Relationship of androgenic activity to splanchnic insulin metabolism and peripheral glucose utilization in premenopausal women

The importance of androgenic activity in mediating the effects of obesity and body fat topography on splanchnic insulin metabolism and peripheral insulin sensitivity was studied in 19 nonhirsute premenopausal women with a wide range of ideal body weight [percent ideal body weight (% IBW), 78-202%] and body fat distribution pattern [waist to hip girth ratio (WHR), 0.67-0.91]. Turnover kinetics of peripheral plasma C-peptide and insulin were measured, and estimates of pancreatic insulin production (PIP) and the hepatic extraction fraction (HEF) were calculated. The peripheral insulin sensitivity index (M/I) was determined during an euglycemic insulin clamp study. Androgenic activity was assessed by estimating the plasma level of sex hormone-binding globulin (SHBG) and percentage of free testosterone (% FT). After iv glucose stimulation, PIP ranged from 40-254 mU/min X m2 and correlated highly with % IBW (r = 0.78; P less than 0.01). Insulin HEF ranged from 5-69% of the pancreatic production and was inversely proportional to WHR (r = -0.60; P less than 0.01). Increasing WHR also correlated with the diminution in M/I (r = -0.47; P less than 0.05), which, in turn, correlated with the decline in the HEF of insulin (r = 0.60; P less than 0.01). Since PIP, HEF, and M/I correlated with SHBG and % FT, and since the degree of androgenic activity correlated with % IBW and WHR, partial regression analysis was performed. After adjusting for the effects of SHBG and % FT, the relationship between % IBW and PIP remained unaltered, whereas the correlation between WHR and HEF or M/I and their relationship to each other were either markedly reduced or became insignificant. Thus, in premenopausal women, the increase in pancreatic insulin production with increasing weight is independent of the degree of androgenic activity. On the other hand, the decline in hepatic insulin extraction and diminution in peripheral insulin sensitivity with upper body fat localization are in part mediated by increased androgenic activity. This association may account for the pronounced hyperinsulinemia and insulin resistance characteristic of this form of obesity.     

Effect of obesity and body fat distribution on sex hormones and insulin in men

To investigate the relationship between body fat distribution, sex hormones, and hyperinsulinemia in male obesity, we examined 52 obese men (body mass index [BMI], 35.0 +/- 6.1, mean +/- SD) and 20 normal-weight controls. Their waist to hip circumference ratio (WHR), which was used as an index of fat distribution, was 0.985 +/- 0.052 and 0.913 +/- 0.061 (P less than .005), respectively. Compared with controls, obese men presented significantly lower levels of total (357 +/- 132 v 498 +/- 142 ng/dL; P less than .005) and free testosterone (14.2 +/- 2.9 v 17.1 +/- 2.6 pg/mL; P less than .05) and sex hormone-binding globulin (SHBG; 41.7 +/- 31.9 v 66.2 +/- 18.6 nmol/L; P less than .001) without any significant difference on the other sex steroid or on gonadotropin concentrations. Fasting and glucose-stimulated insulin and C-peptide levels were significantly higher in obese than in controls, and in obese with the WHR value greater than 0.97 (corresponding to the distribution median) than in those with WHR lower or equal to 0.97. BMI was negatively correlated with testosterone (P less than .005), free testosterone (P less than .01), and SHBG (P less than .001) and positively with fasting (P less than .001) and glucose-stimulated (P less than .005) C-peptide concentrations, whereas no relationship was found between these variables and WHR values. On the contrary, WHR was significantly correlated with fasting and post-glucose insulin levels (P less than .05), but not with those of sex steroids.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between insulin resistance, insulin secretion and insulin metabolism in simple obesity

