Plasma concentrations of growth hormone during hyperglycemic clamp with or without somatostatin infusion in obese subjects

It is known that obese subjects have a blunted GH secretory response to stimulation, but little is known about the inhibition of GH secretion in obesity. The present study was designed to evaluate the effects of obesity on the suppression of GH by hyperglycemia and/or somatostatin. Plasma GH concentrations were measured in eight nondiabetic obese subjects and eight nonobese healthy controls during a 4-h hyperglycemic clamp. During the third hour synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min. Baseline plasma GH levels were similar in obese and nonobese subjects (0.9 +/- 0.1 vs. 0.8 +/- 0.2 micrograms/L; mean +/- SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120 min of the study) plasma GH averaged 0.8 +/- 0.1 micrograms/L in obese patients and 0.4 +/- 0.1 micrograms/L in control subjects (P less than 0.01), with a reduction of 6 +/- 5% in the former and 35 +/- 10% in the latter (P less than 0.01). In both groups somatostatin infusion did not result in a further decrease in plasma GH. Discontinuation of the somatostatin infusion resulted in a rise in both groups; the increase was higher in nonobese subjects (8.1 +/- 3.8 vs. 2.3 +/- 0.9 micrograms/L in the period 220-240 min; P = NS). These results suggest that in human obesity, hyperglycemia has a diminished inhibitory effect on GH secretion, and somatostatin administration has no additional effect in either obese or nonobese nondiabetic subjects.     

Elevated insulin levels contribute to the reduced growth hormone (GH) response to GH-releasing hormone in obese subjects.

We have recently presented experimental evidence indicating that insulin has a physiologic inhibitory effect on growth hormone (GH) release in healthy humans. The aim of the present study was to determine whether in obesity, which is characterized by hyperinsulinemia and blunted GH release, insulin contributes to the GH defect. To this aim, we used a simplified experimental protocol previously used in healthy humans to isolate the effect of insulin by removing the interference of free fatty acids (FFAs), which are known to block GH release. Six obese subjects (four men and two women; age, 30.8 +/- 5.2 years; body mass index, 36.8 +/- 2.8 kg/m2 [mean +/- SE]) and six normal subjects (four men and two women; age, 25.8 +/- 1.9 years; body mass index, 22.7 +/- 1.1 kg/m2) received intravenous (i.v.) GH-releasing hormone (GHRH) 0.6 microg/kg under three experimental conditions: (1) i.v. 0.9% NaCl infusion and oral placebo, (2) i.v. 0.9% NaCl infusion and oral acipimox, an antilipolytic agent able to reduce FFA levels (250 mg at 6 and 2 hours before GHRH), and (3) euglycemic-hyperinsulinemic clamp (insulin infusion rate, 0.4 mU x kg(-1) x min(-1)). As expected, after placebo, the GH response to GHRH was lower for obese subjects versus normals (488 +/- 139 v 1,755 +/- 412 microg/L x 120 min, P < .05). Acipimox markedly reduced FFA levels and produced a mild reduction of insulin levels; under these conditions, the GH response to GHRH was increased in both groups, remaining lower in obese versus normal subjects (1,842 +/- 360 v 4,871 +/- 1,286 microg/L x 120 min, P < .05). In both groups, insulin infusion yielded insulin levels usually observed under postprandial conditions and reduced circulating FFA to the levels observed after acipimox administration. Again, the GH response to GHRH was lower for obese subjects versus normals (380 +/- 40 v 1,075 +/- 206 microg/L x 120 min, P < .05), and in both groups, it was significantly lower than the corresponding response after acipimox. In obese subjects, as previously reported in normals, the GH response to GHRH was inversely correlated with the mean serum insulin (r = -.70, P < .01). In conclusion, our data indicate that in the obese, as in normal subjects, the GH response to GHRH is a function of insulin levels. The finding that after both the acipimox treatment and the insulin clamp the obese still show higher insulin levels and a lower GH response to GHRH than normal subjects suggests that hyperinsulinemia is a major determinant of the reduced GH release associated with obesity.     

