Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y gastric bypass surgery in obese patients with type 2 diabetes.

OBJECTIVE: Limited data on patients undergoing Roux-en-Y gastric bypass surgery (RY-GBP) suggest that an improvement in insulin secretion after surgery occurs rapidly and thus may not be wholly accounted for by weight loss. We hypothesized that in obese patients with type 2 diabetes the impaired levels and effect of incretins changed as a consequence of RY-GBP. RESEARCH DESIGN AND METHODS: Incretin (gastric inhibitory peptide [GIP] and glucagon-like peptide-1 [GLP-1]) levels and their effect on insulin secretion were measured before and 1 month after RY-GBP in eight obese women with type 2 diabetes and in seven obese nondiabetic control subjects. The incretin effect was measured as the difference in insulin secretion (area under the curve [AUC]) in response to an oral glucose tolerance test (OGTT) and to an isoglycemic intravenous glucose test. RESULTS: Fasting and stimulated levels of GLP-1 and GIP were not different between control subjects and patients with type 2 diabetes before the surgery. One month after RY-GBP, body weight decreased by 9.2 +/- 7.0 kg, oral glucose-stimulated GLP-1 (AUC) and GIP peak levels increased significantly by 24.3 +/- 7.9 pmol x l(-1) x min(-1) (P < 0.0001) and 131 +/- 85 pg/ml (P = 0.007), respectively. The blunted incretin effect markedly increased from 7.6 +/- 28.7 to 42.5 +/- 11.3 (P = 0.005) after RY-GBP, at which it time was not different from that for the control subjects (53.6 +/- 23.5%, P = 0.284). CONCLUSIONS: These data suggest that early after RY-GBP, greater GLP-1 and GIP release could be a potential mediator of improved insulin secretion.

Obese subjects respond to the stimulatory effect of the ghrelin agonist growth hormone-releasing peptide-2 on food intake.

OBJECTIVE: The administration of the growth hormone (GH) secretagogue GH-releasing peptide (GHRP)-2, like ghrelin, increases food intake (FI) in lean healthy men. The aim of this study was to investigate whether this effect occurs in obese subjects and whether it is dose-dependent. RESEARCH METHODS AND PROCEDURES: Nineteen subjects (10 lean and nine obese), all healthy and weight stable, received a double-blind randomized subcutaneous infusion of GHRP-2 at high dose (HD; 1 mug/kg per hour), low dose (0.1 microg/kg per hour), or placebo for 270 minutes over three study visits. Blood for hormone assays was collected through an intravenous forearm catheter. Hunger and fullness were rated on visual analog scales before and after a fixed breakfast (320 kcal at 120 minutes) and a buffet lunch at 240 minutes. Before lunch, subjects received taped instructions to eat as much as they wanted. RESULTS: GHRP-2 infusion significantly increased ad libitum FI in a dose-dependent manner by 10.2 +/- 3.9% at low dose (p = 0.011) and by 33.5 +/- 5.8% at HD (p = 0.000) compared with placebo. Obesity status did not influence the effect of GHRP-2 on FI. All subjects had greater ratings of appetite before but similar levels of fullness after the meal with the HD GHRP-2. Serum GH levels increased dose dependently in all subjects. DISCUSSION: The dual stimulatory effect of GHRP-2 on FI and human GH is dose dependent. Obese individuals retain their ability to respond to GHRP-2 both in terms of FI and human GH.

Inhibiting endogenous cortisol blunts the meal-entrained rise in serum leptin.

CONTEXT: Administration of glucocorticoids increases serum leptin levels in lean and obese individuals. A morning meal produces an increase in insulin, a cortisol peak, and an increase in leptin; these changes do not occur during fasting. OBJECTIVE: The objective of this study was to investigate whether inhibiting endogenous cortisol secretion with metyrapone decreases 24-h serum leptin levels and to determine whether a meal-related midmorning surge in cortisol is a prerequisite for the meal-entrained nocturnal rise in leptin. DESIGN: This was a randomized, cross-over study. SETTING: The study was performed at the General Clinical Research Center. PARTICIPANTS: Lean males were studied. INTERVENTION: In study 1, seven lean men were studied for 24 h while their endogenous cortisol secretions were manipulated as follows: 1) CONTROL; 2) cortisol suppression by metyrapone (MET); and 3) MET and oral hydrocortisone (at 0900 h) (MET + CORT). Subjects were all fed a eucaloric diet (two meals at 1100 and 1700 h). In study 2, six men were studied without pharmacological intervention for 24 h on two occasions: once under a complete fast (FAST) and once in a feeding condition (one meal at 1100 h; FED). MAIN OUTCOME MEASURE: The main outcome measure was serum leptin. RESULTS: MET significantly suppressed serum cortisol at 0800 h, midmorning, and over the 24-h period. As a result of cortisol suppression, 24-h serum leptin levels were decreased vs. control values despite similar insulin responses to meals. Administering a single dose of hydrocortisone to MET subjects potently stimulated serum leptin compared with the effect of MET alone. CONCLUSIONS: Our data demonstrate that endogenous cortisol secretion is necessary for the maintenance of serum leptin levels over 24 h in lean, normally fed males.