C. Macor

Visceral adipose tissue impairs insulin secretion and insulin sensitivity but not energy expenditure in obesity

In obesity, a central pattern of fat distribution is mostly associated with hyperinsulinemia, insulin resistance, and hyperlipemia, thus promoting the development of non-insulin-dependent diabetes mellitus and cardiovascular disease. In addition, in obesity, changes in energy expenditure are hypothesized to be involved in the development or maintenance of excessive body fat storage. In this study, abdominal fat distribution by computed tomographic (CT) scan was used to study the relation between the visceral fat depot, insulin secretion, and insulin sensitivity in a group of obese subjects with normal glucose tolerance (n = 26; body mass index [BMI], 39 +/- 1 kg/m2) and a group of normal-weight control subjects (n = 9; BMI, 23 +/- 1 kg/m2). The minimal model method was used to assess insulin sensitivity, S(I), and first-phase (phi1) and second-phase (phi2) beta-cell sensitivity from plasma glucose, insulin, and C-peptide concentrations measured during an intravenous glucose tolerance test ([IVGTT] 0.33 g/kg body weight). Moreover, we evaluated the relationships between these parameters and the resting metabolic rate (RMR) and glucose-induced thermogenesis (GIT) measured by indirect calorimetry. The data show the following: (1) in obese subjects, phi1 is greater but not statistically different from the value in control subjects (252 +/- 41 v 157 +/- 25 dimensionless 10(9)); (2) phi2 is significantly higher in obese subjects (27 +/- 4 v 14 +/- 2 min(-1) x 10(9), P < .05), with a positive correlation between the amount of visceral adipose tissue (VAT) and phi2 (r = .49, P < .05); (3) S(I) is decreased in the obese group (2.8 +/- 0.3 v 9.7 +/- 1.6 10(-4) x min(-1)/microU x mL(-1)), P < .0001), with a negative correlation of S(I) with the adiposity index BMI (r = -.67, P < .0001) and VAT (r = .56, P < .05); (4) RMR, expressed in absolute terms, was significantly increased in obese versus lean subjects (5.9 +/- 0.2 v 4.6 +/- 0.3 kJ/min, P < .01), whereas when RMR was adjusted for fat-free mass (FFM), the difference between the two groups disappeared (0.09 +/- 0.003 v 0.09 +/- 0.002 kJ/min x kg FFM). We did not observe any difference in GIT between lean and obese subjects. Moreover, GIT was significantly correlated with FFM (r = .69, P < .005), but not with BMI. The amount of VAT did not correlate with RMR or GIT. In conclusion, these results suggest that in obese subjects with normal glucose tolerance, insulin sensitivity is impaired and the beta-cell hyperresponse to glucose is mainly due to an enhanced second-phase beta-cell secretion. The degree of visceral fat deposition seems to affect insulin secretion and worsens insulin sensitivity, but does not influence energy expenditure.

Effects of acute hyperinsulinemia on testosterone serum concentrations in adult obese and normal-weight men.

In a previous study performed in adult obese and normal-weight male subjects, we found that suppression of insulin levels by diazoxide reduced testosterone and increased sex hormone-binding globulin (SHBG) blood concentrations. These and other data suggested that insulin may have a regulatory capacity in testosterone secretion and/or metabolism in men, similar to what has already been demonstrated in women. In this study, we investigated the effects of acute hyperinsulinemia on major androgen levels, including testosterone, in two groups of normal-weight in = 11) and obese (n = 9) men. Acute hyperinsulinemia was obtained by the euglycemic-hyperinsulinemic clamp technique. Relationships between the degree of insulin resistance (ie, total glucose disposal [M value]) and testosterone levels were also evaluated. Basal testosterone levels in obese subjects (10.40 +/- 3.02 nmol/L) were significantly lower than in normal-weight controls (15.50 +/- 4.65 nmol/L, P < .01), whereas no difference was present in androstenedione and dehydroepiandrosterone sulfate (DHEA-S) concentrations. During the clamp study, testosterone was significantly increased in the obese group (11.79 +/- 3.64 nmol/L, P < .05) but not in the control group (15.81 +/- 4.54 nmol/L, P = NS). The other two androgens did not significantly change in either the obese or control group. There was a highly significant correlation between baseline testosterone concentrations, with M values suggesting a relationship between impaired peripheral insulin sensitivity and reduced plasma testosterone concentrations. It should be pointed out that there was a certain discrepancy in the testosterone variations, particularly in the control group, in which two thirds of the subjects had no change or some decrease in testosterone levels, whereas in the remainder testosterone increased over the values of the assay variation coefficient. These findings are consistent with the hypothesis that insulin may regulate testosterone blood levels also in male subjects. Whether these effects are primarily due to increased hormone secretion or reduced clearance needs to be investigated.