METABOLIC RESPONSES TO MONOCOMPONENT HUMAN INSULIN INFUSIONS IN NORMAL SUBJECTS AND PATIENTS WITH LIVER AND ENDOCRINE DISEASE

Hypoglycaemic and growth hormone responses were studied at different steady-state plasma insulin concentrations during a graded infusion of monocomponent human insulin. The control group consisted of ten volunteer subjects. The other groups studied included women taking oral contraceptives and patients with obesity, thyrotoxicosis, myxoedema, acromegaly, diabetes mellitus (moderate and severe) and liver disease. The hypoglycaemic response was measured in two ways: (i) the percentage reduction in plasma glucose below basal, and (ii) the rate of fall of plasma glucose (K_g-%/min). Insulin sensitivity was greatest in the normal subjects and in the other groups decreased in the order thyrotoxicosis>oral contraceptive>obesity>myxoedema>acromegaly>liver disease. Insulin sensitivity was difficult to assess in the diabetic patients because basal plasma glucose concentrations were elevated. At any given insulin concentration, the diabetics metabolized approximately the same amount of glucose as the normal subjects but the fact that this rate of glucose turnover occurred at higher plasma glucose concentrations probably indicated insulin resistance. Within each group K_g at each dose level of insulin correlated with the steady state plasma insulin concentration during the same infusion period. Diminishing sensitivity to insulin was reflected in an increasing fasting plasma insulin and insulin/glucose ratio except in patients with diabetes. GH responses to insulin infusion in normal subjects reflected the pattern of fall of plasma glucose. In the diabetic patients GH secretion appeared to be related to the infusion of insulin and occurred before plasma glucose had fallen to hypoglycaemic levels. GH secretory patterns were within normal limits in women taking oral contraceptives and in seven of eleven patients with liver disease but were impaired in three of seven patients with thyrotoxicosis and four of five patients with myxoedema. Four obese patients had a markedly delayed but eventually normal GH response.     

Peripheral hyperinsulinemia of simple obesity: pancreatic hypersecretion or impaired insulin metabolism?

Insulin and C-peptide levels in peripheral blood in the fasting state and after an oral glucose load were measured in 65 nondiabetic, obese subjects and 65 age- and sex-matched nondiabetic normal weight subjects. Fasting insulin and C-peptide levels were significantly higher in obese than in nonobese subjects, whereas 1 and 2 h after the oral glucose load only insulin concentrations were significantly higher in the obese subjects. C-peptide to insulin molar ratios, as well as the relation between the incremental areas of the two peptides, were used as relative measures of hepatic insulin extraction. In the fasting state the ratios between C-peptide and insulin were similar in obese and nonobese subjects, whereas after glucose they were significantly lower in the obese individuals. Similarly, the relations between C-peptide and insulin incremental areas were significantly lower in obese than in nonobese subjects. The comparison of the corresponding plasma levels and areas of C-peptide and insulin after glucose showed that for the same C-peptide value, the insulin value was higher in the obese group. Last, in obese subjects the parameter used as an estimate of hepatic removal of insulin after oral glucose inversely correlated with the fasting insulin concentration and the insulin incremental area after glucose. These results suggest that in obesity peripheral hyperinsulinemia depends on pancreatic hypersecretion of insulin in the fasting state and impaired hepatic insulin metabolism after oral glucose loading.     

