Living near a freeway is associated with lower bone mineral density among Mexican Americans.

UNLABELLED: We hypothesized that chronic exposures to traffic combustion products may lower bone mineral density (BMD). We found that proximity to freeways was associated with reduced BMD. Our findings suggest that traffic-related pollution may contribute to the occurrence of osteopenia and osteoporosis. INTRODUCTION: Adults residing in rural areas have been linked with higher BMD. We aimed to determine if this difference is due in part to air pollution by examining the relationships between traffic metrics and ambient air pollution with total body and pelvic BMD. METHODS: Mexican American adults (n = 1,175; mean 34 years; 72 % female) who had participated in the BetaGene study of air pollution, obesity, and insulin resistance were included in this analysis. Total body and pelvic BMD were estimated using dual-energy X-ray absorptiometry. Traffic and ambient air pollutant exposures were estimated at residences using location and ambient monitoring data. Variance component models were used to analyze the associations between residential distance to the nearest freeway and ambient air pollutants with BMD. RESULTS: Residential proximity to a freeway was associated with lower total body BMD (p-trend = 0.01) and pelvic BMD (p-trend = 0.03) after adjustment for age, sex, weight, and height. The adjusted mean total body and pelvic BMD in participants living within 500 m of a freeway were 0.02 and 0.03 g/cm(2) lower than participants living greater than 1,500 m from a freeway. These associations did not differ significantly by age, sex, or obesity status. Results were similar after further adjustment for body fat and weekly physical activity minutes. Ambient air pollutants (NO2, O3, and PM2.5) were not significantly associated with BMD. CONCLUSIONS: Traffic-related exposures in overweight and obese Mexican Americans may adversely affect BMD. Our findings indicate that long-term exposures to traffic may contribute to the occurrence of osteoporosis and its consequences.

HOMA and Matsuda indices of insulin sensitivity: poor correlation with minimal model-based estimates of insulin sensitivity in longitudinal settings.

AIMS/HYPOTHESIS: Little is known about the performance of surrogates in assessing changes in insulin sensitivity over time. This report compared updated HOMA of insulin sensitivity (HOMA2-%S) and the Matsuda index from OGTTs with minimal model-based estimates of insulin sensitivity (SI) from frequently sampled IVGTTs (FSIGTs) in longitudinal settings and cross-sectional settings. METHODS: Two longitudinal studies were used: one a natural observational study in which 338 individuals were followed for a median of 4 years; one a clinical treatment study in which 97 individuals received pioglitazone treatment and were followed for 1 year. Pairs of OGTTs and FSIGTs were performed at baseline and follow-up. Correlations were computed. Impact of measurement uncertainty was investigated through simulation studies. RESULTS: Correlations between HOMA2-%S and SI from baseline or follow-up data were in the range reported previously (0.61-0.69). By contrast, correlations for changes over time were only 0.35-0.39. The corresponding correlations between the Matsuda index and SI were 0.66-0.72 for cross-sectional data and 0.40-0.48 for longitudinal change. Correlations for changes were significantly lower than the cross-sectional correlations in both studies (p < 0.03). Simulation results demonstrated that the reduced correlations for change were not explained by error propagation, supporting a real limitation of surrogates to fully capture longitudinal changes in insulin sensitivity. CONCLUSIONS/INTERPRETATION: HOMA and Matsuda indices derived from cross-sectional data should be used cautiously in assessing longitudinal changes in insulin sensitivity.

A large sample of finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter.

In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996. Nat. Genet. 13:161-166). Their total sample was comprised of 440 Mexican-American affected sib-pairs from 246 sibships. The strongest evidence for linkage was at marker D2S125 and best estimates of lambdas (risk to siblings of probands/population prevalence) using this marker were 1.37 under an additive model and 1.36 under a multiplicative model. We examined this chromosomal region using linkage analysis in a Finnish sample comprised of 709 affected sib-pairs from 472 sibships. We excluded this region in our sample (multipoint logarithm of odds score /= 1.37. We discuss possible reasons why linkage to 2q37 was not found and conclude that this region is unlikely to be playing a major role in NIDDM susceptibility in the Finnish Caucasian population.

Accurate measurement of endogenous insulin secretion does not require separate assessment of C-peptide kinetics.