The study was designed to evaluate whether the correlation occurring in simple obesity between insulin resistance and peripheral hyperinsulinemia corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the study investigated the relation existing in simple obesity between insulin resistance and insulin metabolism. For these purposes, we measured and correlated: (1) insulin sensitivity, estimated by glucose disappearance rate from plasma after intravenous insulin injection; (2) insulin secretion by the pancreas, estimated by fasting C-peptide levels in peripheral blood; (3) insulin metabolism, estimated by means of C-peptide: insulin molar ratio in peripheral blood. Twenty-five subjects (20 females, five males) aged 21 to 59 years were studied. All were obese and had a normal glucose tolerance. Glucose disappearance rate from plasma after i.v. insulin injection averaged 3.65 +/- 0.42 mg/dl/min (mean +/- s.e.m.). Fasting C-peptide was 0.90 +/- 0.09 nmol/l. Fasting C-peptide: insulin molar ratio averaged 5.94 +/- 0.48. Negative correlations were found between glucose disappearance rates after i.v. insulin injection, ie, insulin sensitivity, and fasting concentrations of both insulin (r = -0.806, P less than 0.001) and C-peptide (r = -0.525, P less than 0.01). A positive relationship was found between glucose disappearance rate from plasma after i.v. insulin injection and fasting C-peptide: insulin molar ratio, ie, insulin metabolism (r = 0.707, P less than 0.001). We conclude that in simple obesity insulin overproduction by the pancreas is negatively related to insulin resistance, and insulin resistance and impaired insulin metabolism are strictly related phenomena.     

The role of the opioid peptides in the development of hyperinsulinemia in obese women with abdominal body fat distribution.

In this study, we investigated the hypothesis that increased opioid activity may be involved in the development of hyperinsulinemia in women with obesity and abdominal body fat distribution. Two groups of nine obese body (body mass index [BMI], 30 to 40 kg/m2) women with abdominal (A-ob) (waist to hip ratio [WHR] greater than 0.85) or gluteo-femoral (F-ob) (WHR greater than or equal to 0.80) fat distribution were examined and compared with eight normal-weight controls. Basal beta-endorphin levels were higher in the A-ob group than in the other groups. Each woman underwent two oral glucose tolerance tests (OGTT, 75 g glucose). A bolus of naloxone (0.8 mg) followed by a constant infusion of naloxone (0.04 mg/kg/h) or saline was also administered during the glucose challenge in random order, and blood samples for glucose, insulin, and C-peptide were collected at regular times after glucose administration. No difference was observed in basal or stimulated glucose concentrations between the three groups, nor between the saline or naloxone study. However, basal and stimulated insulin levels were significantly higher in obese women (particularly in the A-ob group) than in controls. Naloxone administration, however, did not significantly modify insulin and C-peptide glucose-stimulated concentrations in controls and in the F-ob group, whereas it significantly reduced (by approximately 47%) insulin levels in the A-ob group. Partial correlation coefficients showed a significant negative correlation between percent variation of glucose-stimulated insulin incremental areas during the naloxone study and the WHR in all women considered together (r = .544, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced hepatic insulin extraction in obesity: relationship with plasma insulin levels

To elucidate if there are alterations in insulin metabolic clearance in obesity under basal conditions, plasma insulin and C-peptide were measured in 22 obese patients and 8 normal subjects, and the plasma C-peptide to insulin molar ratio was used as an index of hepatic insulin extraction. In obese patients, the C-peptide to insulin molar ratio correlated indirectly with basal plasma insulin levels (r = 0.71; P less than 0.001), being low in the obese patients with higher insulin levels and within the normal range in obese patients in which insulin levels were similar to those of control subjects. It is suggested that hepatic insulin extraction is decreased in obesity, even under basal conditions, but this alteration is only manifested when plasma insulin levels are high.     

Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women

The relationship of body fat distribution to metabolic profiles was determined in 80 healthy premenopausal white women of a wide range of obesity levels [percentage of ideal body weight (% IBW) 92-251]. Distribution of fat between the upper and lower body was assessed from the waist/hips girth ratio (WHR), which varied from 0.64 to 1.02. In 23 women, in vivo insulin sensitivity was also determined from the steady-state plasma glucose (SSPG) level at comparable insulin levels of approximately 100 microU/mL attained by the intravenous infusion of somatostatin, glucose, and insulin. Increasing WHR was accompanied by progressively increasing fasting plasma insulin levels (r = 0.47, P less than 0.001), insulin and glucose areas after glucose challenge (r = 0.53, P less than 0.001; r = 0.50, P less than 0.001, respectively) and fasting plasma triglyceride concentrations (r = 0.48, P less than 0.001). Obesity level was similarly correlated with these metabolic indices. Partial and multiple regression analysis and analysis of variance with a linear contrast model revealed that the effects of body fat topography were independent of, and additive to, those of obesity level. Within obese subjects alone (%IBW: 130), %IBW had no predictive value, but WHR remained a significant predictor of plasma glucose, insulin, and triglyceride concentrations. The WHR also correlated with the plasma cholesterol level, but this association was largely dependent on its relationship to %IBW. Both WHR and %IBW correlated with the insulin resistance index, SSPG (r = 0.60, P less than 0.01; r = 0.61, P less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

DECREASED SEX HORMONE BINDING GLOBULIN (SHBG) AND INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN (IGFBP-1) IN EXTREME OBESITY

Obesity may be characterized by abnormal sex steroid secretion and reduced sex hormone binding globulin (SHBG) which in turn is related to fat distribution and insulin secretion. Recent in-vitro and in-vivo evidence suggests that insulin is the common mechanism regulating the secretion of SHBG and insulin-like growth factor small binding protein (IGFBP-1). IGFBP-1 appears not only to be a carrier for insulin growth factors (IGFs) but also to play an active role in growth processes, independent of growth hormone secretion. We have examined the possible relationship between fasting insulin, SHBG, testosterone, IGF-1, IGFBP-1 and fat distribution in 25 extremely obese, menstruating women (mean weight 107 +/- 3 kg) with normal glucose tolerance. Fat distribution was assessed from measurements of the waist to hip ratio (W/H). The obese women showed an elevated fasting insulin (mean +/- SEM; 21 +/- 2 mumol/l), a normal IGF-1, but reduced IGFBP-1 (14.6 +/- 2 micrograms/l); in 15 women IGFBP-1 levels were undetectable by the present assay. In addition, SHBG levels were reduced in the obese women (24 +/- 2 nmol/l) but total testosterone values (1.9 +/- 0.1 nmol/l) were normal. The elevated fasting insulin levels were positively correlated with increasing upper segment obesity as expressed by a rising W/H ratio (P less than 0.01, r2 = 0.306) and inversely correlated with SHBG (P less than 0.01, r2 = 0.483). Similarly, reduced SHBG values showed an inverse correlation with increasing W/H ratio (P less than 0.001, r2 = 0.383). No correlation was found between IGFBP-1 and W/H ratio but a strong positive correlation was seen between IGFBP-1 and SHBG (P less than 0.001, r2 = 0.466). Furthermore, an equally significant inverse correlation was found between IGFBP-1 and insulin levels (P less than 0.001, r2 = 0.474).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), the main androgen disorder in women, has been suggested to be associated with a high risk of developing cardiovascular disease and type 2 diabetes. In many PCOS patients, overweight or central obesity is generally associated with increases in fasting insulin levels, insulin resistance, and glucose intolerance, and has been identified as a target for new therapeutic strategy, including early change in lifestyle. Early biochemical marker(s) for identifying at-risk patients will be useful for prevention studies. The main goal of the present study was to search for such tool(s). We investigated 16 nonobese PCOS women by performing euglycemic hyperinsulinemic clamp and measuring insulin levels during fasting and oral glucose tolerance test, as well as the serum concentrations of SHBG, leptin, and adiponectin, the newly identified adipose factors. Eight of the 16 patients had a steady-state glucose disposal rate less than 8.5 mg/kg.min, the lowest normal value for nonobese control women. These insulin-resistant patients had significant higher body mass index (BMI) and waist-to-hip ratio (WHR), and lower high-density lipoprotein cholesterol and SHBG levels. As expected, glucose disposal correlated negatively with BMI (P = 0.01), WHR (P = 0.01), and fasting insulin level (P = 0.003). On stepwise regression analysis, however, the glucose-to-insulin ratio (GIR) emerged as the strongest independent parameter to appraise insulin resistance (R(2) = 0.61). SHBG level correlated positively with GIR (P < 0.001) and negatively with BMI (P = 0.003) but did not correlate with either insulin response during the glucose tolerance test or plasma leptin and/or adiponectin levels. In contrast, BMI was the only independent predictive parameter of SHBG (P = 0.003, R(2) = 0.73). Interestingly, plasma adiponectin levels were positively associated with glucose disposal rate (P = 0.043) and negatively with WHR (P = 0.024), waist circumference being the best predictor of adiponectin level (P < 0.01). Leptin level correlated only with BMI (r = 0.62, P = 0.01). This study confirmed that insulin resistance, despite the lack of obesity as such, is clearly present in many PCOS women, and demonstrated that GIR is the best predictor for insulin resistance. It was also shown that adiponectin level is a good indicator of abdominal fat mass and is associated to insulin resistance. Finally, low SHBG levels in PCOS are intimately associated with BMI, suggesting that some signal(s) from the adipose tissue, independent of adiponectin and leptin, may regulate liver production of SHBG.     

