Both 3,5-diiodo-L-thyronine (T2) and T3 modulate glucose-induced insulin secretion.

3,5-diiodo-L-thyronine (T2), a naturally existing iodothyronine, has biological effects on humans, but no information is available on its action on pancreatic b-cells. We evaluated its effect vs triiodothyronine (T3), on glucose-induced insulin secretion in INS-1e cells, a rat insulinoma line, and on human islets. INS-1e were incubated in the presence/absence of T2 or T3 (0.1 nmol/L-10 µmol/L), and glucose (3.3, 7.5, 11.0, and 20 mmol/L). Insulin release and content (at 11.0 and 20 mmol/L glucose) were significantly (p less than 0.01) stimulated by 1-100 nmol/L T2 and 0.1 nmol/L-1.0 µmol/L T3, and inhibited with higher concentrations of both (1–10 µmol/L T2 and 10 µmol/L T3). Human islets were incubated with 3.3 mmol/L glucose in presence/absence of T3 or T2 (0.1 nmol/L, 0.1 µmol/L, and 1 µmol/L). T2 (0.1 nmol/L-0.1 µmol/L) significantly (p less than0.01) stimulated insulin secretion, while higher concentrations (1 µmol/L) inhibited it. A modest increase in insulin secretion was evidenced with 1 µmol/L T3. In conclusion, T2 and T3 have a direct regulatory role in insulin secretion, depending on their concentrations and the glucose level itself. At concentrations near the physiological range, T2 enhances glucose-induced insulin secretion in both rat b-cells and human islets.

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes.

AIMS/HYPOTHESIS: Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss. METHODS: We studied 25 morbidly obese patients (BMI 51.7 ± 1.5 kg/m(2) [mean ± SEM]), 13 with non-insulin-treated type 2 diabetes (HbA(1c) 7.1 ± 0.5% [54 ± 5 mmol/mol]), before and at 2 weeks and 1 year after Roux-en-Y gastric bypass (RYGB). Lean (n = 8, BMI 23.0 ± 0.5 kg/m(2)) and obese (n = 14) volunteers who were BMI-matched (36.0 ± 1.2) to RYGB patients at 1 year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[(2)H(2)]glucose, lipolysis (rate of appearance of [(2)H(5)]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution). RESULTS: At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1 year post-RYGB (BMI 34.4 ± 1.1 kg/m(2)), all diabetic patients were off glucose-lowering treatment and mean HbA(1c) was 5.4 ± 0.14% (36 ± 2 mmol/mol) (p = 0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls. CONCLUSIONS/INTERPRETATION: In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term.

Daylong pituitary hormones in morbid obesity: effects of bariatric surgery.

Moderate obesity is known to be associated with multiple endocrine abnormalities. Less information is available on the hormonal status of patients with morbid obesity and on the effects of major weight loss. We studied 16 severely obese (BMI 40.6-69.9 kg/m(2)) nondiabetic patients and 7 nonobese (BMI range 24.6-27.7 kg/m(2)), sex- and age-matched healthy volunteers. During 24 h in a metabolic ward, four meals were administered and hourly blood samples were drawn from a central venous catheter for the measurement of glucose, insulin, leptin, thyrotropic hormone (TSH), growth hormone (GH) and prolactin. Insulin sensitivity was measured by a euglycaemic hyperinsulinaemic clamp. Studies were repeated 6 months after biliopancreatic diversion, a mainly malabsorptive surgical approach, which caused an average weight loss of 35+/-4 kg (or 26+/-2% of initial weight). Compared with controls, patients were hyperinsulinaemic (290+/-31 vs 88+/-4 pmol l(-1), P=0.0002), insulin resistant (23.5+/-2.8 vs 52.9+/-4.9 micromol min(-1) kg(FFM)(-1), P=0.0006) and hyperleptinaemic (52.5+/-5.8 vs 10.9+/-3 ng ml(-1), P=0.0002). Plasma TSH levels were increased throughout the day-night cycle (averaging 2.02+/-0.18 vs 1.09+/-0.19 muU ml(-1) of controls, P=0.01), whereas serum GH levels were suppressed (0.46+/-0.10 vs 3.01+/-1.15, P=0.002). Following surgery, the hyperinsulinaemia and insulin resistance were fully normalized; in concomitance with a major drop in leptin levels (to 14.4+/-2.7 ng ml(-1), P=0.02), TSH decreased and GH increased to near-normal levels. In the whole dataset, mean 24-h leptin levels were directly related to mean 24-h TSH levels after controlling for confounders this relationship was lost only after adjusting for fat mass. We conclude that in morbid obesity leptin is a determinant of changes in pituitary function.

Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: effects of weight loss.

OBJECTIVE: Increased thyroid-stimulating hormone (TSH) and FT(3) levels are often found in clinically euthyroid obese individuals. Information on thyroid gene expression in human adipose tissue is scarce. The objective of this study was to measure the expression of the TSH receptor (TSHR) and the thyroid hormone receptor (TRalpha1) genes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese individuals and to test the effect of weight loss on these genes. STUDY DESIGN AND PARTICIPANTS: This study is a prospective study involving 107 obese (body mass index (BMI)=46+/-8 kg m(-2), 52 with type 2 diabetes or impaired glucose tolerance) and 12 lean nondiabetic participants. A total of 27 obese patients were restudied 1 year after gastric bypass surgery. Total RNA was extracted from SAT and VAT obtained at baseline from all participants, and from SAT in obese patients post surgery. RESULTS: Circulating TSH and FT(3) levels were 170 and 36%, respectively, higher in obese patients than in controls. In SAT, TSHR and TRalpha1 were reduced in the obese by 67 and 33%, respectively, regardless of glucose tolerance. A similar trend was found in VAT. Post surgery, a BMI decrease of 33% was associated with a decrease in TSH and FT(3) levels and with a 150 and 70% increase in SAT of TSHR and TRalpha1, respectively. CONCLUSION: In both subcutaneous and visceral fat, the thyroid gene expression (especially TSHR) is reduced in obesity. The reversal of these changes with major weight loss and the reciprocal changes in plasma TSH and FT(3) levels suggest a role for adipocytes in the regulation of TSH and thyroid hormones.

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.

Hyperinsulinemia and autonomic nervous system dysfunction in obesity: effects of weight loss.

BACKGROUND: Because hyperinsulinemia acutely stimulates adrenergic activity, it has been postulated that chronic hyperinsulinemia may lead to enhanced sympathetic tone and cardiovascular risk. METHODS AND RESULTS: In 21 obese (body mass index, 35+/-1 kg/m(2)) and 17 lean subjects, we measured resting cardiac output (by 2-dimensional echocardiography), plasma concentrations and timed (diurnal versus nocturnal) urinary excretion of catecholamines, and 24-hour heart rate variability (by spectral analysis of ECG). In the obese versus lean subjects, cardiac output was increased by 22% (P:<0.03), and the nocturnal drop in urinary norepinephrine output was blunted (P:=0.01). Spectral power in the low-frequency range was depressed throughout 24 hours (P:<0.04). During the afternoon and early night, ie, the postprandial phase, high-frequency power was lower, heart rate was higher; and the ratio of low to high frequency, an index of sympathovagal balance, was increased in direct proportion to the degree of hyperinsulinemia independent of body mass index (partial r=0.43, P:=0.01). In 9 obese subjects who lost 10% to 18% of their body weight, cardiac output decreased and low-frequency power returned toward normal (P:<0.05). CONCLUSIONS: In free-living subjects with uncomplicated obesity, chronic hyperinsulinemia is associated with a high-output, low-resistance hemodynamic state, persistent baroreflex downregulation, and episodic (postprandial) sympathetic dominance. Reversal of these changes by weight loss suggests a causal role for insulin.

Insulin resistance and hyperinsulinemia: No independent relation to left ventricular mass in humans.