Ethanol decreases glucose utilization in healthy man

The effect of ethanol on glucose utilization during hyperinsulinemia was studied by the euglycemic clamp technique. Normal subjects were given 1 g ethanol/kg body weight for 210 min (oral priming dose of 0.67 g/kg followed by iv infusion of 0.33 g/kg) or 0.9% saline. Insulin infusion, started 90 min after the beginning of ethanol administration, resulted in a mean plasma insulin concentration of 87 +/- 5 (SEM) mU/liter. Plasma glucose was maintained at 5.2 mmol/liter. The rate of glucose metabolism was 23% lower during ethanol (7.1 +/- 0.1 mg/kg X min) than during the control (9.0 +/- 0.8 mg/kg X min) experiment (P less than 0.001). During hyperinsulinemia blood lactate concentrations rose in the control study but this change was abolished by ethanol. The insulin-induced fall of serum triglyceride levels was also inhibited by ethanol. It is concluded that acute intake of alcohol in moderate doses induces insulin resistance.     

An abnormality of the growth hormone/insulin-like growth factor-I axis in women with polycystic ovary syndrome due to coexistent obesity.

In order to evaluate the GH/insulin-like growth factor-I (IGF-I) axis in the polycystic ovary syndrome (PCO), 21 women aged 18-38 yr were studied. The GH responses to the GH-releasing hormone (GHRH), and plasma concentrations of IGF-I were measured in seven obese women with PCO, seven obese healthy controls without PCO, and in seven nonobese subjects. Total GH secretion, as expressed by the integrated GH response to GHRH, in PCO obese women (617.4 +/- 150 micrograms/L.min) and in obese women without PCO (327.1 +/- 161.4 micrograms/L.min) were lower than that in nonobese healthy controls (3181.4 +/- 644.3 micrograms/L.min, P less than 0.001 and P less than 0.001, respectively). Plasma concentrations of IGF-I in obese PCO women (199.5 +/- 39.1 micrograms/L), and in obese women without PCO (192.4 +/- 36.8 micrograms/L) were similar to the IGF-I levels in nonobese controls (224.3 +/- 33.2 micrograms/L). In obese women with and without PCO, a negative correlation was found between the body mass index and the peak GH responses to GHRH (r = -0.639, P less than 0.02) and between age and IGF-I levels (r = -0.520, P less than 0.05). These findings suggest that an abnormality of the GH/IGF-I axis in PCO women may be due to coexistent obesity.     

Plasma free fatty acid concentration during hyperglycemic glucose clamp with and without somatostatin infusion in obese subjects with normal glucose tolerance

In the present study we evaluated the regulation of plasma free fatty acid (FFA) concentration by glucose and insulin in human obesity. To this purpose we measured plasma FFA concentration in normoglycemic, normoinsulinemic obese (n = 8) and nonobese (n = 8) healthy subjects during 240 min of exogenous hyperglycemia (hyperglycemic glucose clamp) in presence of both glucose-stimulated (0-120 min and 180-240 min) and somatostatin-inhibited (120-180 min) insulin secretion. We found that plasma FFA curves were roughly parallel in the 0-120 min period and FFA values of obese subjects were constantly higher throughout the experimental period. Moreover, the difference between the two groups was significant when individual data were expressed as a percent of fasting FFA value (P less than 0.0001 from 0 to 120 min). Plasma insulin levels were similar in the two groups during the entire study. The amount of glucose metabolized during the 80-120 min period was significantly lower in obese than in nonobese subjects (172 +/- 7 v. 341 +/- 11 mg/m2.min, P less than 0.01; means +/- s.e.). During the somatostatin period (120-180 min) plasma insulin was lowered close to basal values in both groups (116 +/- 15 and 109 +/- 11 pmol/l) and plasma FFA concentrations rose in a linear fashion. Our data suggest that suppression of plasma FFA concentrations by glucose and insulin is qualitatively similar in healthy nonobese and obese subjects, the latter having higher FFA values. Insulin action on FFA metabolism isn ot grossly impaired in obese subjects who are clearly insulin resistant as far as glucose metabolism is concerned.     