Increased upper body and overall adiposity is associated with decreased sex hormone binding globulin in postmenopausal women

An unfavorable body fat distribution is associated with many metabolic abnormalities including a high prevalence and incidence of noninsulin dependent diabetes mellitus and decreased high density lipoprotein cholesterol and increased triglyceride levels. One mechanism for the effect of body fat distribution on metabolic variables may be through sex hormones. We examined the relationship of body mass index (BMI), ratio of subscapular-to-triceps skinfold ratio (centrality index) and ratio of waist-to-hip ratio (WHR) to sex hormone binding globulin (SHBG) (an in vivo measure of androgenicity) in 101 postmenopausal Mexican-American and non-Hispanic white women from the San Antonio Heart Study, a population based study of diabetes and cardiovascular disease. SHBG was significantly correlated with BMI (r = -0.440, P less than 0.001), WHR (r = -0.255, P less than 0.01) and centrality index (r = -0.210, P less than 0.05). In a multiple linear regression analysis, SHBG remained significantly associated with BMI (P less than 0.001) and WHR (P less than 0.05) but not with age, ethnicity or centrality index. This work suggests that in postmenopausal women overall adiposity and an unfavorable body fat distribution are associated with increased androgenicity as measured by a lower SHBG concentration. Our finding may help to explain the association of body fat distribution with diabetes and cardiovascular risk factors in older women.     

Increased visceral adipose tissue is associated with increased circulating insulin and decreased sex hormone binding globulin levels in massively obese adolescent girls.

The current study was designed to examine the relationship between body fat distribution, as evaluated by anthropometry and magnetic resonance imaging (MRI), and circulating insulin, sex hormone and SHBG levels in obese adolescent girls. Twenty-nine obese adolescent girls, aged 12.6-16.9 years with a mean BMI of 30.51+/-1.86 participated in this study. All girls had breast stage B4-5 and pubic hair stage P4-5. Percent obesity and BMI as indices of being overweight were calculated; the waist-to-hip ratio (WHR) and the waist-to-thigh ratio (WTR) were calculated to obtain two anthropometric indices for the pattern of body fat distribution. The areas of visceral (VAT) and subcutaneous adipose tissue (SAT) were evaluated by MRI at the L4-L5 level. Serum concentrations of total T, DHEAS, 17beta-estradiol, progesterone and SHBG were measured. Plasma glucose and insulin concentrations were evaluated during an oral glucose tolerance test. WHR was the only anthropometric parameter that was significantly associated with the area of VAT. Insulin level showed correlation with both WHR and the area of VAT; no correlation was found between insulin levels and WTR. Both WHR and VAT were negatively correlated with serum DHEAS level and positively correlated with T level. There were strong negative correlations between serum SHBG level and the area of VAT and WHR. Inverse correlation was found between serum SHBG level and insulin. Serum 17beta-estradiol and progesterone levels showed no significant correlation with all the patterns of body fat distribution. SAT was not significantly correlated with both anthropometric parameters and any of the sex hormones evaluated. We can draw two main conclusions. Firstly, in massively obese adolescent girls, the WHR seems to be a good indicator for the accumulation of VAT, and abdominal obesity, rather than adiposity per se, appears to be related to biochemical complications. Secondly, increased upper body adiposity and, in particular, the intra-abdominal fat area are associated with increased insulin levels in massively obese adolescent girls. The associated reductions in SHBG and DHEAS levels represent an early general risk factor for the development of metabolic and cardiovascular diseases in this population, as previously described for obese adult women.     

