.-Ghrelin is an orexigenic hormone that is implicated in meal initiation, in part because circulating levels rise before meals. Because previous human studies have examined subjects fed on known schedules, the observed preprandial ghrelin increases could have been a secondary consequence of meal anticipation. A causal role for ghrelin in meal initiation would be better supported if preprandial increases occurred before spontaneously initiated meals not prompted by external cues. We measured plasma ghrelin levels among human subjects initiating meals voluntarily without cues related to time or food. Samples were drawn every 5 min between a scheduled lunch and a freely requested dinner, and hunger scores were obtained using visual analog scales. Insulin, glucose, fatty acids, leptin, and triglycerides were also measured. Ghrelin levels decreased shortly after the first meal in all subjects. A subsequent preprandial increase occurred over a wide range of intermeal intervals (IMI; 320 -425 min) in all but one subject. Hunger scores and ghrelin levels showed similar temporal profiles and similar relative differences in magnitude between lunch and dinner. One subject displayed no preprandial ghrelin increase and was also the only individual whose insulin levels did not return to baseline between meals. This finding, along with a correlation between area-under-the-curve values of ghrelin and insulin, suggests a role for insulin in ghrelin regulation. The preprandial increase of ghrelin levels that we observed among humans initiating meals voluntarily, without time-or food-related cues, and the overlap between these levels and hunger scores are consistent with a role for ghrelin in meal initiation. appetite; insulin ALTHOUGH MEALTIME HUNGER IS a common, daily experience, the nature of the molecular determinants underlying this sensation is debated. Ghrelin is a recently discovered enteric peptide hormone that is the only known circulating orexigen and one of very few substances shown to stimulate appetite and food intake when administered to humans (22,36,46,51). Orexigenic actions of ghrelin have been demonstrated after modestdose peripheral injections that generate approximately physiological blood levels in humans and rodents, suggesting that normal fluctuations in endogenous circulating ghrelin can affect appetite (51, 52). Considerable evidence in multiple species implicates ghrelin in the control of preprandial hunger and meal initiation. Additional evidence suggests that ghrelin may also participate in long-term body-weight regulation, and blockade of ghrelin signaling is actively being explored as a potential anti-obesity modality (13, 14).The following observations are consistent with the hypothesis that ghrelin contributes to preprandial hunger and meal initiation (12,14). 1) The greatest amount of ghrelin is produced by the stomach and duodenum, organs that are well positioned to sense the presence or absence of recently ingested food (3,16,19,22,24). 2) As predicted for a meal initiator, ghrelin levels incre...

Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.

The plasma concentration of the adipocyte-derived peptide adiponectin is decreased in patients with obesity and type 2 diabetes. The adiponectin gene is located on chromosome 3q27, where a diabetes susceptibility locus has been mapped. Adiponectin gene polymorphisms (single nucleotide polymorphisms [SNPs]) have been associated with BMI, insulin sensitivity, and type 2 diabetes in some cross-sectional studies. Our aim was to assess the contribution of these SNPs in the development of features of the insulin resistance syndrome in a 3-year prospective study in ϳ4,500 French Caucasian subjects from the Epidemiologic Data on the Insulin Resistance Syndrome (DESIR) cohort. For subjects who were normoglycemic at baseline, the 3-year risk of becoming hyperglycemic (diabetes or impaired fasting glucose) was affected by two SNPs: G-11391A and T45G. T he role of the newly described adipocyte-derived peptide adiponectin is still poorly understood. Nevertheless, its plasma concentration is decreased in patients with obesity, type 2 diabetes, or coronary artery disease (1,2). The treatment of diabetic animals with adiponectin has been shown (3,4) to improve insulin sensitivity. The adiponectin gene consists of three exons and two introns located on chromosome 3q27, where a diabetes susceptibility locus has been mapped (5,6). Single nucleotide polymorphisms (SNPs) of the adiponectin gene have been associated with BMI, insulin sensitivity, and type 2 diabetes in some cross-sectional studies (7-9), but these associations have not been seen in all studies (10,11). The aim of our study was to assess the effects of these polymorphisms on the 3-year evolution of features of the insulin resistance syndrome in a large Caucasian population of men and women, aged 30 -64 years, known as the Epidemiologic Data on the Insulin Resistance Syndrome (DESIR) cohort. The influence of baseline plasma adiponectin levels on the 3-year risk of developing hyperglycemia (impaired fasting glycemia or type 2 diabetes) was also estimated. RESEARCH DESIGN AND METHODSThe study population consisted of men and women, aged 30 -64 years, who participated in DESIR, a 9-year follow-up study that aims to clarify the Additional information for this article can be found in two online appendixes at http://diabetes.diabetesjournals.org. DESIR, Epidemiologic Data on the Insulin Resistance Syndrome; IFG, impaired fasting glucose; SNP, single nucleotide polymorphism; WHR, waistto-hip ratio.

Mutations in the translated part of the leptin gene (LEP) have been found in only two families. Nevertheless DNA polymorphisms in the LEP region are linked to extreme obesity. We previously found in the 5' region of LEP a polymorphism, G-2548A, associated with a differerce in BMI reduction following a low calorie diet in overweight women. Recently, this polymorphism was associated with extreme obesity in women. In this work, we genotyped a new sample from the general population including 314 normal weight (BMI < 27 kg/m2) and 109 overweight subjects (BMI > or = 27 kg/m2). The genotype and allele frequencies were significantly different between groups, with the G-2548 allele being more frequent in the overweight subjects (p < 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass (p = 0.05). Our results indicate that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.