Impaired counterregulatory hormonal and metabolic response to exhaustive exercise in obese subjects

Abstract A reduction of postprandial thermogenesis has been described in obesity; insulin resistance and/or decreased sympathetic nervous system activity seem to play the major role in its pathogenesis. On the other hand, a normal energy expenditure during exercise has been reported. At present, the response and the role of catecholamines in energy metabolism during exercise in obesity have not been well clarified yet. The aim of this work was to study the metabolic and hormonal changes caused by intense exercise in obesity. Nine obese subjects and ten normal weight controls were submitted to exhaustive exercise on a cycloergometer. Blood glucose, free fatty acids (FFA), glycerol, lactate, β-OH-butyrate, insulin, glucagon, plasma growth hormone (HGH), catecholamine plasma levels were assayed before and at the end of exercise, and after a recovery period. The energy cost of exercise was evaluated by indirect calorimetry. In our experiment muscular exercise did not provoke any change in blood glucose and FFA plasma levels in either of our groups. In the obese subjects the insulin plasma levels were higher than in the controls. Glucagon plasma levels did not change. The exercise responses of norepinephrine (NE) (4.28±0.74 vs 8.81±1.35 nmol/l; P<0.01), epinephrine (E) (234.21±64.18 vs 560.51±83.38 pmol/l; P<0.01) and plasma growth hormone (HGH) (134.84±58.97 vs 825.92±195.25 pmol/l; P<0.01) were significantly lower in obese subjects. At the end of exercise, the thermic effect of exercise did not differ between obese and control subjects (0.335±0.038 vs 0.425±0.040 kJ/min×kg fat-free mass. Our findings indicate that an impaired counterregulatory hormone response to exercise exists in obese subjects. The thermic effect of exercise does not seem to be affected by either the reduced catecholamine response nor insulin resistance.

Substrate competition and insulin action in animal models.

Increased basal plasma FFA and lactate concentrations are often present in obesity and may deeply affect insulin action. The inhibition of glucose transport or phosphorylation is thought to be involved in this phenomenon, but the molecular mechanisms on the basis are still unknown. In our laboratory we observed that a chronic infusion of Intralipid plus heparin in rats significantly decreased the insulin dependent-glucose uptake, as well as GLUT4 gene expression in muscular tissue. On the other hand it has been shown that an enhanced plasma lactate concentration may increase insulin secretion and hepatic insulin clearance. Moreover we observed that chronic hyperlactatemia in rats is able to decrease glucose uptake in muscles, while reducing GLUT4 mRNA and protein in the same tissues. In obesity, lactate and FFA overproduction from visceral fat may therefore play a synergic role in reducing insulin sensitivity.

Effect of endogenous organic hyperinsulinaemia on blood pressure and serum triglycerides

Abstract Hyperinsulinaemia and insulin resistance have been hypothesized to be the common pathophy‐siological factor of hypertension, NIDDM and obesity. To evaluate the possible role of hyperinsulinaemia and insulin resistance on hypertension, we studied a group of 37 patients with insulinoma who were admitted to our department in the period from 1966 to 1990. We recorded blood pressure and assayed blood glucose, plasma insulin, plasma triglycerides and serum uric acid levels, before and after surgery, in these patients and in a 37‐subject control group. No significant increase in blood pressure and triglyceride plasma levels was recorded in the chronic hyperinsulinaemic hypoglycaemic patients, suggesting the lack of a direct role of hyperinsulinaemia on hypertension.

Dietary-induced thermogenesis in obesity. Response to mixed and carbohydrate meals

SummaryThe possibility that dietary-induced thermogenesis may be decreased in obesity has been proposed in recent years. However, the results of human studies so far obtained are conflicting. The present research was undertaken in order to clarify this question. We studied postprandial thermogenesis induced by ingestion of a mixed meal and of a carbohydrate mixture in 15 normal and 12 obese subjects. Blood glucose and plasma insulin levels were measured at the same time. The data obtained have shown that the mean resting metabolic rate (RMR) expressed as a function of body weight3/4, is almost the same in obese as in normal-weight subjects (0.115±0.018vs 0.133±0.021 kj/min/kg3/4, respectively). Moreover, the increment of mixed-meal induced thermogenesis (MM-IT) was 48±22% in normal and −0.8±12% in obese subjects, respectively (p<0.01). Carbohydrate induced thermogenesis (CHO-IT) appeared slightly higher in normal-weight than in obese subjects (159±66vs 98±46). After carbohydrate ingestion we observed a higher glycemic and insulinemic response in obesity. These results indicate that thermogenesis induced by ingestion of food is reduced in obese subjects; they are also compatible with the idea that insulin resistance could play a role in this phenomenon.