BACKGROUND: Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy. In humans, however, the evidence is inconclusive. METHODS AND RESULTS: We studied 50 nondiabetic subjects covering a wide range of age (20 to 65 years), body mass index (BMI, 19 to 40 kg x m(-2)), and mean blood pressure (72 to 132 mm Hg). Plasma insulin concentrations and secretory rates were measured at baseline and during an oral glucose tolerance test; insulin sensitivity was measured by the insulin clamp technique. Left ventricular mass (LVM) (by 2D M-mode echocardiography) was distributed normally and was higher in obese (BMI >/=27 kg x m(-2), n=16) or hypertensive patients (blood pressure >140/90 mm Hg, n=21) (50+/-8 and 55+/-10 g x m(-2.7), respectively) than in 13 nonobese, normotensive subjects (40+/-8 g x m(-2.7), P:=0.0004). In a multivariate model adjusting for sex, age, BMI, and blood pressure, neither insulin concentrations (fasting or postglucose) nor insulin sensitivity or secretory rates were significant correlates of LVM. Systolic blood pressure (P:=0.003) and BMI (P:=0.01) were the only independent correlates of LVM. From the regression, the impact of hypertension (as a systolic pressure of 180 versus 140 mm Hg=+20%) was twice as large as that of obesity (as a BMI of 35 versus 25 kg x m(-2)=+11%), the two factors being additive. CONCLUSIONS: When adequate account is taken of body mass and blood pressure, insulin, as concentration, secretion, or action, is not an independent determinant of LVM in nondiabetic subjects.

A model for glucose control of insulin secretion during 24 h of free living.

The aim of this work was to develop a mathematical model describing the functional dependence of insulin secretion on plasma glucose concentrations during 24 h of free living. We obtained hourly central venous blood samples from a group of healthy volunteers who spent 24 h in a calorimetric chamber, where they consumed standardized meals. Insulin secretory rates were reconstructed from plasma C-peptide concentrations by deconvolution. The relationship between insulin release and plasma glucose concentrations was modeled as the sum of three components: a static component (describing the dependence on plasma glucose concentration itself, with an embedded circadian oscillation), a dynamic component (modeling the dependence on glucose rate of change), and a residual component (including the fraction of insulin secretion not explained by glucose levels). The model fit of the individual 24-h secretion profiles was satisfactory (within the assigned experimental error of glucose and C-peptide concentrations). The static component yielded a dose-response function in which insulin release increased quasi-linearly (from 40 to 400 pmol/min on average) over the range of 4-9 mmol/l glucose. The dynamic component was significantly different from zero in coincidence with meal-related glucose excursions. The circadian oscillation and the residual component accounted for the day/night difference in the ability of glucose to stimulate insulin release. Over 24 h, total insulin release averaged 257+/-58 nmol (or 43+/-10 U). The static and dynamic component together accounted for approximately 80% of total insulin release. The model proposed here provides a detailed robust description of glucose-related insulin release during free-living conditions. In nondiabetic subjects, non-glucose-dependent insulin release is a small fraction of total insulin secretion.

Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study.

