GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide

Objective: Glucagon‐like peptide‐1 (GLP‐1) (7–36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP‐1 are mediated through its principal metabolite, GLP‐1 (9–36) amide (GLP‐1m). Methods and Procedures: Glucose turnover during two, 2‐h, euglycemic clamps was measured in 12 lean and 12 obese (BMI <25 or >30 kg/m²) male and female subject volunteers with normal oral glucose tolerance test. Saline or GLP‐1m were infused from 0 to 60 min in each study. Additionally, seven lean and six obese subjects underwent a third clamp in which the GLP‐1 receptor (GLP‐1R) antagonist, exendin (9–39) amide was infused from ?60 to 60 min with GLP‐1m from 0 to 60 min. Results: No glucose infusion was required in lean subjects to sustain euglycemia (glucose clamp) during saline or GLP‐1m infusions. However, in obese subjects glucose infusion was necessary during GLP‐1m infusion alone in order to compensate for a marked (>50%) inhibition of hepatic glucose production (HGP). Plasma insulin levels remained constant in lean subjects but rose significantly in obese subjects after termination of the peptide infusions. During GLP‐1R blockade, infusion of glucose was immediately required upon starting GLP‐1m infusions in all subjects due to a more dramatic reduction in HGP, as well as a delayed and modest insulinotropic response. Discussion: We conclude that GLP‐1m potently inhibits HGP and is a weak insulinotropic agent. These properties are particularly apparent and pronounced in obese but only become apparent in lean subjects during GLP‐1 (7–36) receptor blockade. These previously unrecognized antidiabetogenic actions of GLP‐1m may have therapeutic usefulness.     

Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women

We measured whole body and regional lipolytic and adipose tissue blood flow (ATBF) sensitivity to epinephrine in 8 lean [body mass index (BMI): 21 +/- 1 kg/m(2)] and 10 upper body obese (UBO) women (BMI: 38 +/- 1 kg/m(2); waist circumference >100 cm). All subjects underwent a four-stage epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 microgram. kg fat-free mass(-1). min(-1)) plus pancreatic hormonal clamp. Whole body free fatty acid (FFA) and glycerol rates of appearance (R(a)) in plasma were determined by stable isotope tracer methodology. Abdominal and femoral subcutaneous adipose tissue lipolytic activity was determined by microdialysis and (133)Xe clearance methods. Basal whole body FFA R(a) and glycerol R(a) were both greater (P < 0.05) in obese (449 +/- 31 and 220 +/- 12 micromol/min, respectively) compared with lean subjects (323 +/- 44 and 167 +/- 21 micromol/min, respectively). Epinephrine infusion significantly increased FFA R(a) and glycerol R(a) in lean (71 +/- 21 and 122 +/- 52%, respectively; P < 0.05) but not obese subjects (7 +/- 6 and 39 +/- 10%, respectively; P = not significant). In addition, lipolytic and ATBF sensitivity to epinephrine was blunted in abdominal but not femoral subcutaneous adipose tissue of obese compared with lean subjects. We conclude that whole body lipolytic sensitivity to epinephrine is blunted in women with UBO because of decreased sensitivity in upper body but not lower body subcutaneous adipose tissue.     

Leptin production during early starvation in lean and obese women

We evaluated abdominal adipose tissue leptin production during short-term fasting in nine lean [body mass index (BMI) 21 +/- 1 kg/m(2)] and nine upper body obese (BMI 36 +/- 1 kg/m(2)) women. Leptin kinetics were determined by arteriovenous balance across abdominal subcutaneous adipose tissue at 14 and 22 h of fasting. At 14 h of fasting, net leptin release from abdominal adipose tissue in obese subjects (10.9 +/- 1.9 ng x 100 g tissue x (-1) x min(-1)) was not significantly greater than the values observed in the lean group (7.6 +/- 2.1 ng x 100 g(-1) x min(-1)). Estimated whole body leptin production was approximately fivefold greater in obese (6.97 +/- 1.18 microg/min) than lean subjects (1.25 +/- 0.28 microg/min) (P < 0.005). At 22 h of fasting, leptin production rates decreased in both lean and obese groups (to 3.10 +/- 1.31 and 10.5 +/- 2.3 ng x 100 g adipose tissue(-1) x min(-1), respectively). However, the relative declines in both arterial leptin concentration and local leptin production in obese women (arterial concentration 13.8 +/- 4.4%, local production 10.0 +/- 12.3%) were less (P < 0.05 for both) than the relative decline in lean women (arterial concentration 39.0 +/- 5.5%, local production 56.9 +/- 13.0%). This study demonstrates that decreased leptin production accounts for the decline in plasma leptin concentration observed after fasting. However, compared with lean women, the fasting-induced decline in leptin production is blunted in women with upper body obesity. Differences in leptin production during fasting may be responsible for differences in the neuroendocrine response to fasting previously observed in lean and obese women.     

Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes

AIMS/HYPOTHESIS: Since insulin secretion in response to exogenous gastric inhibitory polypeptide (GIP) is diminished not only in patients with type 2 diabetes, but also in their normal glucose-tolerant first-degree relatives, it was the aim to investigate the integrity of the entero-insular axis in such subjects. METHODS: Sixteen first-degree relatives of patients with type 2 diabetes (4 male, 12 female, age 50+/-12 years, BMI 26.1+/-3.8 kg/m(2)) and 10 matched healthy controls (negative family history, 6 male, 4 female, 45+/-13 years, 26.1+/-4.2 kg/m(2)) were examined with an oral glucose load (75 g) and an "isoglycaemic" intravenous glucose infusion. Blood was drawn over 240 min for plasma glucose (glucose oxidase), insulin, C-peptide, GIP and glucagon-like peptide 1 (GLP-1; specific immunoassays). RESULTS: The pattern of glucose concentrations could precisely be copied by the intravenous glucose infusion (p=0.99). Insulin secretion was stimulated significantly more by oral as compared to intravenous glucose in both groups (p<0.0001). The percent contribution of the incretin effect was similar in both groups (C-peptide: 61.9+/-5.4 vs. 64.4+/-5.8%; p=0.77; insulin: 74.2+/-3.3 vs. 75.8+/-4.9; p=0.97; in first-degree relatives and controls, respectively). The individual responses of GIP and GLP-1 secretion were significantly correlated with each other (p=0.0003). The individual secretion of both GIP and GLP-1 was identified as a strong predictor of the integrated incremental insulin secretory responses as well as of the incretin effect. CONCLUSION/INTERPRETATION: Despite a lower insulin secretory response to exogenous GIP, incretin effects are similar in first-degree relatives of patients with type 2 diabetes and control subjects. This may be the result of a B cell secretory defect that affects stimulation by oral and intravenous glucose to a similar degree. Nevertheless, endogenous secretion of GIP and GLP-1 is a major determinant of insulin secretion after oral glucose.     

Effects of gastric bypass surgery on insulin resistance and insulin secretion in nondiabetic obese patients

Roux-en-Y-Gastric-Bypass (RYGB) reduces overall and diabetes-specific mortality by 40% and over 90%. This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time-courses of glucose, insulin, C-peptide, and the incretin glucagon like peptide-1 (GLP-1) following an oral glucose load. Insulin-sensitivity was measured by a hyperinsulinemic-isoglycemic-clamp-test; glucose-turnover was determined using D-[6,6-(2)H(2)] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m(2)) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m(2)), in a lean (CON: BMI: 22.6 ± 0.6 kg/m(2)) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m(2)). RYGB reduced fasting plasma concentrations of insulin and C-peptide (P < 0.01, respectively) whereas fasting glucose concentrations remained unchanged. After RYGB increase of C-peptide concentration following glucose ingestion was significantly higher compared to all other groups (dynamic-area under the curve (Dyn-AUC): 0-90 min: POST: 984 ± 115 ng·min/ml, PRE: 590 ± 67 ng·min/ml, CONob: 440 ± 44 ng·min/ml, CON: 279 ± 22 ng·min/ml, P < 0.01 respectively). Early postprandial increase of glucose concentration was however not affected. GLP-1 concentrations following glucose ingestion were sixfold higher after RYBG than before (P = 0.01). Insulin-stimulated glucose uptake tended to increase postoperatively (M-value: PRE: 1.8 ± 0.5, POST: 3.0 ± 0.3, not significant (n.s.)). Endogenous glucose production (EGP) was unaffected by RYGB. Hepatic insulin resistance index improved after RYGB and was then comparable to both control groups (PRE: 29.2 ± 4.3, POST: 12.6 ± 1.1, P < 0.01). RYGB results in hyper-secretion of insulin and C-peptide, whereas improvements of insulin resistance are minor and seem to occur rather in the liver and the adipose tissue than in the skeletal muscle.     