Effect of obesity on ambient plasma glucose, free fatty acid, insulin, growth hormone, and glucagon concentrations

Fasting and postprandial plasma concentrations of glucose, FFA, insulin, glucagon, and GH concentrations were determined in 10 nonobese and 10 obese subjects with normal glucose tolerance. Measurements were made at 0800 h (after a 14-h fast) and at hourly intervals from then until 1600 h. During this time period all individuals ate breakfast at 0800 h (20% of total daily calories) and lunch (40% of total daily calories). Although plasma glucose concentrations were similar throughout the 8-h period in the 2 groups, plasma insulin concentrations were significantly (P less than 0.001) higher in the obese individuals. However, despite the presence of hyperinsulinemia, the obese group also had higher (P less than 0.001) plasma FFA concentration throughout the day. On the other hand, both the absolute and the relative declines in plasma FFA concentration after meals were similar in the 2 groups. Since plasma glucagon and GH concentrations were similar in the 2 groups, altered production of these lipolytic hormones was not responsible for the elevated plasma FFA levels in the obese individuals. These data document the presence in obese individuals of a disassociation in their ability to maintain normal plasma glucose as opposed to plasma FFA homeostasis, and indicate that the increase in plasma FFA concentrations in obesity occurs in the presence of hyperinsulinemia and is not related to abnormalities of either glucagon or GH secretion.     

The impact of obesity and chronic hyperinsulinemia on gonadotropin release and gonadal steroid secretion in the polycystic ovary syndrome

We investigated whether obesity was a marker for a neuroendocrinologically distinct form of the polycystic ovary syndrome (PCO). Further, since women with PCO have significantly higher basal and/or glucose-stimulated plasma insulin levels, we also examined the effects of chronic hyperinsulinemia on gonadotropin and gonadal steroid secretion. Ten obese women (nine with acanthosis nigricans) and five nonobese women (one with acanthosis nigricans) with PCO as well as seven obese and six nonobese women of comparable age and weight in the midfollicular phase of their cycles were studied. Pulsatile gonadotropin release was determined for 6-24 h as well as gonadotroph sensitivity to GnRH (10 micrograms, iv). The obese PCO women had significantly increased basal and glucose-stimulated plasma insulin levels compared to the other groups, the nonobese PCO and the obese normal women had similar insulin levels, and the nonobese normal women had the lowest insulin levels. All four groups had similar plasma estradiol levels. Both the obese and the nonobese PCO women had similar and significantly higher mean plasma LH levels, LH pulse amplitude, and integrated LH responses to GnRH compared to values in both normal groups (P less than 0.01 to P less than 0.001); the obese PCO women did not differ from the nonobese PCO women. The mean LH pulse frequencies per 6 h were similar in the four groups. FSH secretion did not differ significantly in the four groups. The levels of the putative gonadal feedback steroids, plasma total and non-sex hormone-binding globulin-bound testosterone, non-sex hormone-binding globulin-bound estradiol, and estrone, were similar in both PCO groups and were significantly higher than those in both normal groups (all P less than 0.001). The only independent effect of obesity was on plasma androstenedione levels and the androstenedione to estrone ratio, both of which were significantly higher in PCO women than normal women (P less than 0.01 to P less than 0.001), but significantly lower in the obese (PCO and normal) women than in nonobese (PCO and normal) women (P less than 0.05). These findings suggest that 1) the impact, if any, of obesity in PCO is not reflected in discernible changes in gonadotropin release or in the gonadal steroid feedback environment; and 2) insulin does not have a major role in the perpetuation of PCO, since obese and nonobese PCO women had similar reproductive hormone levels despite significantly different degrees of hyperinsulinemia.     