The implication of beta-cell failure as an early defect in type 2 diabetes exacerbates the need for accurate but facile assessment of islet cell secretory rate, particularly in large group studies in which individual assessment of C-peptide kinetics is impractical. This study was designed to examine whether it is possible to obtain accurate secretory rates from the extended combined model, which provides insulin and C-peptide kinetics from plasma measurements of the two peptides. Equimolar intraportal infusions of insulin and C-peptide that are designed to simulate insulin secretion rates during both oral and intravenous glucose tolerance tests were used to generate plasma insulin and C-peptide data in conscious dogs that were examined under clamped glucose conditions. The plasma peptide kinetics were analyzed using the extended combined model to generate estimates of prehepatic insulin secretion that were then compared with the known intraportal infusion rates. The extended combined model was able to reproduce the known intraportal infusion profiles. The model-predicted rates were similar to those calculated with methods that require separate assessment of C-peptide kinetics. Simulation results supported lesser clearance of insulin during rapid changes of portal insulin (as measured by an intravenous glucose tolerance test) versus slow changes in portal insulin (as measured by an oral glucose tolerance test). The extended combined model accurately calculates prehepatic insulin appearance. It may be possible to apply this approach to large studies of beta-cell function designed to identify changes in islet function in subjects at risk for diabetes. Such an approach could strengthen epidemiological and genetic studies of the pathogenesis of diabetes.

The role of liver glucosensors in the integrated sympathetic response induced by deep hypoglycemia in dogs.

The significance of the portohepatic glucosensors for counterregulation in deep hypoglycemia (i.e., glycemia < 2.8 mM) was studied in chronically cannulated male mongrel dogs in the conscious state. A total of 16 experiments were carried out on 6 dogs using the liver clamp technique under hyperinsulinemic conditions (insulin infusion, 39 pmol.min-1.kg-1, 0-150 min). The level of glycemia presented to the liver was made to differ from the systemic arterial glucose level via portal glucose infusion. Tracer-determined rates of glucose clearance and hepatic glucose output (HGO) were assessed using D-[3-3H]glucose (0.26 microCi.min-1). Three protocols were used. In protocol I, liver clamp, systemic hypoglycemia at 2.60 +/- 0.09 mM, and liver glycemia at 3.86 +/- 0.05 mM were achieved with portal glucose infusion (28.2 +/- 3.0 mumol.min-1.kg-1). For protocol II, glucose was infused peripherally (18.2 +/- 4.3 mumol.min-1.kg-1), while systemic and liver glycemia were sustained at deep hypoglycemia, 2.50 +/- 0.08 mM. In protocol III, via peripheral glucose infusion (62.9 +/- 5.8 mumol.min-1.kg-1), systemic and liver glycemia were maintained at a level matched to the liver glycemia during protocol I (3.98 +/- 0.05 mM, P > 0.10). When compared with protocols I and III, the catecholamine response above basal was significantly greater during protocol II with liver and systemic deep hypoglycemia (7.30 +/- 1.51 and 2.89 +/- 0.5 nM for epinephrine and norepinephrine, respectively, P < 0.005). These values reflect net increases in the catecholamine responses of 100% and 85% for epinephrine and norepinephrine when compared with protocol I.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity accounts for glucose and lactate kinetics after intravenous glucose injection.

Mathematical modeling was used to explore the interaction between glucose, insulin, and lactate during the frequently sampled intravenous glucose tolerance test (FSIGTT). Insulin-modified FSIGTs were performed in 25 lean volunteers, and an additional 5 volunteers underwent FSIGTs with glucose injection alone to illustrate the effect of insulin on both glucose and lactate kinetics. The model chosen as the best representation of the system extended the minimal model of glucose kinetics (MM) by including a two-compartment model of lactate kinetics. The model accounted for both glucose and lactate kinetics, provided traditional MM parameters of insulin sensitivity and glucose effectiveness, and descriptive parameters of lactate kinetics. Modeling suggested that lactate production was limited by the rate of glucose disappearance, with no indication of direct effects of insulin on lactate. Inclusion of lactate kinetics had no adverse effect on MM parameters (SG: 0.023 +/- 0.009 vs. 0.023 +/- 0.010 min-1, SI: 1.01 +/- 0.70 vs. 1.03 +/- 0.71 x 10(4).min-1.pmol-1.1; P > 0.50, lactate model vs. MM), and indicated that approximately 1.2% min-1 of total glucose disappearance during the FSIGT is converted to lactate. An additional benefit of including lactate kinetics was the significant improvement in precision in MM parameter estimates as reflected by the fractional standard deviations (FSDs). This effect was most prominent for SG, in which a threefold improvement in parameter precision was observed (FSD: 13.5 +/- 3.1 vs. 42.5 +/- 48.5; means +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study.

An insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis was compared with the glucose clamp in 11 subjects with normal glucose tolerance (NGT), 20 with impaired glucose tolerance (IGT), and 24 with non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity index (SI) was calculated from FSIGTT using 22- and 12-sample protocols (SI(22) and SI(12), respectively). Insulin sensitivity from the clamp was expressed as SI(clamp) and SIP(clamp). Minimal model parameters were similar when calculated with SI(22) and SI(12). SI could not be distinguished from 0 in approximately 50% of diabetic patients with either protocol. SI(22) correlated significantly with SI(clamp) in the whole group (r = 0.62), and in the NGT (r = 0.53), IGT (r = 0.48), and NIDDM (r = 0.41) groups (P < 0.05 for each). SI(12) correlated significantly with SI(clamp) in the whole group (r = 0.55, P < 0.001) and in the NGT (r = 0.53, P = 0.046) and IGT (r = 0.58, P = 0.008) but not NIDDM (r = 0.30, P = 0.085) groups. When SI(22), SI(clamp), and SIP(clamp) were expressed in the same units, SI(22) was 66 +/- 5% (mean +/- SE) and 50 +/- 8% lower than SI(clamp) and SIP(clamp), respectively. Thus, minimal model analysis of the insulin-modified FSIGTT provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp. The correlation was weaker, however, in NIDDM. The insulin-modified FSIGTT can be used as a simple test for assessment of insulin sensitivity in population studies involving nondiabetic subjects. Additional studies are needed before using this test routinely in patients with NIDDM.

The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences.

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.

Intravenous insulin infusion to simulate subcutaneous absorption. Bioavailability and metabolic sequelae.

OBJECTIVE: To determine the bioavailability and bioactivity of subcutaneously injected insulin. RESEARCH DESIGN AND METHODS: A randomized block design with six male mongrel dogs as subjects. In protocol 1, purified pork insulin was infused intravenously to simulate the pattern of appearance in the blood that would have been expected from subcutaneous injection. Three intravenous doses (0.05, 0.10, and 0.15 U/kg) were infused on separate days in a pattern (0-300 min) designed to approximately simulate the absorption rate of subcutaneously injected insulin. In protocol 2, interscapular subcutaneous injections of pork insulin at 0.10 U/kg were made. RESULTS: Integrated insulin, decrement in plasma glucose, and maximal glucose clearance for subcutaneous injection experiments were similar to intravenous infusion of equal dose (P greater than 0.10) but significantly different from low-dose infusions (P less than 0.025). Similar results were observed for hepatic glucose output and glucose uptake. Hypoglycemia elicited counterregulatory responses that appeared to be under a threshold differentiated at a plasma glucose of approximately 3 mM. Integrated insulin was plotted against insulin dose to create dose-response curves for intravenous data. The curve was then used to predict the actual appearance rate of insulin in plasma for subcutaneous injection. The estimated bioavailability of subcutaneous insulin was 103.0 +/- 10.5% of the injected dose. CONCLUSIONS: We concluded that, in dogs, insulin delivered subcutaneously in the interscapular area is not significantly degraded before absorption, resulting in metabolic effects equal to intravenous insulin infusion of equivalent dose.

Mapping genes for NIDDM. Design of the Finland-United States Investigation of NIDDM Genetics (FUSION) Study.

OBJECTIVE: To map and identify susceptibility genes for NIDDM and for the intermediate quantitative traits associated with NIDDM. RESEARCH DESIGN AND METHODS: We describe the methodology and sample of the Finland-United States Investigation of NIDDM Genetics (FUSION) study. The whole genome search approach is being applied in studies of several different ethnic groups to locate susceptibility genes for NIDDM. Detailed description of the study materials and designs of such studies are important, particularly when comparing the findings in these studies and when combining different data sets. RESULTS: Using a careful selection strategy, we have ascertained 495 families with confirmed NIDDM in at least two siblings and no history of IDDM among the first-degree relatives. These families were chosen from more than 22,000 NIDDM patients, representative of patients with NIDDM in the Finnish population. In a subset of families, a spouse and offspring were sampled, and they participated in a frequently sampled intravenous glucose tolerance test (FSIGT) analyzed with the Minimal Model. An FSIGT was completed successfully for at least two nondiabetic offspring in 156 families with a confirmed nondiabetic spouse and no history of IDDM in first-degree relatives. CONCLUSIONS: Our work demonstrates the feasibility of collecting a large number of affected sib-pair families with NIDDM to provide data that will enable a whole genome search approach, including linkage analysis.

