E. Muscelli

GLP-1 and Adiponectin: Effect of Weight Loss After Dietary Restriction and Gastric Bypass in Morbidly Obese Patients with Normal and Abnormal Glucose Metabolism

BackgroundIt has been proposed that there is improvement in glucose and insulin metabolism after weight loss in patients who underwent diet restriction and bariatric surgery.MethodsEleven normal glucose tolerant (NGT) morbidly obese patients [body mass index (BMI), 46.1u2009±u20092.27xa0g/m2] and eight abnormal glucose metabolism (AGM) obese patients (BMI, 51.20xa0kg/m2) were submitted to diet-restriction and bariatric surgery. Prospective study on weight loss changes, over the glucose, insulin metabolism, glucagon-like peptide-1 (GLP-1), and adiponectin levels were evaluated by oral glucose tolerance test during three periods: T1 (first evaluation), T2 (pre-surgery), and T3 (9xa0months after surgery).ResultsInsulin levels improved after surgery. T1 was 131.1u2009±u200917.60xa0pmol/l in the NGT group and 197.57u2009±u200957.94xa0pmol/l in the AGM group, and T3 was 72.48u2009±u20093.67xa0pmol/l in the NGT group and 61.2u2009±u20099.33xa0pmol/l in the AGM group. The major reduction was at the first hour of the glucose load as well as fasting levels. At 9xa0months after surgery (T3), GLP-1 levels at 30 and 60xa0min had significantly increased in both groups. It was observed that the AGM group had higher levels of GLP-1 at 30xa0min (34.06u2009±u20096.18xa0pmol/l) when compared to the NGT group (22.69u2009±u20094.04xa0pmol/l). Homeostasis model assessment of insulin resistance from the NGT and AGM groups had a significant reduction at periods T3 in relation to T1 and T2. Adiponectin levels had increased concentration in both groups before and after surgical weight loss. However, it did not have any statistical difference between periods T1 vs. T2.ConclusionsWeight loss by surgery leads to improvement in the metabolism of carbohydrates in relation to sensitivity to the insulin, contributing to the reduction of type 2 diabetes incidence. This improvement also was expressed by the improvement of the levels of adiponectin and GLP-1.

Acute insulin administration does not affect plasma leptin levels in lean or obese subjects

Abstract. Whether leptin levels are related to insulin sensitivity or subject to acute regulation by insulin is not known. In 12 obese [body mass index (BMI) = 34.0 ±1.5 kg m‐2] and 12 lean (BMI = 22.2 ±0.6 kg m‐2) non‐diabetic subjects, plasma leptin concentrations were measured in the fasting state and during 2 hours of euglycaemic hyperinsulinaemia (˜600 pmol L‐2). Fasting plasma leptin was significantly higher in obese (26.6 ±3.2) than in lean subjects (6.4 ±1.2 ng mL‐1, P= 0.0001), and in women (21.1 ±3.3) than in men (7.3 = 2.3 ng mL‐1, P= 0.01). In univariate analysis, fasting plasma leptin was strongly related to all anthropometric measures (body weight, fat mass, percent fat mass, waist and hip circumferences). In multiple regression, per cent adiposity, hip circumference and duration of obesity explained 90% of the variability in fasting leptin concentrations. Fasting and stimulated (OGTT) insulin levels, insulin sensitivity (22.6 ±1.9 vs 36.7 ±2.0 μmol min‐1 kg‐1 in lean and obese subjects, respectively, P < 0.0001), glucose area, and serum triglycerides were positively related to fasting plasma leptin concentrations; none of these associations, however, was statistically significant after adjusting for BMI. During the clamp, plasma leptin concentrations remained constant in both lean and obese subjects. We conclude that neither insulin levels nor sensitivity relate to leptin levels independently of fat mass, and that leptin is not subject to acute (2 hours) regulation by insulin in lean or obese humans.