The contribution of gluconeogenesis (GNG) to endogenous glucose output (EGO) in type 2 diabetes is controversial. Little information is available on the separate influence of obesity on GNG. We measured percent GNG (by the 2H2O technique) and EGO (by 6,6-[2H]glucose) in 37 type 2 diabetic subjects (9 lean and 28 obese, mean fasting plasma glucose [FPG] 8.3 +/- 0.3 mmol/l) and 18 control subjects (6 lean and 12 obese) after a 15-h fast. Percent GNG averaged 47 +/- 5% in lean control subjects and was significantly increased in association with both obesity (P < 0.01) and diabetes (P = 0.004). By multivariate analysis, percent GNG was independently associated with BMI (partial r = 0.27, P < 0.05, with a predicted increase of 0.9% per BMI unit) and FPG (partial r = 0.44, P = 0.0009, with a predicted increase of 2.7% per mmol/l of FPG). In contrast, EGO was increased in both lean and obese diabetic subjects (15.6 +/- 0.5 micromol x min(-1) x kg(-1) of fat-free mass, n = 37, P = 0.002) but not in obese nondiabetic control subjects (13.1 0.7, NS) as compared with lean control subjects (12.4 +/- 1.4). Consequently, gluconeogenic flux (percent GNG x EGO) was increased in obesity (P = 0.01) and markedly elevated in diabetic subjects (P = 0.0004), whereas glycogenolytic flux was reduced only in association with obesity (P = 0.05). Fasting plasma glucagon levels were significantly increased in diabetic subjects (P < 0.05) and positively related to EGO, whereas plasma insulin was higher in obese control subjects than lean control subjects (P = 0.05) and unrelated to measured glucose fluxes. We conclude that the percent contribution of GNG to glucose release after a 15-h fast is independently and quantitatively related to the degree of overweight and the severity of fasting hyperglycemia. In obese individuals, reduced glycogenolysis ensures a normal rate of glucose output. In diabetic individuals, hyperglucagonemia contributes to inappropriately elevated rates of glucose output from both GNG and glycogenolysis.

Effect of vitamin C on forearm blood flow and glucose metabolism in essential hypertension.

In 9 patients with essential hypertension, we tested whether a high-dose (12 mg. min(-1)) vitamin C infusion into the brachial artery, by improving endothelium-dependent vasodilatation, would also attenuate the insulin resistance of deep forearm tissues. We measured the effect of vitamin C on acetylcholine (Ach)-induced vasodilatation and on forearm glucose uptake during systemic hyperinsulinemia; in all studies, the contralateral forearm served as the control. Intrabrachial Ach infusion produced a stable increase in forearm blood flow, from 2.6+/-0.3 to 10.6+/-2.1 mL. min(-1). dL(-1); when vitamin C was added, a further rise in forearm blood flow (to 13.4 mL. min(-1). dL(-1); P<0.03 vs Ach alone) was observed. In response to insulin, blood flow in both the infused and control forearms did not significantly change from baseline values (+10+/-16% and +2+/-11%, respectively). In contrast, when vitamin C was added, blood flow in the infused forearm increased significantly (to 3.7+/-0.7 mL. min(-1). dL(-1); P<0.02 vs 2.8+/-0.6 mL. min(-1). dL(-1) in the control forearm). Insulin stimulated whole-body glucose disposal to 20+/-2 micromol. min(-1). kg(-1), compatible with the presence of marked insulin resistance. Forearm glucose uptake was similarly stimulated after 80 minutes of insulin infusion (to 2.11+/-0.42 and 2.06+/-0.43 micromol. min(-1). dL(-1), infused and control, respectively). When intrabrachial vitamin C was added, no difference in glucose uptake was observed between the 2 forearms (infused, 2.37+/-0.44 micromol. min(-1). dL(-1)and control, 2.36+/-0. 53 micromol. min(-1). dL(-1)). Forearm O(2) uptake at baseline was also similar in the 2 forearms (infused, 9.7+/-0.7 micromol. min(-1). dL(-1) and control, 9.6+/-1.1 micromol. min(-1). dL(-1)) and was not changed by either insulin or vitamin C. We conclude that in the deep forearm tissues of patients with essential hypertension and insulin resistance, an acute improvement in endothelial function, obtained with pharmacological doses of vitamin C, restores insulin-mediated vasodilatation but does not improve insulin-mediated glucose uptake. Thus, the endothelial dysfunction of essential hypertension is unlikely to be responsible for their metabolic insulin resistance.

Metabolic and cardiovascular assessment in moderate obesity: effect of weight loss.