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.     

Associations between regional body fat distribution, fasting plasma free fatty acid levels and glucose tolerance in premenopausal women

The associations between total adiposity, body fat distribution measured by computed tomography (CT) and estimated by the waist-to-hip ratio (WHR), regional fat cell morphology, fasting plasma free fatty acid (FFA) levels and glucose tolerance were studied in a sample of 37 premenopausal women aged 35.3 +/- 4.6 years (mean +/- s.d.). Body fat mass, CT-derived abdominal and femoral fat areas, as well as the abdominal fat cell weight were all significantly associated with fasting plasma FFA levels (0.34 less than r less than 0.49, 0.005 less than P less than 0.05), and with the glucose and insulin areas during the oral glucose tolerance test (OGTT) (0.36 less than r less than 0.70, 0.0001 less than P less than 0.05). No associations were found between the WHR, the femoral fat cell weight and fasting plasma FFA levels or glucose area during the OGTT. However, the WHR and the femoral fat cell weight were positively associated with insulin area. Plasma FFA levels were positively correlated with the glucose area during the OGTT, whereas no association was found between plasma FFA levels and the insulin area. Covariance analysis indicated that this effect of plasma FFA levels on the magnitude of glucose response to OGTT was independent from that of total adiposity or regional body fat distribution variables. These results emphasize the importance of plasma FFA levels as a correlate of glucose tolerance and suggest that the associations previously reported between obesity, regional body fat distribution, fat cell size and glucose tolerance are, at least partly, mediated by variations in plasma FFA levels.     

Racial disparities in metabolism, central obesity, and sex hormone-binding globulin in postmenopausal women

Increased total and intraabdominal fat (IAF) obesity as well as other metabolic conditions associated with the insulin resistance syndrome (IRS) are related to low levels of sex hormone-binding globulin (SHBG) in young and older Caucasian (CAU) and young African-American (AA) women. We examined whether postmenopausal AA women, a population with a high incidence of obesity and IRS despite low IAF, would have higher levels of circulating SHBG compared with CAU women, and whether there would be negative relationships between indexes of obesity and risk factors associated with IRS and SHBG levels. We measured body composition, SHBG, free testosterone, leptin, glucose tolerance, insulin, and lipoprotein lipids in 55 CAU (mean +/- SD, 59 +/- 7 yr) and 35 AA (57 +/- 6 yr) sedentary women of comparable obesity (48% body fat, by dual energy x-ray absorptiometry). Compared with CAU women, AA women had larger waist (101 vs. 96 cm), larger fat mass (44.9 +/- 8.8 vs. 39.9 +/- 8.1 kg), larger sc fat area (552 +/- 109 vs. 452 +/- 109 cm(2)), and lower IAF/SC ratio (0.28 +/- 0.12 vs. 0.38 +/- 0.15; P < 0.01), but similar waist to hip ratio (0.83). Both groups had similar SHBG (117 vs. 124 nmol/L) and free testosterone (3.7 vs. 3.4 pmol/L) levels, but AA women had a 35% higher leptin, 34% higher fasting insulin, and 39% greater insulin response to a glucose load (P < 0.05) compared with CAU women. In CAU, but not AA, women SHBG correlated negatively with body mass index (r = -0.28; P < 0.05), waist (r = -0.36; P = 0.01), IAF (r = -0.34; P = 0.01), and insulin response to oral glucose (r = -0.37; P < 0.05) and positively with high density lipoprotein cholesterol (r = 0.30; P = 0.03). The relationship between insulin area and SHBG in CAU women disappeared after adjusting for IAF, whereas the relationship between high density lipoprotein cholesterol and SHBG persisted after adjusting for IAF, but not for fat mass. Leptin was positively related to fat mass (P < 0.05) in both groups, but it was related to insulin only in the Caucasian women (P< 0.01). There was a racial difference in the slopes (P< 0.05) of the relationships of leptin to fat mass (P < 0.05). Racial differences in leptin disappeared after adjustment for fasting insulin. These results suggest that the metabolic relationships between total and regional obesity, glucose, and lipid metabolism with SHBG in CAU women are different from those in postmenopausal obese AA women.     