Influence of duration of obesity on the insulin resistance of obese non-diabetic patients

OBJECTIVE: To investigate whether duration of obesity has an independent impact on insulin resistance.DESIGN: Case-control study.SUBJECTS: 30 non-diabetic obese subjects (age, 34±2u2005y, body mass index (BMI), 33.5±0.8u2005kgċm−2) with a range (1–35u2005y) of self-reported duration of obesity, and 12 age- and gender-matched non-obese controls (BMI, 22.1±0.6u2005kgċm−2).MEASUREMENTS: Oral glucose tolerance (40u2005gċm−2), insulin sensitivity (by the euglycaemic insulin clamp technique), and insulin secretion (as the product of post-hepatic insulin clearance and plasma insulin concentration).RESULTS: The obese group presented hyperinsulinaemia in the basal state and after glucose loading (insulin area=58±5 vs 33±3u2005nmolċl−1ċ2u2005h, P=0.005), insulin resistance (M value=37.4±4.8 vs 50.6±2.6u2005μμmolċmin−1 ċkg FFM−1, P=0.002), and insulin hypersecretion (61.9±6.0 vs 33.9±4.0u2005nmolċ2u2005h, P=0.007); endogenous glucose production was similar in the two groups. In the whole dataset, insulin resistance was directly related to BMI, the waist-to-hip ratio (WHR), endogenous glucose production, insulin secretion, and fasting serum triglycerides and uric acid concentrations. When the obese subjects were stratified by duration of obesity, insulin resistance was progressively lower with longer obesity duration (P=0.04). When simultaneously adjusting by age, gender and BMI, obesity duration was independently associated with greater insulin sensitivity (P=0.003), lower plasma insulin response to oral glucose (P=0.001), and lower fasting and glucose-stimulated insulin release (P=0.01 for both).CONCLUSIONS: In obese subjects with preserved glucose tolerance, duration of obesity is associated with better insulin sensitivity irrespective of the degree of overweight.

Overcoming metabolic syndrome in severe obesity: adiponectin as a marker of insulin sensitivity and HDL-cholesterol improvements after gastric bypass

OBJECTIVEnTo assess the relationship between adiponectin and metabolic parameters in severely obese women during surgical-induced weight loss.nnnMETHODSnNineteen lean (CT - BMI:21.2 +/- 0.3 kg.m(2)), 14 overweight/class II obese (OB/OW - BMI: 29.7 +/- 0.7 kg/m(2)) and 8 morbidly obese (OBIII - BMI: 56.4 +/- 3.6 kg/m(2)) were evaluated by hyperinsulinemic-euglycemic clamp, adiponectin, and lipids. OBIII were evaluated at 5th and 16th month post-operatively.nnnRESULTSnCompared to lean, obese groups had lower adiponectin (OB/OW: 9.4 +/- 0.9, OBIII: 7.1 +/- 1.3 versus 12.2 +/- 0.9 ng/dL; p < 0.01), lower HDL-cholesterol (OB/OW:1.05 +/- 0.05, OBIII: 0.88 +/- 0.04 versus 1.22 +/- 0.07 mmol/L; p < 0.01) and insulin resistance-IR (glucose uptake, M-value - OB/OW: 43.6 +/- 2.7, OBIII: 32.4 +/- 3.2 versus 20.0 +/- 1.8 umol/kgFFM.min; p < 0.001). Considering all subjects, adiponectin levels were inversely correlated to BMI and waist circumference, and directly to M-value and HDL-cholesterol (p < 0.01). During weight loss, improvements in IR (Study III: 36.1 +/- 3.9 umol/kg/FFM.min, p < 0.0001), adiponectin (11.8 +/- 1.4 ng/dL, p = 0.006) and HDL-cholesterol were observed (1.10 +/- 0.04 mmol/L, p = 0.007). Moreover, HDL-cholesterol improvement was significantly and independently related to variations of adiponectin and BMI (r(2) = 0.86; p < 0.0002).nnnCONCLUSIONSnThe improvements of IR and adiponectin were related to surgical-induced weight loss, suggesting an important role of adiponectin in HDL-cholesterol regulation.