Metabolic and hemodynamic abnormalities have been separately described in obesity, and weight reduction is known to lead to some improvement in each. Our aim was to simultaneously assess metabolic and cardiovascular function in normotensive, normotolerant patients with moderate obesity (body mass index = 32.6 +/- 1.1 kg/m2) before and after weight loss. The obese were insulin resistant [37.4 +/- 4.8 mumol/min.kg FFM; P < 0.02 vs. 12 lean controls (50.6 +/- 2.6), on a euglycemic insulin clamp], secreted more insulin both in the fasting state and after oral glucose (70 +/- 10 vs. 48 +/- 6 nmol/mmol.L plasma glucose; P < 0.05), and had higher resting energy expenditure (4.62 +/- 0.18 vs. 4.00 +/- 0.23 kJ/min), systolic and mean blood pressure, stroke volume (87 +/- 8 vs. 67 +/- 4 mL/min; P = 0.05), and cardiac output. There was, however, no relationship between the metabolic and hemodynamic abnormalities. After a weight loss of 11 +/- 1 kg (approximately 15%), insulin sensitivity improved in proportion to the weight reduction, whereas insulin hypersecretion and high energy expenditure persisted. In contrast, all hemodynamic changes reverted to normal. We conclude that in moderate obesity, the metabolic and cardiovascular abnormalities are largely independent of one another; accordingly, weight loss affects them differentially. Partial weight normalization may provide sufficient cardiovascular protection.

Autonomic and hemodynamic responses to insulin in lean and obese humans.

To study the acute effects of insulin on autonomic control of cardiac function, we performed spectral analysis of heart rate variability and measured cardiac dynamics (by two-dimensional echocardiography) in 18 obese (BMI = 35 +/- 1 kg.m-2) and 14 lean (BMI = 24 +/- 1 kg.m-2) subjects in the basal state and in response to physiological hyperinsulinemia (1 mU.min-1.kg-1 insulin clamp). In the lean group, insulin promptly (within 20 min) and consistently depressed spectral powers, both in the low-frequency and high-frequency range. These changes were twice as large as accounted for by the concomitant changes in heart rate (68 +/- 2 to 70 +/- 2 beats/min). At the end of the 2-h clamp, stroke volume (67 +/- 4 to 76 +/- 9 ml.min-1) and cardiac output (4.45 +/- 0.21 to 5.06 +/- 0.55 l.min-1) rose, whereas peripheral vascular resistance fell. The low-to-high frequency ratio increased from 1.7 +/- 0.2 to 2.3 +/- 0.3 (P < 0.01), indicating sympathetic shift of autonomic balance. In the obese group, all basal spectral powers were significantly lower (by 40% on average) than in the lean group, and were further reduced by insulin administration. The low-to-high frequency ratio was higher than in controls at baseline (2.4 +/- 0.4, P < 0.03), and failed to increase after insulin (2.2 +/- 0.3, P = ns). Furthermore, obesity was associated with higher resting stroke volume (89 +/- 5 vs. 67 +/- 4 ml.min-1, P < 0.01) and cardiac output (6.01 +/- 0.31 vs. 4.45 +/- 0.21 l.min-1, P = 0.001) but lower peripheral vascular resistance (15.1 +/- 0.8 vs. 19.2 +/- 1.1 mmHg.min.L-1, P = 0.002), whereas mean arterial blood pressure was similar to control (90 +/- 2 vs. 86 +/- 2 mmHg, P = not significant). We conclude that physiological hyperinsulinemia causes acute desensitization of sinus node activity to both sympathetic and para-sympathetic stimuli, sympathetic shift of autonomic balance, and a high-output, low-resistance hemodynamic state. In the obese, these changes are already present in the basal state, and may therefore be linked with chronic hyperinsulinemia.

A soluble PC-1 circulates in human plasma: relationship with insulin resistance and associated abnormalities.