Plasma concentrations of glucagon during hyperglycemic clamp with or without somatostatin infusion in obese subjects

Summary The aim of the present study was to evaluate whether the inhibitory effect on pancreatic A-cell exerted by hyperglycemic hyperinsulinemia and/or by somatostatin administration is impaired in human obesity. For this purpose plasma glucagon concentrations were measured in 8 obese and 8 nonobese nondiabetic subjects during a 4-h hyperglycemic clamp. Synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min during the third hour of the study. Fasting plasma glucagon was higher in obese than in nonobese subjects (242±32vs 163±15 pg/ml, p<0.05) (mean±SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100–120 min of the study) plasma glucagon averaged 195±26 pg/ml in obese and 122±13 pg/ml in nonobese subjects (p<0.05), with a reduction of 19±3% in the former and 28±4% in the latter (p=n.s.). In both groups somatostatin infusion did not result in a further decrease in plasma glucagon, which averaged 192±27 pg/ml in obese and 123±16 pg/ml in nonobese subjects (p<0.05) in the 160–180 min period of the study. Also after discontinuing somatostatin infusion plasma glucagon levels did not change. These results suggest that in human obesity hyperglycemic hyperinsulinemia has a normal inhibitory effect on pancreatic A-cell and that somatostatin administration has no additive effect on hyperglycemia and hyperinsulinemia in either obese or nonobese nondiabetic subjects. Supported by grants n^o 83.02749.56, 84.03099.56, 85.00681.56, 86.01873.56, 83.02591.04, 85.00502.04 and 86.00102.04 fromConsiglio Nazionale delle Ricerche, Italy, and by grants fromMinistero della Pubblica Istruzione, Italy.     

Obesity and insulin resistance in humans: a dose-response study

Insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance.     

Insulin and renal sodium retention in obese adolescents

The effect of insulin on the renal handling of sodium was studied in obese and nonobese subjects by using euglycemic hyperinsulinemia. Seven water-loaded obese (14-19 years old) and five nonobese young adults (18-21 years old) had insulin given intravenously at a rate of 40 munits/m2/min. Blood glucose and creatinine clearance were not altered by euglycemic hyperinsulinemia in either the obese or the nonobese group. Hyperinsulinemia resulted in a significant decrease in urinary sodium excretion in both groups of subjects (by 54.2 +/- 3% [mean +/- SEM] in the obese and by 50.9 +/- 3.1% in the nonobese group). However, the amount of glucose required to maintain euglycemia was significantly less in the obese versus nonobese group, 89.5 +/- 6.2 versus 329.2 +/- 16 mg glucose/m2/min (p less than 0.001). There was no relation in either group between the amount of glucose required to maintain euglycemia and the change in urinary sodium excretion. On a separate day, all of the obese subjects underwent 3 hours of water diuresis but without insulin. There was no change in urinary sodium excretion with sustained water diuresis alone. However, when compared with the nonobese group, the obese group of subjects had a significantly higher resting mean arterial pressure, heart rate, and plasma norepinephrine concentration; during the insulin clamp, neither group experienced a significant change in mean arterial pressure or heart rate, and only the nonobese group experienced an increase in plasma norepinephrine. In obese subjects, we have found, despite the presence of insulin resistance to carbohydrate metabolism, that euglycemic hyperinsulinemia was associated with a normal decrease in urinary sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxidative stress is associated with adiposity and insulin resistance in men

To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2alpha (PGF2alpha) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2alpha than nonobese men (P < 0.05). The plasma levels of 8-epi-PGF2alpha were significantly correlated with body mass index (r = 0.408; P < 0.05), body fat weight (r = 0.467; P < 0.05), visceral (r = 0.387; P < 0.05) and total fat area (r = 0.359; P < 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2alpha and glucose infusion rate in obese men (r = -0.552; P < 0.05) and all men (r = -0.668; P < 0.01). In all subjects, the plasma levels of 8-epi-PGF2alpha were significantly correlated with fasting serum levels of insulin (r = 0.487; P < 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2alpha are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.     

Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes

GH hypersecretion in type 1 diabetes has been implicated in the pathogenesis of insulin resistance, and microangiopathic complications, and may result from reduced circulating IGF levels. We examined the effects of recombinant human (rh)IGF-I [complexed in equimolar ratio with rhIGF binding protein (BP)-3 (rhIGF-I/IGFBP-3)] replacement on overnight GH levels and insulin sensitivity in type 1 diabetes. Fifteen subjects, 13-24 yr old (10 male), were given rhIGF-I/IGFBP-3 or placebo as a daily sc injection for 2 d. After the second injection overnight, insulin requirements for euglycemia were determined (0400-0800 h), followed by a 4-h, two-step (insulin, 0.6 and 1.5 mU/kg.min) hyperinsulinemic euglycemic [90 mg/dl (5 mmol/liter)] clamp. In each subject, the protocol was repeated on three occasions in random order. Seven subjects received placebo and rhIGF-I/IGFBP-3 (0.1 mg/kg.d and 0.4 mg/kg.d), and eight subjects received placebo and rhIGF-I/IGFBP-3 (0.2 mg/kg.d and 0.8 mg/kg.d). We found dose-dependent increases in circulating IGF-I and IGFBP-3 concentrations after rhIGF-I/IGFBP-3. These were paralleled by significant reductions in mean overnight GH levels and GH pulse amplitude. We also observed dose-dependent effects of rhIGF-I/IGFBP-3 on overnight insulin requirements for euglycemia, with reductions of up to 41%. Insulin sensitivity, defined by M-values, was improved with rhIGF-I/IGFBP-3 (0.4 and 0.8 mg/kg.d). Thus, restoration of circulating IGF-I and IGFBP-3 levels with rhIGF-I/IGFBP-3 suppresses GH secretion in adolescents with type 1 diabetes, leading to reduced insulin requirements and improvements in insulin sensitivity.     

The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance.

PC-1 is a membrane glycoprotein that impairs insulin receptor function. Its K121Q polymorphism is a genetic determinant of insulin resistance. We investigated whether the PC-1 gene modulates insulin sensitivity independently of weight status (i.e. both in nonobese and obese individuals). Nondiabetic subjects [164 males, 267 females; age, 37 +/- 0.6 yr, mean +/- SEM; body mass index (BMI), 32.7 +/- 0.5 kg/m(2)], who were subdivided into 220 nonobese (BMI < or = 29.9) and 211 obese, were studied. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P < 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. Insulin sensitivity, measured by euglycemic clamp in a representative subgroup of 131 of 431 randomly selected subjects, progressively decreased (P < 0.001) from nonobese K121K [n = 61; glucose disposal (M) = 34.9 +/- 1.1 micromol/kg/min] to nonobese Q (n = 21; M = 29.9 +/- 2.0), obese K121K (n = 31, M = 18.5 +/- 1.2), and obese Q (n = 18, M = 15.5 +/- 1.2) carriers. The K121Q polymorphism was correlated with insulin sensitivity independently (P < 0.05) of BMI, gender, age, and waist circumference. In conclusion, the Q121 PC-1 variant and obesity have independent and additive effects in causing insulin resistance.     

Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome

Controversial data were reported concerning fasting ghrelin (decreased, normal or elevated) in polycystic ovary syndrome (PCOS). The aim of our study was to clarify ghrelin levels in non-obese, overweight, and obese PCOS patients; to investigate the effect of acute insulin infusion on ghrelin in PCOS as a chronic insulin-resistant state, with and without the impact of obesity, and to examine ghrelin-androgen interaction. In that order, we evaluated 1) ghrelin levels among 8 nonobese patients with PCOS [body mass index (BMI): 20.52+/-1.31 kg/m2], 8 overweight and obese patients with PCOS (BMI: 34.36+/-6.53 kg/m2) and their respective controls, 2) ghrelin suppression during euglycemic hyperinsulinemic clamp, and 3) ghrelin-androgen interrelationship. After overnight fast, 2-h euglycemic hyperinsulinemic clamp, was performed in all investigated women. Fasting ghrelin was significantly lower in non-obese PCOS than in controls (64.74+/-25.69 vs 108.36+/-52.60; p<0.05) as well as in overweight and obese PCOS in comparison with controls (38.71+/-14.18 vs 98.77+/-40.49; p<0.05). Insulin infusion significantly suppressed ghrelin in all subgroups of investigated women. Analysis of variance for repeatable measures confirmed that there was no significant difference in pattern of response between PCOS and controls. In conclusion, women with PCOS had lower fasting ghrelin and decreased insulin sensitivity independently of their BMI, compared to the controls. In addition, there were no differences between fasting ghrelin levels among non-obese, overweight, and obese women with PCOS. During euglycemic hyperinsulinemic clamp, ghrelin decreased in all studied groups to a similar extent, implying that, compared to chronic hyperinsulinemia, acute hyperinsulinemia reduces ghrelin levels independently of the degree of insulin resistance.     