Restored insulin inhibition on insulin secretion in nondiabetic severely obese patients after weight loss induced by bariatric surgery

OBJECTIVE: To examine the impact of important weight loss on insulin inhibition of its own secretion during experimentally induced hyperinsulinemia under euglycemic conditions.DESIGN: Longitudinal, clinical intervention study—bariatric surgery (vertical banded gastroplasty—gastric bypass—Capella technique), re-evaluation after 4 and 14 months.SUBJECTS: Nine obese patients class III (BMI=54.6±2.6u2009kg/m2) and nine lean subjects (BMI=22.7±0.7u2009kg/m2).MEASUREMENTS: Euglycemic hyperinsulinemic clamp (insulin infusion: 40u2009mU/minu2009m2), C-peptide plasma levels, electrical bioimpedance methodology, and oral glucose tolerance test (OGTT).RESULTS: BMI was reduced in the follow-up: 44.5±2.2 and 33.9±1.5u2009kg/m2 at 4 and 14 months. Insulin-induced glucose uptake was markedly reduced in obese patients (19.5±1.9u2009μmol/minu2009kg FFM) and improved with weight loss, but in the third study, it was still lower than that observed in controls (35.9±4.0 vs 52.9±2.2u2009μmol/minu2009kg FFM). Insulin-induced inhibition of its own secretion was blunted in obese patients (19.9±5.7%, relative to fasting values), and completely reversed to values similar to that of lean ones in the second and third studies (−60.8±4.2 and −54.0±6.1%, respectively).CONCLUSION: Weight loss in severe obesity improved insulin-induced glucose uptake, and completely normalized the insulin inhibition on its own secretion.

Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency.

Objective Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross‐talk and by direct action on pancreatic beta‐cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance.

Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients

OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance.SUBJECTS: Twelve obese patients, normotolerant to glucose (8u2005F/4u2005M, body mass index (BMI)=54.8±2.5u2005kg/m2, 39u2005y) and 16 lean control subjects (10u2005F/6u2005M, BMI=22.0±0.5u2005kg/m2, 31u2005y).DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280u2005pmol/min/m2 of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry.RESULTS: The obese subjects were insulin resistant (M=19.8±1.6 vs 48.7±2.6u2005μmol/minu2005kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425±131u2005pmol/l vs lean 550±63u2005pmol/l; P<0.0001) decreased less during the clamp in the obese groups (−16.9±6.9% vs −43.0±5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation.CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.

Short-term Acute Hyperinsulinemia and Prothrombotic Factors in Subjects with Normal Glucose Tolerance

Some cytokines and proinflammatory mediators are considered markers of increased atherothrombotic risk. Few information is available on the effects of acute glucose and insulin variations on these markers of atherosclerosis. We assessed the acute effect of glucose and insulin on soluble CD40 ligand (sCD40L), IL-6, and P-selectin levels, evaluating their relationship with insulin sensitivity in normal glucose tolerance subjects (NGT). Twenty-four NGT subjects underwent a 3-h oral glucose tolerance test (OGTT) with measurements of sCD40L, IL-6, and P-selectin levels at 0, 90 and 180 min. Insulin sensitivity was assessed by the Oral Glucose Sensitivity Index (OGIS). To distinguish the role of glucose and insulin, eight subjects had the plasma glucose profile of the OGTT reproduced by a variable IV glucose infusion (ISO-G study) and nine underwent a euglycemic clamp. Lastly, a 3-h time-control (TC) study was performed in eleven subjects. A significant reduction of sCD40L was observed during OGTT and ISO-G study. This reduction was not due to time-related changes, since it was not observed in TC study. During the clamp, insulin induced a marked drop in sCD40L (from 4.89+/-1.34 to 1.60+/-0.29 ng/ml, p<0.05). In the pooled data from all studies, fasting sCD40L was indirectly related to LDL-cholesterol (r=-0.38; p=0.04), while IL-6 was directly related with BMI, fat mass, waist circumference, and P-selectin (p<0.05). sCD40L levels are downregulated during a short-term period of acute hyperinsulinemia, whether induced by oral or intravenous glucose administration or by insulin infusion, while it does not seem to affect P-selectin and IL-6.

Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes

Aims/hypothesisIncretin effect—the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route—is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans.MethodsThirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3xa0h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (β-GS), glucose-induced potentiation (PGLU) and incretin-induced potentiation (PINCR); the oral glucose sensitivity index was used to estimate insulin sensitivity.ResultsLipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m2 on OGTT and from 29xa0nmol/m2 [26] to 57xa0nmol/m2 [30] on ISO) and induced insulin resistance. PINCR decreased from 1.6 [1.1] to 1.3 [0.1] (pu2009<u20090.05). β-GS, PGLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change β-GS, PINCR, PGLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes.Conclusions/interpretationRaising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.