Relationship of body fat distribution to the metabolic clearance of insulin in premenopausal women

The effects of body fat distribution on the metabolic clearance rate of insulin (MCR) and its relationship to peripheral insulin sensitivity (M/I) and androgenic activity were assessed in six nonobese and 20 obese premenopausal women with varying waist-to-hip girth ratio (WHR). As an index of androgenic activity, plasma levels of the sex hormone binding globulin (SHBG) and percentage free testosterone (%FT) were determined. The mean MCR in the obese and nonobese groups were similar (571 +/- 29 vs 578 +/- 31 ml/min/m2). Within the obese group, MCR varied between 401 and 822 ml/min/m2 and was inversely correlated with the WHR (r = -0.50, P less than 0.05). The reduction in MCR with upper body fat localization was observed at both sub- and supra-maximal plasma insulin levels. MCR correlated negatively with fasting and postglucose challenge plasma insulin levels and positively with M/I. MCR also correlated with plasma SHBG and %FT levels. We conclude that upper body fat localization is associated with diminished insulin clearance. This diminution is closely aligned with the degree of peripheral insulinemia and insulin sensitivity. The increase in androgenic activity may contribute to the aberrant insulin clearance observed in upper body obese subjects.     

The relationship of sex hormones to hyperinsulinemia and hyperglycemia

Mexican-Americans, a high-risk population for non-insulin-dependent diabetes mellitus (NIDDM), have been previously reported to have decreased levels of sex-hormone-binding globulin (SHBG). We measured total testosterone, total estradiol and SHBG, glucose and insulin in premenopausal women (58 Mexican-Americans and 38 non-Hispanic whites) as part of the San Antonio Heart Study, a population-based study of cardiovascular risk factors. Although total estradiol and total testosterone were, in general, not correlated with metabolic variables, SHBG was negatively correlated with glucose and insulin. After adjustment for body mass index (BMI), ratio of waist-to-hip circumference (WHR) and ratio of subscapular-to-triceps skinfold (Centrality Index), SHBG was still significantly correlated with insulin concentrations (P less than .001). Since Mexican-Americans were previously reported to be more hyperinsulinemic than non-Hispanic whites, we examined the effect of adjusting for SHBG on insulin levels in this small population. While unadjusted insulin concentrations in Mexican-Americans were higher than in non-Hispanic whites (354 microU/mL v 236 microU/mL, respectively, P = .009), adjustment for BMI, WHR, and centrality index reduced the ethnic difference in insulin levels considerably (P = .014). However, only after adjusting for SHBG as well, did the ethnic difference in insulin levels became nonsignificant. Our data suggest that alterations in sex hormones and SHBG in particular may be related to the hyperinsulinemia and the high rates of NIDDM in Mexican-Americans.     