Increased synthesis rate of fibrinogen as a basis for its elevated plasma levels in obese female adolescents

Increased concentrations of plasma fibrinogen, an independent risk factor for cardiovascular disease (CVD), in obese children have been reported. The underlying mechanism for this, however, remains to be defined. In the current study, we measured the fractional synthesis rates (FSR) of plasma fibrinogen in six healthy postpubertal obese girls [body mass index (BMI) 36.6 +/- 1.8 kg/m(2); age 16.6 +/- 0.5 yr] and six age-matched lean normal control girls (BMI 20.8 +/- 0.7 kg/m(2); age 16.4 +/- 0.4 yr) during a primed, continuous infusion of L-[1-(13)C]leucine in the postabsorptive state. The method involved purification of plasma fibrinogen by use of immunoaffinity chromatography followed by measurement of [(13)C]leucine enrichment using gas chromatography-combustion-isotope ratio mass spectrometry. The FSR of fibrinogen in obese girls (35.06 +/- 2.61%/day) was almost double that in lean girls (17.02 +/- 1.43%/day), and this increase was associated with a relative increase in plasma concentration of fibrinogen as well as BMI in the subjects studied. Obese subjects had high fasting insulin levels (138 +/- 47 pmol/l) compared with lean subjects (54 +/- 11 pmol/l), whereas their glucose concentrations were similar (4.5 +/- 0.3 mmol/l in obese and 4.4 +/- 0.4 mmol/l in lean subjects), suggesting insulin resistance. The doubling of the FSR of fibrinogen provides novel insight into the mechanism of elevated levels of plasma fibrinogen and suggests a primary role for increased synthesis in producing the hyperfibrinogenemia associated with obesity. This finding may have important implications in the design of therapies for modulating plasma fibrinogen levels in obesity and/or CVD in childhood.     

Effect of a conjugated linoleic acid and omega-3 fatty acid mixture on body composition and adiponectin

This study aimed to determine the effect of supplementation with conjugated linoleic acids (CLAs) plus n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) on body composition, adiposity, and hormone levels in young and older, lean and obese men. Young (31.4+/-3.9 years) lean (BMI, 23.6+/-1.5 kg/m2; n=13) and obese (BMI, 32.4+/-1.9 kg/m2; n=12) and older (56.5+/-4.6 years) lean (BMI, 23.6+/-1.5 kg/m2; n=20) and obese (BMI, 32.0+/-1.6 kg/m2; n=14) men participated in a double-blind placebo-controlled, randomized crossover study. Subjects received either 6 g/day control fat or 3 g/day CLA (50:50 cis-9, trans-11:trans-10, cis-12) and 3 g/day n-3 LC-PUFA for 12 weeks with a 12-week wash-out period between crossovers. Body composition was assessed by dual-energy X-ray absorptiometry. Fasting adiponectin, leptin, glucose, and insulin concentrations were measured and insulin resistance estimated by homeostasis model assessment for insulin resistance (HOMA-IR). In the younger obese subjects, CLA plus n-3 LC-PUFA supplementation compared with control fat did not result in increased abdominal fat and raised both fat-free mass (2.4%) and adiponectin levels (12%). CLA plus n-3 LC-PUFA showed no significant effects on HOMA-IR in any group but did increase fasting glucose in older obese subjects. In summary, supplementation with CLA plus n-3 LC-PUFA prevents increased abdominal fat mass and raises fat-free mass and adiponectin levels in younger obese individuals without deleteriously affecting insulin sensitivity, whereas these parameters in young and older lean and older obese individuals were unaffected, apart from increased fasting glucose in older obese men.     

Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity

BACKGROUND: Plasma ghrelin levels have been shown to decrease after insulin infusion in lean subjects. Nevertheless, the mechanism of the suggested inhibitory effect of insulin on ghrelin is still unclear and no data about the effect of acute insulin infusion on plasma ghrelin concentration in obese subjects are available. OBJECTIVE: We sight to evaluate plasma ghrelin concentration during an hyperinsulinemic euglycemic clamp in uncomplicated obese subjects. METHODS: 35 uncomplicated obese subjects, body mass index (BMI) 43.3+/-10.1 kg/m(2), 33 women and 2 men, mean age 34.9+/-10, with a history of excess fat of at least 10 years underwent euglycemic hyperinsulinemic clamp. Blood samples for ghrelin were performed at baseline and steady state of euglycemic insulin clamp. RESULTS: Ghrelin concentrations decreased over time to 10.6+/-15% (range 2-39%) of baseline, from a mean of 205.53+/-93.79 pg/ml to 179.03+/-70.43 pg/ml during the clamp (95% CI, 10.69 to 36.44, P<0.01). In a univariate linear regression analysis baseline plasma ghrelin levels were inversely correlated to BMI (r=-0.564, P=0.04). A linear positive trend between whole body glucose utilization (M(FFMkg) index) and ghrelin reduction during the clamp was found (chi(2) 3.05, p=0.05). CONCLUSIONS: Our data seem to suggest that hyperinsulinemia during a euglycemic clamp is able to suppress plasma ghrelin concentrations in uncomplicated obesity. This effect appears to be positively related to insulin sensitivity.     

Excess body fat in men decreases plasma fatty acid availability and oxidation during endurance exercise

The effect of relative body fat mass on exercise-induced stimulation of lipolysis and fatty acid oxidation was evaluated in 15 untrained men (5 lean, 5 overweight, and 5 obese with body mass indexes of 21 +/- 1, 27 +/- 1, and 34 +/- 1 kg/m2, respectively, and %body fat ranging from 12 to 32%). Palmitate and glycerol kinetics and substrate oxidation were assessed during 90 min of cycling at 50% peak aerobic capacity (VO2 peak) by use of stable isotope-labeled tracer infusion and indirect calorimetry. An inverse relationship was found between %body fat and exercise-induced increase in glycerol appearance rate relative to fat mass (r2 = 0.74; P < 0.01). The increase in total fatty acid uptake during exercise [(micromol/kg fat-free mass) x 90 min] was approximately 50% smaller in obese (181 +/- 70; P < 0.05) and approximately 35% smaller in overweight (230 +/- 71; P < 0.05) than in lean (354 +/- 34) men. The percentage of total fatty acid oxidation derived from systemic plasma fatty acids decreased with increasing body fat, from 49 +/- 3% in lean to 39 +/- 4% in obese men (P < 0.05); conversely, the percentage of nonsystemic fatty acids, presumably derived from intramuscular and possibly plasma triglycerides, increased with increasing body fat (P < 0.05). We conclude that the lipolytic response to exercise decreases with increasing adiposity. The blunted increase in lipolytic rate in overweight and obese men compared with lean men limits the availability of plasma fatty acids as a fuel during exercise. However, the rate of total fat oxidation was similar in all groups because of a compensatory increase in the oxidation of nonsystemic fatty acids.     

Inhibition of insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion by octreotide has no effect on post-heparin plasma lipoprotein lipase activity.

This study examines the immediate effect of modulating postprandial insulin and insulinotropic hormone (glucose-dependent insulinotropic polypeptide, GIP; glucagon-like peptide-1, GLP-1) secretion on the activation of lipoprotein lipase (LPL) in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal of carbohydrate alone or combined with an IV infusion of octreotide, (100 microg infusion from 30 min before the meal for 150 min). Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes post-carbohydrate. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p < 0.01). Glucose tolerance was slightly impaired in obese subjects. Insulin, GIP and GLP-1 secretion post-carbohydrate was markedly reduced by octreotide in lean and obese subjects. LPL activity was similar in the two groups after carbohydrate administration and was unaffected by octreotide. Inhibition of postprandial insulin, GIP and GLP-1 secretion acutely did not reduce post-heparin LPL activity either in lean or obese subjects.     

Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity.

We evaluated plasma fatty acid availability and plasma and whole body fatty acid oxidation during exercise in five lean and five abdominally obese women (body mass index = 21 +/- 1 vs. 38 +/- 1 kg/m(2)), who were matched on aerobic fitness, to test the hypothesis that obesity alters the relative contribution of plasma and nonplasma fatty acids to total energy production during exercise. Subjects exercised on a recumbent cycle ergometer for 90 min at 54% of their peak oxygen consumption. Stable isotope tracer methods ([(13)C]palmitate) were used to measure fatty acid rate of appearance in plasma and the rate of plasma fatty acid oxidation, and indirect calorimetry was used to measure whole body substrate oxidation. During exercise, palmitate rate of appearance increased progressively and was similar in obese and lean groups between 60 and 90 min of exercise [3.9 +/- 0.4 vs. 4.0 +/- 0.3 micromol. kg fat free mass (FFM)(-1). min(-1)]. The rate of plasma fatty acid oxidation was also similar in obese and lean subjects (12.8 +/- 1.7 vs. 14.5 +/- 1.8 micromol. kg FFM(-1). min(-1); P = not significant). However, whole body fatty acid oxidation during exercise was 25% greater in obese than in lean subjects (21.9 +/- 1.2 vs. 17.5 +/- 1.6 micromol. kg FFM(-1). min(-1); P < 0.05). These results demonstrate that, although plasma fatty acid availability and oxidation are similar during exercise in lean and obese women, women with abdominal obesity use more fat as a fuel by oxidizing more nonplasma fatty acids.     

GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve

The present study was undertaken to establish in normal volunteers the alterations in beta-cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol x kg(-1) x min(-1)) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 +/- 12.4 pmol x min(-1) x mM(-1) during the saline study to 241.7 +/- 36.6 pmol x min(-1) x mM(-1) during the constant GLP-1 infusion (P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the beta-cell response to glucose (P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.     

Regional muscle and adipose tissue amino acid metabolism in lean and obese women

The effect of obesity on regional skeletal muscle and adipose tissue amino acid metabolism is not known. We evaluated systemic and regional (forearm and abdominal subcutaneous adipose tissue) amino acid metabolism, by use of a combination of stable isotope tracer and arteriovenous balance methods, in five lean women [body mass index (BMI) <25 kg/m(2)] and five women with abdominal obesity (BMI 35.0-39.9 kg/m(2); waist circumference >100 cm) who were matched on fat-free mass (FFM). All subjects were studied at 22 h of fasting to ensure that the subjects were in net protein breakdown during this early phase of starvation. Leucine rate of appearance in plasma (an index of whole body proteolysis), expressed per unit of FFM, was not significantly different between lean and obese groups (2.05 +/- 0.18 and 2.34 +/- 0.04 micromol x kg FFM(-1) x min(-1), respectively). However, the rate of leucine release from forearm and adipose tissues in obese women (24.0 +/- 4.8 and 16.6 +/- 6.5 nmol x 100 g(-1) x min(-1), respectively) was lower than in lean women (66.8 +/- 10.6 and 38.6 +/- 7.0 nmol x 100 g(-1) x min(-1), respectively; P < 0.05). Approximately 5-10% of total whole body leucine release into plasma was derived from adipose tissue in lean and obese women. The results of this study demonstrate that the rate of release of amino acids per unit of forearm and adipose tissue at 22 h of fasting is lower in women with abdominal obesity than in lean women, which may help obese women decrease body protein losses during fasting. In addition, adipose tissue is a quantitatively important site for proteolysis in both lean and obese subjects.     

Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance

Adipose tissue expresses tumor necrosis factor (TNF) and interleukin (IL)-6, which may cause obesity-related insulin resistance. We measured TNF and IL-6 expression in the adipose tissue of 50 lean and obese subjects without diabetes. Insulin sensitivity (S(I)) was determined by an intravenous glucose tolerance test with minimal-model analysis. When lean [body mass index (BMI) <25 kg/m(2)] and obese (BMI 30-40 kg/m(2)) subjects were compared, there was a 7.5-fold increase in TNF secretion (P < 0.05) from adipose tissue, and the TNF secretion was inversely related to S(I) (r = -0.42, P < 0.02). IL-6 was abundantly expressed by adipose tissue. In contrast to TNF, plasma (rather than adipose) IL-6 demonstrated the strongest relationship with obesity and insulin resistance. Plasma IL-6 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S(I) (r = -0.71, P < 0.001). To separate the effects of BMI from S(I), subjects who were discordant for S(I) were matched for BMI, age, and gender. By use of this approach, subjects with low S(I) demonstrated a 3.0-fold increased level of TNF secretion from adipose tissue and a 2.3-fold higher plasma IL-6 level (P < 0.05) compared with matched subjects with a high S(I). Plasma IL-6 was significantly associated with plasma nonesterified fatty acid levels (r = 0.49, P < 0.002). Thus the local expression of TNF and plasma IL-6 are higher in subjects with obesity-related insulin resistance.     

VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity

We have previously shown that sex and obesity independently affect basal very low density lipoprotein (VLDL)-triglyceride (TG) kinetics. In the present study, we investigated the effect of hyperglycemia-hyperinsulinemia on VLDL-TG kinetics in lean and obese men and women (n = 6 in each group). VLDL-TG kinetics were measured during basal, postabsorptive conditions and during glucose infusion (5.5 mg x kg FFM(-1) x min(-1)) by using [(2)H(5)]glycerol bolus injection in conjunction with compartmental modeling analysis. Basal VLDL-TG secretion in plasma was greater in obese than in lean men (7.8 +/- 0.6 and 2.9 +/- 0.4 micromol x l plasma(-1) x min(-1); P < 0.001) but was not different in lean and obese women (5.0 +/- 1.1 and 5.9 +/- 1.1 micromol x l plasma(-1) x min(-1)). Glucose infusion decreased the VLDL-TG secretion rate by approximately 50% in lean and obese men and in lean women (to 1.5 +/- 0.4, 4.0 +/- 0.6, and 2.2 +/- 0.4 micromol x l plasma(-1) x min(-1), respectively; all P < 0.05) but had no effect on the VLDL-TG secretion rate in obese women (4.9 +/- 1.0 micromol x l plasma(-1) x min(-1)). These results demonstrate that both sex and adiposity affect the regulation of VLDL-TG metabolism. Glucose and insulin decrease VLDL-TG production in both lean men and lean women; obesity is associated with resistance to the glucose- and insulin-mediated suppression of VLDL-TG secretion in women, but not in men.     

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.     

Lipolysis index: evaluation of a new tool for metabolic assessment in epidemiological studies on obesity

Lipid mobilization through adipocyte lipolysis is central for energy metabolism and is decreased in obesity. However, the factors of importance for lipolytic activity in the general population are not known. To further examine this we performed a cross-sectional study on teenagers and adults. We constructed and evaluated a simple index of lipolytic activity (ratio of fasting p-glycerol and body fat %) in population based samples in 316 teenagers (BMI 16-51 kg/m (2)) and 3,039 adults (BMI 16-70 kg/m (2)). In the adults, multiple regression analysis showed that waist and BMI but not age, plasma insulin, plasma noradrenaline or waist-to-hip ratio contributed independently and inversely to lipolytic activity (partial r=-0.37 and -0.28, respectively, p<0.0001). Together waist and BMI explained about 45% of the variability of lipolysis. Waist was a stronger factor than BMI in stepwise regression. The same analysis in teenagers showed that only BMI contributed independently and inversely to lipolytic activity (partial r=-0.90, p<0.0001) and explained about 55% of lipolysis variation. BMI had the strongest effect on lipolysis in lean teenagers. The results were the same for men and women. At all levels of lipolytic activity plasma fatty acid levels were elevated in obese subjects (p<0.0001). We conclude that during adolescence BMI is the major factor negatively influencing lipolytic activity, in particular among lean young subjects. In adulthood central fat accumulation together with increasing BMI decreases lipolysis. In spite of low lipolytic activity circulating fatty acid levels are increased in obesity, probably due to an adipose mass effect.     