An increased tissue content of PC-1, an inhibitor of insulin receptor signaling, may play a role in insulin resistance. Large scale prospective studies to test this hypothesis are difficult to carry out because of the need for tissue biopsies. The aim of this study was to investigate whether PC-1 is measurable in human plasma and whether its concentration is related to insulin sensitivity. A soluble PC-1, with mol wt and enzymatic activity similar to those of tissue PC-1, was measurable in human plasma by a specific enzyme-linked immunosorbent assay and was inversely correlated to skeletal muscle PC-1 content (r = -0.5; P < 0.01). The plasma PC-1 concentration was decreased (P < 0.05) in insulin-resistant (22.7 +/- 3.0 ng/mL; n = 25) compared to insulin-sensitive (36.7 +/- 4.5; n = 25) nondiabetic subjects and was correlated negatively with the waist/hip ratio (r = -0.48; P < 0.001) and mean blood pressure (r = -0.3; P < 0.05) and positively with high density lipoprotein/total cholesterol (r = 0.38; P < 0.01) and both the M value and the plasma free fatty acid level decrement at clamp studies (r = 0.28; n = 50; P = 0.05 and r = 0.43; n = 22; P < 0.05, respectively). A plasma PC-1 concentration of 19 ng/mL or less identified a cluster of insulin resistance-related alterations with 75% accuracy. In conclusion, PC-1 circulates in human plasma, and its concentration is related to insulin sensitivity. This may help to plan studies aimed at understanding the role of PC-1 in insulin resistance.

Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones.

CONTEXT: In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control. OBJECTIVE: The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. PATIENTS, SETTING, AND INTERVENTION: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG). MAIN OUTCOME MEASURES: Insulin sensitivity, ß-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured. RESULTS: T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, ß-cell glucose sensitivity improved both early and long term (P < .005), whereas insulin sensitivity improved long term only (P < .006), in proportion to body mass index changes (P < .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P = .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery ß-cell glucose sensitivity (positive, P < .0001) and meal-stimulated GLP-1 response (negative, P = .004) were the only predictors of remission. CONCLUSIONS: RYGB and SLG have a similar impact on diabetes remission, of which baseline ß-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.

The role of beta-cell function and insulin sensitivity in the remission of type 2 diabetes after gastric bypass surgery.

CONTEXT: Bariatric surgery can induce remission in a high proportion of severely obese patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: Our objective was to investigate predictors and mechanisms of surgery-induced diabetes remission. PATIENTS AND SETTING: Forty-three morbidly obese subjects (body mass index = 45.6 ± 5.0 kg/m(2)), 32 with T2DM and 11 nondiabetic [normal glucose tolerance (NGT)], participated at a clinical research center. INTERVENTION: Patients underwent Roux-en-Y gastric bypass. MAIN OUTCOME MEASURES: Diabetes remission and ß-cell function were evaluated. RESULTS: Subjects were tested before and 45 d and 1 yr after surgery. Weight decreased similarly in T2DM and NGT (-39 kg at 1 yr, P < 0.0001). Insulin sensitivity improved in both groups in proportion to the changes in body mass index but remained lower in T2DM than NGT (386 ± 91 vs. 479 ± 89 ml/min · m(2), P < 0.01). Based on glycosylated hemoglobin and oral glucose testing, diabetes had remitted in nine patients at 45 d and in an additional 16 at 1 yr. In T2DM, ß-cell glucose sensitivity increased early after surgery but was no further improved and still abnormal at 1 yr [median, 48 (coefficient interval, 53) pmol/min · m(2) · mm vs. median, 100 (coefficient interval, 68) of NGT, P < 0.001]. Baseline ß-cell glucose sensitivity was progressively worse in early remitters, late remitters, and nonremitters (median, 54[coefficient interval, 50] vs. median, 22[coefficient interval, 26] vs. median, 4[coefficient interval, 10] pmol/min · m(2) · mm) and, by logistic regression, was the only predictor of failure [odds ratio for bottom tertile = 7.9 (95% confidence interval = 1.2-51.9); P = 0.03]. CONCLUSIONS: In morbid obesity, Roux-en-Y gastric bypass causes rapid and profound metabolic adaptations; insulin sensitivity improves in proportion to the weight loss, and ß-cell glucose sensitivity increases independently of weight loss. Over a period of 1 yr after surgery, diabetes remission depends on the starting degree of ß-cell dysfunction.

Relationship between impaired glucose tolerance, non-insulin-dependent diabetes mellitus and obesity.

