretion, but prolonged lipid exposure impairs β-cell function in both in vitro studies and in vivo animal studies. In humans data are limited to short-term (≤48 h) lipid infusion studies and have led to conflicting results. We examined insulin secretion and action during a 4-day lipid infusion in healthy normal glucose tolerant subjects with (FH+ group, n = 13) and without (control subjects, n = 8) a family history of type 2 diabetes. Volunteers were admitted twice to the clinical research center and received, in random order, a lipid or saline infusion. On days 1 and 2, insulin and C-peptide concentration were measured as part of a metabolic profile after standardized mixed meals. Insulin secretion in response to glucose was assessed with a +125 mg/dl hyperglycemic clamp on day 3. On day 4, glucose turnover was measured with a euglycemic insulin clamp with [3-³H]glucose. Day-long plasma FFA concentrations with lipid infusion were increased within the physiological range, to levels seen in type 2 diabetes (∼500–800 μmol/l). Lipid infusion had strikingly opposite effects on insulin secretion in the two groups. After mixed meals, day-long plasma C-peptide levels increased with lipid infusion in control subjects but decreased in the FH+ group (+28 vs. −30%, respectively, P < 0.01). During the hyperglycemic clamp, lipid infusion enhanced the insulin secretion rate (ISR) in control subjects but decreased it in the FH+ group (first phase: +75 vs. −60%, P < 0.001; second phase: +25 vs. −35%, P < 0.04). When the ISR was adjusted for insulin resistance (ISR_Rd = ISR ÷ [1/R_d], where R_d is the rate of insulin-stimulated glucose disposal), the inadequate β-cell response in the FH+ group was even more evident. Although ISR_Rd was not different between the two groups before lipid infusion, in the FH+ group, lipid infusion reduced first- and second-phase ISR_Rd to 25 and 42% of that in control subjects, respectively (both P < 0.001 vs. control subjects). Lipid infusion in the FH+ group (but not in control subjects) also caused severe hepatic insulin resistance with an increase in basal endogenous glucose production (EGP), despite an elevation in fasting insulin levels, and impaired suppression of EGP to insulin. In summary, in individuals who are genetically predisposed to type 2 diabetes, a sustained physiological increase in plasma FFA impairs insulin secretion in response to mixed meals and to intravenous glucose, suggesting that in subjects at high risk of developing type 2 diabetes, β-cell lipotoxicity may play an important role in the progression from normal glucose tolerance to overt hyperglycemia.

Context: Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear. Objective: To examine glucose metabolism and β-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery. Design: Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial. Patients: In all, 16 T2DM patients (9 males and 7 females, 52±14 years, 47±9 kg m⁻², HbA1c 7.2±1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery. Outcome measures: Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery. Results: At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95±3 mg 100 ml⁻¹). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and β-cell sensitivity to glucose only after RYGB (P<0.05). Conclusion: RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and β-cell responsiveness to glucose, in part because of an incretin effect.

OBJECTIVE To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition. RESEARCH DESIGN AND METHODS This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA_1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m²) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months. RESULTS Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA_1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (−16 vs. −10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels. CONCLUSIONS Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.

Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.