Prehepatic beta-cell secretion during the intravenous glucose tolerance test in humans: application of a combined model of insulin and C-peptide kinetics.

A previously introduced method by which prehepatic beta-cell secretion is calculated in vivo from plasma measurements of insulin and C-peptide was applied to data derived from iv glucose tolerance tests performed in normal women. Prehepatic secretory rates calculated using the combined model appeared biphasic in nature after glucose injection. Basal insulin secretion was 63.9 +/- 9.8 pmol/min. The duration of first phase was approximately 5 min, with secretion reaching a peak of 2033 +/- 342 pmol/min. The first phase was followed by a significant refractory period in which the secretory rate fell below basal values. The magnitude of second phase secretion was small relative to first phase secretion and appeared pulsatile in nature. Total integrated insulin secretion was 22.2 +/- 2.7 nmol, of which first phase accounted for 32%, and second phase accounted for the remaining 68%. Total incremental integrated secretion was 10.6 +/- 1.4 nmol, accounting for approximately half of the total insulin secretion. Proportions of first and second phase secretion changed to 66.5% and 33.5%, respectively, with incremental data. This study shows that the combined model of insulin and C-peptide is capable of estimating prehepatic insulin secretion from the iv glucose tolerance test and may provide a useful tool to measure secretion in vivo under various pathological conditions.

Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors.

We performed oral glucose tolerance tests and frequently sampled iv glucose tolerance tests in a cross-sectional sample of women taking monophasic norgestrel containing oral contraceptives (OC). The goal of the study was to quantify the individual factors that determine glucose tolerance to assess responsibility for the reduced glucose tolerance associated with the use of OCs. Subjects were selected using stringent criteria to exclude confounding effects of ethnicity, adiposity, or conditions that may predispose subjects to metabolic disorders. Users of the low dose OC (Lo/Ovral and Nordette) and high dose OC (Ovral) were compared to controls, who were required to never have used OCs or to have discontinued OC use for at least 24 months. Oral glucose tolerance tests results confirmed the development of impaired glucose tolerance in both pill groups. Frequently sampled iv glucose tolerance test data were analyzed using the minimal model method to estimate parameters of insulin sensitivity, glucose effectiveness (SG), and beta-cell function. Lo/Ovral users had lower insulin sensitivity and SG compared to controls and inappropriately low beta-cell function in relation to the insulin resistance. Ovral users had metabolic parameters that were not different from controls. Based upon comparisons between normal and impaired glucose tolerant subjects combined with stepwise regression analysis, we conclude that Lo/Ovral use results in insulin and glucose resistance, which is not compensated by increased beta-cell function. The reduced glucose tolerance is due primarily to the defect in SG, and these OC users may place themselves at higher risk for the development of diabetes or cardiovascular disease. The reduced tolerance in Ovral users cannot be explained by the parameters measured in this study. We speculate that these latter subjects represent a special self-selected population in which tolerance is regulated by other factors. Ovral appears to be well tolerated by these women.

Relationship of plasma insulin concentration and insulin sensitivity to blood pressure. Is it modified by obesity?

OBJECTIVE: To investigate the relationship between insulin level, insulin sensitivity and blood pressure in normoglycaemic men (n = 51) and women (n = 64) aged 53-61 years who were not receiving blood pressure medication and were participants in a previous population-based study. METHODS: Insulin sensitivity was estimated by the minimal model from a frequently sampled intravenous glucose tolerance test. RESULTS: Systolic blood pressure (SBP) did not correlated significantly with fasting insulin level, 2 h insulin level or insulin sensitivity. Diastolic blood pressure (DBP) correlated positively with fasting insulin level but not with 2 h insulin level or insulin sensitivity. However, the positive association between fasting insulin level and DBP was not significant after adjustment for obesity and age. The relationship between high fasting insulin concentration and high DBP was stronger in lean than in obese subjects. The positive correlation between fasting insulin level and DBP was significant in lean but not in obese subjects. CONCLUSIONS: The relationships between decreased insulin sensitivity and compensatory hyperinsulinaemia and blood pressure were rather weak. It is possible that different mechanisms may control blood pressure in lean and obese subjects, with a weaker association between insulin level and blood pressure in obese subjects. Alternatively, in obese subjects long-standing hyperinsulinaemia might increase blood pressure by mechanisms such as sympathetic activation and effects of vasculature, which may mask the underlying contribution of hyperinsulinaemia.