Does aging intensify the insulin resistance of human obesity?

Relative insulin sensitivity in aging and obesity was studied during 6-h euglycemic-hyperinsulinemic clamp procedures in seven nonobese weight-matched premenopausal (Pre-M) and postmenopausal (Post-M) women and in nine weight-matched obese Pre-M and Post-M subjects. Peripheral glucose disappearance rates (Rd) and endogenous glucose production rates (EGPR) were measured during baseline (0-2 h) and at insulin delivery rates of 10 (2-4 h) and 40 mU/m2.min (4-6 h). Baseline Rd and EGPR were comparable in the four groups. In Pre-M nonobese women, Rd rose 1.6- and 4-fold above baseline, respectively, at 2-4 and 4-6 h. In all other groups Rd did not change at the lower insulin delivery rate and rose only 2-fold above baseline at the higher delivery rate. EGPR was suppressed 61% and 100% at the two insulin infusion rates, respectively, in Pre-M nonobese subjects. Similar normal suppression was observed in Post-M nonobese individuals. However, in both obese groups, EGPR suppression was comparable and significantly less than that in nonobese groups. These results confirm the presence of peripheral tissue insulin resistance in both obese and aging women. However, in aging, unlike obesity, EGPR is normally suppressed by insulin. In addition, aging does not appear to intensify the insulin resistance of obese states when both coexist in the same individual.     

Evidence supporting a direct suppressive effect of growth hormone on serum IGFBP-1 levels. Experimental studies in normal, obese and GH-deficient adults.

It has occasionally been suggested that GH directly suppresses circulating IGFBP-1 levels, although it is generally believed that such an effect is secondary to a GH-induced increase in insulin levels. We present data from several experiments in which the effects of GH on IGFBP-1 could be studied more extensively. In normal subjects (n = 36), an i.v. GH bolus caused a small but significant decrease in plasma IGFBP-1 concentrations without changes in insulin [IGFBP-1 (microgram/l): 2.6 +/- 0.3 (GH) vs 3.2 +/- 0.4 (placebo), P < 0.05]. Conversely, a 28-h somatostatin infusion with and without GH administration during fasting in normal subjects yielded higher IGFBP-1 levels in the non-GH substituted study [50.5 +/- 5.3 (GH-suppression) vs 22.6 +/- 5.6 (GH-substitution), P < 0.01], comparable with an increased concentration of IGFBP-1 during fasting in GH-deficient patients without usual GH substitution [23.4 +/- 7.6 (GH pause) vs 14.1 +/- 4.9 (GH substitution), P < 0.01]. In both fasting studies insulin levels remained stable. During a hypocaloric diet, long-term GH treatment in obesity lead to a significant decline in IGFBP-1 level (2.3 +/- 0.6 vs 1.2 +/- 0.2, P < 0.01), while no changes were found in the placebo group. Again, insulin levels remained equally low in both studies. Finally, a significant rebound increase in IGFBP-1 level in response to insulin induced hypoglycemia was only observed among GH-deficient patients, but not in control subjects, the latter of whom responded to hypoglycemia with a significant increase in serum GH levels [23.2 +/- 7.2 (GHDA) vs 2.5 +/- 0.3 (controls), P < 0.01]. In conclusion, a suppressive effect of GH on IGFBP-1 appears to be unmasked in the presence of low or suppressed insulin levels, making GH a potential regulator of IGF-1 bioactivity in a hitherto unrecognized way.     