Impaired plasma fatty acid oxidation in extremely obese women

Skeletal muscle from extremely obese individuals exhibits decreased lipid oxidation compared with muscle from lean controls. It is unknown whether this effect is observed in vivo or whether the phenotype is preserved after massive weight loss. The objective of this study was to compare free fatty acid (FFA) oxidation during rest and exercise in female subjects who were either lean [n = 7; body mass index (BMI) = 22.6 +/- 2.2 kg/m(2)] or extremely obese (n = 10; BMI = 40.8 +/- 5.4 kg/m(2)) or postgastric bypass patients who had lost >45 kg (weight reduced) (n = 6; BMI = 33.7 +/- 9.9 kg/m(2)) with the use of tracer ([(13)C]palmitate and [(14)C]acetate) methodology and indirect calorimetry. The lean group oxidized significantly more plasma FFA, as measured by percent fatty acid uptake oxidized, than the extremely obese or weight-reduced group during rest (66.6 +/- 14.9 vs. 41.5 +/- 16.4 vs. 39.9 +/- 15.3%) and exercise (86.3 +/- 11.9 vs. 56.3 +/- 22.1 vs. 57.3 +/- 20.3%, respectively). BMI significantly correlated with percent uptake oxidized during both rest (r = -0.455) and exercise (r = -0.459). In conclusion, extremely obese women and weight-reduced women both possess inherent defects in plasma FFA oxidation, which may play a role in massive weight gain and associated comorbidities.     

Glucose homeostasis in abdominal obesity: hepatic hyperresponsiveness to growth hormone action

It has been suggested that (abdominally) obese individuals are hypersensitive to growth hormone (GH) action. Because GH affects glucose metabolism, this may impact glucose homeostasis in abdominal obesity. Therefore, we studied the effect of GH on glucose metabolism in abdominally obese (OB) and normal-weight (NW) premenopausal women. A 1-h intravenous infusion of GH or placebo was randomly administered to six NW [body mass index (BMI) 21.1 +/- 1.9 kg/m(2)] and six OB (BMI 35.5 +/- 1.5 kg/m(2)) women in a crossover design. Insulin, glucagon, and GH secretion were suppressed by concomitant infusion of somatostatin. Glucose kinetics were measured using a 10-h infusion of [6,6-(2)H(2)]glucose. In both groups, similar physiological GH peaks were reached by infusion of GH. GH strongly stimulated endogenous glucose production (EGP) in both groups. The percent increase was significantly greater in OB than in NW women (29.8 +/- 11.3 vs. 13.3 +/- 7.4%, P = 0.014). Accordingly, GH responsiveness, defined as the maximum response of EGP per unit GH, was increased in OB vs. NW subjects (6.0 +/- 2.1 vs. 2.2 +/- 1.5 micromol.min(-1).mU(-1).l(-1), P = 0.006). These results suggest that the liver is hyperresponsive to GH action in abdominally obese women. The role of the somatotropic ensemble in the control of glucose homeostasis in abdominal obesity is discussed.     

Nutrient regulation of post-heparin lipoprotein lipase activity in obese subjects.

This study examines the immediate effect of ingestion of oral carbohydrate and fat on lipoprotein lipase (LPL) activity post-heparin in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal carbohydrate or an equicaloric amount of fat, both in 300 ml of water. Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes after ingestion of the meal. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p < 0.01). Impaired glucose tolerance was seen in the obese group. GIP secretion was similar in lean and obese subjects both during oral fat and carbohydrate ingestion. GLP-1 secretion post-carbohydrate was lower in obese subjects. Total LPL activity unadjusted for body weight was similar in the two groups after carbohydrate administration but was significantly lower when adjusted per kg body weight. Total LPL activity was lower in the lean group at 130 minutes after fat administration (p < 0.02). Fasting serum triglycerides were higher in the obese group and were inversely related to the post-carbohydrate LPL activity (r = - 0.65, p < 0.02). Intraluminal lipoprotein lipase activity is not increased in established obesity. Fat and carbohydrate nutrients may affect LPL activity differently in lean and obese subjects.