Use of urinary C-peptide to estimate insulin secretion during starvation

The usefulness of measurements of urinary C-peptide excretion in indirectly assessing integrated insulin secretion during starvation was studied in eight obese subjects during a 72-h fast. Blood and urine samples were collected at 12-h intervals for measurement of insulin and C-peptide immunoreactivity. After 60 h, serum insulin and plasma C-peptide levels declined 47% and 37%, respectively, and the values were highly correlated (r = 0.8; P less than 0.001). By 72 h, urinary C-peptide excretion had declined to 70% of the level in the first 12-h period. The urinary clearance of C-peptide was not altered by starvation. A highly significant correlation was found between urinary C-peptide and C-peptide secretory rate (P less than 0.001). The molar ratio of plasma C-peptide to insulin remained constant during the fasting period. These data indicate that basal insulin secretion can be added to the list of physiological conditions in which beta-cell secretion can be effectively evaluated by urinary C-peptide measurement.     

Relationships between insulin secretion, insulin metabolism and insulin resistance in mild glucose intolerance

The aim of this study was to evaluate whether the correlation between insulin resistance and peripheral hyperinsulinaemia existing in mild glucose intolerance corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the possibility that insulin resistance is related to insulin metabolism was examined. Twenty five subjects with fasting normoglycaemia and an abnormal glucose response to the oral glucose tolerance test (OGTT) were studied. Insulin secretion by the pancreas was estimated by means of fasting C-peptide levels in peripheral blood. Insulin resistance was estimated by the rate of glucose disappearance from plasma after i.v. insulin injection. Insulin metabolism was estimated indirectly by the C-peptide: insulin molar ratio. A negative correlation was found between the glucose disappearance rate from plasma after i.v. insulin injection and fasting insulin levels (r = -0.677, p less than 0.001), but not fasting C-peptide concentrations (r = -0.164, p = NS). Glucose disappearance rate from plasma correlated positively with the C-peptide: insulin molar ratio (r = 0.626, p less than 0.001). These results suggest that in mild glucose intolerance insulin resistance and insulin secretion by the pancreas are not related phenomena, and that the defect responsible for insulin resistance might also be implicated in the impaired insulin metabolism.     

Relationships of obesity indices to serum insulin and lipoproteins in relatives of black patients with noninsulin-dependent diabetes mellitus (NIDDM)

We have examined the relationships between obesity indices and various metabolic parameters in seven obese (body mass index (BMI) mean +/- s.e.m. 42 +/- 2.5 kg/m2), ten nonobese (BMI 25.3 +/- 1.2 kg/m2) nondiabetic female relatives of black patients with NIDDM and eight healthy controls (BMI 24.5 +/- 1.1 kg/m2). Despite the greater BMI in the obese relatives, percent body fat was not different from that of the nonobese relatives (38 +/- 2 vs 34 +/- 3 percent). Both values were, however, significantly (P less than 0.05) greater than that of the healthy controls (25 +/- 3 percent). Mean waist-to-hip circumference ratio (WHR) was greatest in obese relatives (0.89 +/- 0.01), intermediate in nonobese relatives (0.83 +/- 0.01) and least in the healthy controls (0.77 +/- 0.04). Mean sum of skinfold thickness from biceps, triceps and subscapular (SS) region was also greatest in obese relatives, intermediate in nonobese relatives and least in controls. Centrality index was not, however, different among the groups. Mean fasting serum glucose levels were slightly higher but not significantly different in the relatives compared to controls (obese 82 +/- 3; nonobese 81 +/- 4; controls 75 +/- 3 mg/dl). Following oral glucose ingestion, serum glucose rose to significantly (P less than 0.05) greater levels at 30, 60 and 90 min in the relative subgroups vs controls. Mean fasting and post-prandial peak serum insulin concentrations were significantly (P less than 0.05-0.01) greater in both relative subgroups vs controls. While mean serum glucose profiles and glucose disappearance decay (KG) following intravenous glucose load were identical in the relatives and controls, serum insulin responses were significantly greater in the relatives. The mean basal and post-stimulation serum C-peptide concentrations were similar in all the three groups, irrespective of the stimulus; thus suggesting a reduced hepatic insulin extraction in the relatives. Fasting serum cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) as well as FFA levels were not different between the relatives and controls despite the hyperinsulinemia in the former group. WHR correlated with basal insulin in the relatives (r = 0.416, P less than 0.05) and controls (r = 0.68, P less than 0.01) but not with stimulated insulin, lipids and lipoproteins in any of the groups. In contrast, both percent BFM and SS thickness correlated significantly (P less than 0.001) with post-glucose insulin concentrations in the relatives only.(ABSTRACT TRUNCATED AT 400 WORDS)     

Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia

This study examined the prevalence of both basal and glucose-stimulated hyperinsulinemia and acanthosis nigricans (AN) as well as the relationship between insulin and androgen levels in hyperandrogenic women. Sixty-two women who had an elevation of 1 or more plasma androgen levels were studied. The results in these women, grouped for analysis on the basis of obesity and ovulatory status, were compared to those in 36 control women of similar ages and weights. The anovulatory hyperandrogenic women had the clinical and biochemical features of the polycystic ovary syndrome (PCO). Oral glucose tolerance tests were performed with measurement of glucose, insulin, sex hormone-binding globulin (SHBG), and total and non-SHBG-bound sex steroid levels. AN was present in 29% of the hyperandrogenic women, the majority of them obese. Fifty percent of obese PCO women had AN, but they did not otherwise differ from PCO women lacking this dermatological change. Only women with PCO had significant hyperinsulinemia independent of obesity, and obese PCO women with AN had the highest serum insulin levels. Plasma glucose values during the oral glucose tolerance test were significantly increased in obese PCO women independent of the presence of AN, and 20% of these women had frank impairment of glucose tolerance. Ovulatory hyperandrogenic women had normal insulin levels and glucose tolerance. Obese and nonobese women had different relationships between sex steroid and insulin levels; obese women had significant correlations between insulin and non-SHBG testosterone levels (r = 0.30; P less than 0.05), whereas nonobese women had significant correlations between insulin and FSH (r = 0.40; P less than 0.01), dehydroepiandrosterone sulfate (r = 0.33; P less than 0.05), and SHBG (r = 0.37; P less than 0.05) levels, suggesting that the mechanisms underlying the association between sex steroid and insulin levels are complex. These findings suggest that 1) only women with PCO have hyperinsulinemia independent of obesity; hyperinsulinemia is not a feature of hyperandrogenic states in general; 2) AN is a common finding in obese hyperandrogenic women, particularly those with PCO; 3) only obese PCO women are at risk for impairment of glucose tolerance, independent of the presence of AN, suggesting that the negative impact of PCO and obesity on insulin action is additive; and 4) PCO women with AN can be considered as a subgroup of PCO and do not appear to have a distinct endocrine disorder.     

Accuracy of C-peptide:insulin molar ratio as a measure of hepatic removal of insulin

We measured transhepatic C-peptide and insulin concentrations in plasma, and hepatic removal of insulin, to examine whether the practice of reporting the C-peptide:insulin molar ratio as a measure of the hepatic removal of insulin is valid. In anesthetized dogs (n = 6), during electromagnetic hepatic blood flow monitoring, endogenous insulin was suppressed with somatostatin, while equimolar proportions of porcine insulin and simian C-peptide (2.4 and 6.0 pmol/kg.min) were infused during two consecutive 45-min periods. Insulin reached steady state within 20 min (t1/2 = 4.5 min); however, C-peptide concentrations continued to rise (t1/2 V 12.5 min). The ratio decreased when the peptide infusion was changed to the higher rate and increased when it was stopped, reflecting the more rapid removal of insulin than of C-peptide. Hepatic removal of insulin remained constant during the two infusion periods (average 60% extraction) and never correlated with the changing molar ratios. Hepatic net flux of insulin correlated with the ratio (P less than 0.05) only while plasma insulin concentrations were rising during constant-rate infusion. We therefore conclude that the molar ratio is not a reliable measure of the hepatic removal of insulin during non-steady states of insulin or C-peptide.