Decreased hepatic insulin extraction in subjects with mild glucose intolerance

The fact that hyperinsulinemia occurs in simple obesity and mild glucose intolerance has been well established. Altered hepatic insulin extraction may influence the levels of circulating hormone. The simultaneous measurement of insulin and C-peptide concentrations in peripheral blood enables an in vivo estimation of hepatic insulin removal. To evaluate hepatic insulin extraction, insulin and C-peptide responses to oral glucose were studied in 176 obese and nonobese subjects with normal, impaired, or diabetic glucose tolerance. Insulin levels as well as insulin incremental areas in glucose intolerant subjects were significantly higher than in weight-matched controls. The levels of C-peptide as well as C-peptide incremental areas were only slightly enhanced in subjects with impaired glucose tolerance, whereas they were reduced in subjects with diabetic tolerance. The molar ratios of C-peptide to insulin, both in the fasting state and after ingestion of glucose, as well as the relationship between the incremental areas of the two peptides were used as measures of hepatic insulin extraction. They were significantly reduced in glucose intolerant subjects and, to a lesser extent, in nondiabetic obese subjects. These results indicate that peripheral hyperinsulinemia in subjects with simple obesity or impaired glucose tolerance is a result of both pancreatic hypersecretion and diminished hepatic insulin extraction. In subjects with a more severe degree of glucose intolerance, decreased hepatic insulin removal is the primary cause of hyperinsulinemia.     

Obesity worsens cardiovascular risk profiles independently of hyperinsulinaemia

OBJECTIVE: To investigate whether human obesity is characterized by a worse cardiovascular risk profile (than no obesity) even in the absence of hyperinsulinaemia. SUBJECTS AND DESIGN: A total of 367 healthy subjects (247 nonobese and 120 obese) with normal glucose tolerance and without family history of diabetes mellitus. INTERVENTIONS: A 75-g oral glucose tolerance test was performed in all participants. MAIN OUTCOME MEASURES: Anthropometry, blood pressure, fasting plasma lipids and urate, plasma glucose and insulin concentrations at fasting, 1 h and 2 h after oral glucose load. RESULTS: In a multivariate linear regression analysis, body mass index was strongly related to all cardiovascular risk factors, independently of sex, age and plasma insulin. When risk factors were compared in 37 normoinsulinaemic obese subjects (plasma insulin within one standard deviation of the mean values observed in the 247 nonobese subjects), and in 37 sex- and age-matched normoinsulinaemic nonobese subjects, we found that plasma glucose levels were similar in the two groups, whereas plasma triglyceride (1.50 +/- 0.13 vs. 1.13 +/- 0.08 mmol L-1; mean +/- SE), low-density lipoprotein cholesterol (3.42 +/- 0.25 vs. 2.77 +/- 0.18 mmol L-1) and urate (290 +/- 12 vs. 255 +/- 12 mumol L-1) levels were significantly higher, and plasma high-density lipoprotein cholesterol concentrations were lower (1.27 +/- 0.04 vs. 1.46 +/- 0.06 mmol L-1) in obese than in nonobese subjects with normal plasma insulin levels (P < 0.01). Also systolic (132 +/- 2 vs. 124 +/- 2 mmHg) and diastolic (86 +/- 1 vs. 81 +/- 1 mmHg) blood pressure values were significantly higher in normoinsulinaemic obese subjects than in normoinsulinaemic nonobese individuals (P < 0.001). CONCLUSIONS: These results suggest that in human obesity a worse cardiovascular risk profile is found (than in the nonobese) independently of the presence of hyperinsulinaemia.