The multiphasic profile of free fatty acids during the intravenous glucose tolerance test is unresponsive to exogenous insulin.

As small increments in insulin concentration profoundly affect lipolysis, our goal was to describe the free fatty acid (FFA) profile during the frequently sampled intravenous glucose tolerance test (FSIGT) and determine if both endogenous and exogenous insulin influenced the FFA profile. Thirteen subjects had both a glucose-only (GO-FSIGT) and insulin-modified FSIGT (IM-FSIGT). Both protocols were of 6 hours duration. At baseline an intravenous glucose bolus (0.3 g/kg) was given. In the IM-FSIGT, insulin was infused from 20 to 25 minutes (4 mU/kg. min). Six additional subjects had both an IM-FSIGT and a normal saline study (NS-Study). For the NS-Study, normal saline solution was infused instead of glucose and insulin. Fasting glucose, insulin, FFA and epinephrine concentrations were similar for all tests. Endogenous insulin peaked at 4 +/- 1 minute in both FSIGTs. The mean calculated peak time of exogenous insulin in the IM-FSIGT was 26 +/- 1 minute. Glucose concentrations were lower and epinephrine concentrations higher in the IM-FSIGT versus GO-FSIGT. During the FSIGTs, the FFA time course revealed four distinct phases, which did not differ between protocols. In phase I (0 to 11 minutes), FFA levels remained near basal (491 +/- 183 micromol/L); in phase II (11 to 79 minutes), FFA levels declined achieving a nadir of 139 +/- 63 micromol/L; in phase III (79 to 188 minutes), FFA levels rose linearly and reattained basal levels; and in phase IV (188 to 360 minutes), FFA levels rose above basal and plateaued at 732 +/- 214 micromol/L (P <.001). In the NS-Study, FFA levels remained near baseline (388 +/- 118 mEq/L) until 180 minutes and then trended upward to 618 +/- 258 micromol/L at 360 minutes. FFA concentrations from 180 to 360 minutes did not differ in the IM-FSIGT versus NS-Study. As the 4 FFA phases did not differ between protocols, the insulin effect on FFA levels in the FSIGT can be attributed to endogenous insulin. But the similarity in FFA levels from 180 to 360 minutes in the IM-FSIGT and NS-Study suggests diurnal variation and not a dynamic related to insulin or the FSIGT protocol is responsible for the final suprabasal FFA plateau.

Insulin and insulin-like growth factor-I responsiveness in polycystic ovarian syndrome.

OBJECTIVE: To assess insulin and insulin-like growth factor I (IGF-I) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Hyperinsulinemia was determined by measuring the insulin responses during a 2-hour oral glucose tolerance test (OGTT). Quantification of in vivo insulin action was determined by a frequently sampled intravenous (IV) OGTT with minimal modeling analysis. In vitro sensitivity to insulin at physiological and supraphysiological concentrations and to IGF-I was assessed by examining colony formation of two hematopoietic cell populations, burst-forming units of the erythroid line (BFU-E) and human leukemia virus immortalized T-cell lines. (The proliferative responses of BFU-E, a primary tissue explant, are presumably conditioned by factors in the immediate blood-borne environment, whereas proliferative responses of T-cell lines are presumed to reflect intrinsic target-cell hormone sensitivity.) SETTING: Tertiary care research institution. PATIENTS: Eight patients (4 obese and 4 nonobese) with PCOS and three healthy women for reference controls. RESULTS: Nonobese (P less than 0.04) and obese patients with PCOS (P less than 0.01) both demonstrated significant hyperinsulinemia after OGTT. In vivo insulin resistance was observed in both nonobese (P less than 0.03) and obese PCOS subjects (P less than 0.01) using frequently sampled IV OGTT. Both nonobese (P less than 0.03) and obese patients with PCOS (P less than 0.01) had blunted in vitro clonal responses of BFU-E, with normal T-cell line clonal responsiveness to physiological levels of insulin and normal BFU-E and T-cell line clonal responses to IGF-I. CONCLUSIONS: These findings demonstrate the following in both nonobese and obese patients with PCOS: (1) there is in vivo hyperinsulinemia and resistance to insulin action on glucose disposal; (2) with BFU-E, there is in vitro resistance to the mitogenic action of insulin but normal responsiveness to IGF-I; and (3) there is normal in vitro mitogenic responsiveness of T-cell lines to both insulin and IGF-I. The intrinsically normal mitogenic responsiveness to insulin and, especially to IGF-I, whether or not under the influence of the bloodborne milieu, provides a mechanism whereby hyperinsulinemia could directly contribute to the ovarian abnormalities that characterize PCOS.