Plasma glucose concentration is the best predictor for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, obesity is also a recognized risk factor for development of the disease, and is easier to track over time. Thus obesity could be of considerable clinical importance as a predictor of diabetes. Studies have shown that the degree of overweight, the change in weight and the duration of overweight are all separate predictors of diabetes. The British Regional Heart Study showed that an increasing body mass index (BMI) was associated with increased risk of developing diabetes, even at BMI values not considered obese. A separate study showed that weight gain increased the risk of diabetes independently of BMI, while weight loss decreased the risk. The duration of obesity was also an important factor in developing NIDDM. A long duration increased the risk of diabetes, irrespective of the final BMI value. The effects of obesity on insulin action have also been investigated. Studies have shown that insulin sensitivity is inversely related to insulin secretion, with a disproportionate increase in insulin secretion seen with decreasing sensitivity. A recent European study showed that the prevalence of both insulin hypersecretion and insulin resistance increased with increasing BMI. Thus, in obesity, higher insulin levels are necessary to maintain glucose tolerance, leading to increased stress on the beta-cells. In obese individuals, weight loss improved insulin sensitivity in proportion to the degree of weight loss, leading to decreased insulin secretion. Weight loss can therefore, at least in the short term, act to decrease the risk of developing diabetes by reducing insulin resistance, and thus relieving beta-cell stress, the factor ultimately responsible for hyperglycaemia in predisposed individuals.

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+/-12 y, body mass index (BMI), 33.5+/-0.8 kg x m[-2]) with a range (1-35 y) of self-reported duration of obesity, and 12 age- and gender-matched non-obese controls (BMI, 22.1+/-0.6 kg x m[-2]). MEASUREMENTS: Oral glucose tolerance (40 g x m[-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+/-3 nmol x I[-1] x 2 h, P = 0.005), insulin resistance (M value = 37.4+/-4.8 vs 50.6+/-2.6 micromol x min[-1] x kg FFM[-1], P = 0.002), and insulin hypersecretion (61.9+/-6.0 vs 33.9 +/- 4.0 nmol x 2 h, 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.

Effect of obesity and insulin resistance on resting and glucose-induced thermogenesis in man. EGIR (European Group for the Study of Insulin Resistance).

OBJECTIVE: To assess the impact of obesity and insulin sensitivity on resting (REE) and glucose-induced thermogenesis (GIT). DESIGN: Data from 322 studies carried out in non-diabetic subjects of either gender, covering a wide range of age (18-80y) and body mass index (BMI, 18-50 kg/m2). MEASUREMENTS: Insulin sensitivity and thermogenesis were measured by combining the euglycaemic insulin clamp technique with indirect calorimetry. RESULTS: REE was inversely related to age (P = 0.001) and the respiratory quotient (P = 0.03), and positively related to BMI, lean body mass (LBM), fat mass, and percentage fat mass (all P<0.0001). In a multiple regression model, LBM-adjusted REE was estimated to decline by 9% between 18 and 80 y, independently of obesity and insulin sensitivity. In contrast, GIT was strongly associated with insulin sensitivity (P<0.0001) but not with gender, age or BMI. By multiple regression analysis, GIT was linearly related to insulin sensitivity after controlling for gender, age, BMI and steady-state plasma insulin levels. Furthermore, both of the main components of insulin-mediated glucose disposal (glucose oxidation and glycogen synthesis) correlated with GIT independently of one another. In the subset of subjects (n = 89) in whom waist-to-hip ratio (WHR) measurements were available, GIT was inversely associated with WHR (P<0.001 after adjustment by gender, age, BMI, insulin sensitivity and steady-state plasma insulin concentration). In this model, a significant interaction between WHR and gender indicated a stronger adverse effect on GIT of a high WHR in women than in men. CONCLUSIONS: In healthy humans, age, lean mass and respiratory quotient are the main independent determinants of resting thermogenesis. In contrast, insulin sensitivity and, to a lesser extent, abdominal obesity are the principal factors controlling glucose-induced thermogenesis.