The influence of luteinizing hormone and insulin on sex steroids and sex hormone-binding globulin in the polycystic ovarian syndrome.

OBJECTIVE: To examine the relationship between hyperinsulinemia, sex hormone-binding globulin (SHBG), and body mass index (BMI) on LH-induced hyperandrogenemia in patients with polycystic ovarian syndrome (PCOS). DESIGN: Insulin responses during an oral glucose tolerance test (OGTT) were assessed in 25 consecutive women with PCOS and 20 control women matched for BMI. Insulin responses and sensitivity (SI) were also determined using a frequently sampled intravenous glucose tolerance test (IVGTT). SETTING: The clinical research center at a university medical center. MAIN OUTCOME MEASURES: Serum LH, SI, and basal, peak, and area under the curve (AUC-insulin responses) were determined and correlated with SHBG, androstenedione (A), T, and free T concentrations. RESULTS: Compared with controls, the AUC-insulin response during OGTT was greater in PCOS, with an average increase of 44%. During IVGTT, AUC-insulin response was also significantly higher in PCOS versus controls, with an average increase of 53%. In addition, SI was reduced in PCOS versus controls with an average decrease of 53%. The average differences in oral- and intravenous-glucose-induced hyperinsulinemia and in insulin sensitivity between PCOS and controls were relatively constant across the entire physiological range of BMI. In PCOS, baseline LH showed strong positive correlations with baseline A and T. However, there were no significant correlations between either basal, peak, or AUC-insulin response during OGTT and IVGTT with basal T or A concentrations or between insulin and androgen levels measured at 30-minute intervals throughout the OGTT. However, basal, peak, and AUC-insulin responses during OGTT were strongly correlated with fasting SHBG binding capacity. CONCLUSIONS: These data are consistent with the hypothesis that hyperinsulinemia in PCOS influences the biologically active component of T by lowering SHBG concentrations while having little apparent impact on LH-induced secretion of androgens in vivo.

Compensatory responses to insulin resistance in obese African-American and Latina girls.

PURPOSE: Insulin responses to oral and intravenous glucose markedly differ by ethnicity. This study examined whether ethnic differences in pancreatic insulin secretion, hepatic insulin extraction and clearance explain these disparate findings in 35 obese African-American and 41 Latina girls (Tanner Stages: IV-V; ages: 14-18; body mass index percentile: 85.9-99.8%). METHODS: Pancreatic insulin secretion, hepatic insulin extraction and clearance were estimated by C-peptide and insulin modeling during an oral glucose tolerance test. Insulin sensitivity (SI), acute insulin response to glucose (AIRG ) and disposition index were derived from a frequently sampled intravenous glucose tolerance test. RESULTS: Compared to Latinas, obese African-American adolescents had lower pancreatic insulin secretion (21.3%; P < 0.01), glucose incremental area under the curve (IAUC) (41.7%, P = 0.02), C-peptide IAUC (25.1%, P < 0.01) and SI (33.7%; P < 0.01). There were no ethnic differences in hepatic insulin extraction and clearance (P's > 0.05). CONCLUSIONS: Compensatory mechanisms to insulin resistance do not appear to explain the ethnic differences in insulin responses to oral and intravenous glucose in obese African-American and Latina girls.

Critical evaluation of the combined model approach for estimation of prehepatic insulin secretion.

The combined model approach uses kinetic analysis of both plasma insulin and C-peptide dynamics to estimate prehepatic insulin secretion rates and parameters of insulin and C-peptide kinetics. The original model used single-compartment kinetics to describe both insulin and C-peptide despite knowledge that C-peptide follows two-compartment kinetics. The performance of the model under rapidly changing secretory conditions has come into question. Thus a more complex combined model is introduced, incorporating two-compartmental C-peptide disappearance. The addition of two-compartment C-peptide kinetics required a novel numerical approach to allow estimation of model parameters. This simulation study was undertaken to 1) compare the performance of the original combined model and 2) examine the numerical method used to identify parameters for the extended combined model with two-compartment C-peptide kinetics under simulated conditions of rapidly changing insulin and C-peptide. Monte Carlo simulation revealed that the original combined model does not provide accurate estimates of prehepatic insulin secretion under rapid kinetics. However, the extended combined model provides accurate reconstruction of prehepatic insulin secretory profile without separate quantification of C-peptide kinetics.