Standard Intravenous Glucose Tolerance Test Research Articles

Determining insulin sensitivity from glucose tolerance tests in sheep.

A mathematical model of the dynamics of insulin and glucose during a frequently sampled intravenous glucose tolerance test (IVGTT) in sheep was developed that characterizes the large second-phase insulin secretion response in sheep during IVGTT. The model was fit to measurements of the glucose and insulin dynamics during standard IVGTT ( = 42) and modified IVGTT ( = 40), where insulin was injected 60 min after the initiation of the IVGTT. The correlation between log insulin sensitivity determined by hyperglycemic clamps (HGC) and standard IVGTT was = 0.43 ( = 0.005). The correlation between log insulin sensitivity determined by HGC and modified IVGTT was = 0.51 ( = 0.002). The model, therefore, provides a method to determine insulin sensitivity through a cheaper and more easily performed IVGTT. We validated our estimation procedure using 2 independent experiments on the effect of 1) pregnancy and 2) being born preterm and exposed to dextrose or dextrose with insulin on HGC-derived insulin sensitivity. The IVGTT-derived insulin sensitivity was significantly greater in pregnant ewes than in prepregnant ewes (difference of 0.39 ± 0.12 log n ng mL; < 0.05), and this was consistent with the significantly greater hyperinsulinemic euglycemic clamp-derived insulin sensitivity in pregnant ewes than in prepregnant ewes (difference of 4.03 ± 0.66 µmol mL kg min ng; < 0.001). There was no significant effect of being born preterm on IVGTT/HGC-derived insulin sensitivity. Basal insulin, insulin sensitivity, insulin production, and insulin clearance were lower in prepregnant ewes ( < 0.05). That is, prepregnant ewes have a lower insulin equilibrium status and less responsive insulin turnover. There was also a significant effect of insulin therapy on the rate of insulin clearance in preterm lambs ( < 0.05). This effect was independently significant of its covariance with all other model parameters. Therefore, it can be interpreted as a direct effect on the rate of insulin clearance by the insulin treatment. All other parameter responses to the insulin treatment effect can be regarded as being due to the covariance between these parameters. These analyses demonstrate that treatment effects on insulin sensitivity can be detected using IVGTT experiments.

Robust set‐membership parameter estimation of the glucose minimal model

SummaryThe minimal model of glucose‐insulin dynamics is currently being used in several diabetes‐related applications, such as investigating the glucose metabolism, and in the developments of model predictive controllers and fault detection techniques for automatic blood glucose control (i.e., artificial pancreas). Different approaches have been proposed to identify this model, but none of them is capable of providing guaranteed robust enclosures for its parameters, something very desired in applications such as the artificial pancreas, where robustness is paramount. This paper presents a novel approach for guaranteed set‐membership parameter estimation of the minimal model based on the well‐renowned Set Inversion via Interval Analysis (SIVIA) algorithm. Because the computational complexity of this algorithm is the main barrier for its applicability, an efficient vectorial implementation of SIVIA was employed. Clinical data from a standard intravenous glucose tolerance test were used to prove the validity of the presented approach. Finally, Modal Interval Analysis was used to reduce the numerical overestimation due to the dependency problem of interval arithmetic and significantly speeding up the computations. Copyright © 2015 John Wiley &amp; Sons, Ltd.

Response of plasma glucose, insulin, and nonesterified fatty acids to intravenous glucose tolerance tests in dairy cows during a 670-day lactation

This experiment investigated the metabolic response of dairy cows undergoing an extended lactation to a frequently sampled intravenous glucose tolerance test. The experiment used 12 multiparous Holstein cows that calved in late winter in a seasonally calving pasture-based system and were managed for a 670-d lactation by delaying rebreeding. In each of four 5-wk experimental periods commencing at approximately 73, 217, 422, and 520 (±9.1) days in milk (DIM), cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM) supplemented with 1kg of DM grain (control; CON) or 6kg of DM grain (GRN) as a ration. Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for the CON and GRN treatments, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated minimum daily total intake of 180 MJ of metabolizable energy/cow. Cows were fitted with an indwelling jugular catheter during the final week of each experimental period. The standard intravenous glucose tolerance test using 0.3g of glucose per kilogram of body weight was performed on each cow at approximately 100, 250, 460, and 560 DIM. Plasma concentrations of glucose, insulin, and nonesterified fatty acids (NEFA) responses were measured. Milk yield, milk solids yield, body weight, and basal plasma glucose were greater in the GRN compared with the CON treatment. The area under the plasma response curve relative to baseline (AUC) for glucose, insulin, and NEFA and their apparent fractional clearance rates indicated varied whole body responsiveness to insulin in terms of glucose metabolism throughout the 670-d lactation. The glucose AUC 0 to 20 min postinfusion was increased at 560 DIM, indicating reduced utilization of glucose by the mammary gland at this stage of lactation. The NEFA clearance rate, 6 to 30 min postinfusion, was greater at 460 and 560 DIM. These data indicated an increase in lipogenic activity or a decrease in lipolysis as lactation progressed, suggestive of an overall increase in responsiveness to insulin in terms of whole body lipid metabolism as lactation progressed. These observations are consistent with decreased priority of lactation beyond 300 DIM. Cows in the GRN treatment had decreased whole body responsiveness to hyperglycemia compared with CON cows in terms of glucose clearance and AUC for the glucose response. Variation in the response curves of plasma glucose, NEFA, and insulin was predominantly a result of stage of lactation and not diet. This may be due to changes in mammary gland uptake of glucose that is independent of insulin and the responsiveness of peripheral tissues to the actions of insulin at different stages of the lactation that are independent of diet.

Portal Versus Systemic Venous Drainage of the Pancreatic Graft: The Effect on Glucose Metabolism in Pancreas and Kidney Transplant Recipients

Two different methods of graft venous drainage are used in pancreas transplantation: portal (PVD) and systemic (SVD). PVD is considered to be more physiologic due to its similarity to venous outflow of the native pancreas. The aim of our study was to compare glucose metabolism in Type 1 diabetic recipients of kidney and pancreatic grafts with PVD versus SVD by intravenous glucose tolerance test (IVGTT). We examined 28 insulin-independent patients after simultaneous pancreas and kidney transplantation: 14 recipients with PVD of the pancreatic graft and 14 with SVD after a mean post-transplant period of 1 year. All recipients had stable good function of the kidney graft. Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA1c), and standard IVGTT with coefficient of glucose assimilation (KG) calculation were assessed. Insulin sensitivity and production were evaluated using the homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA-IR], homeostasis model assessment of B-cell function [HOMA-B]). Total C-peptide and insulin secretions were calculated as areas under the curves (AUCs) from the serum levels during the IVGTT. PVD and SVD groups did not differ in age, body mass index (BMI) and duration of post-transplantation period (P ≥ .05). We did not find any significant difference in fasting glycemia, HbA1c, KG, HOMA-IR, parameters of C-peptide level, fasting insulin level, and response during IVGTT. HOMA-B and AUC of insulin level were higher in the SVD group (45.1 ± 35.1 versus 19.8 ± 15.5, P =.03 and 1075 ± 612 versus 1799 ± 954 mIU/L/60 minutes, P < .03, respectively). In the PVD group, 1 patient had an abnormal response to the glucose stimulus, 8 patients had an impaired glucose tolerance, and 5 patients had a normal glucose tolerance. In the SVD group, an abnormal response was present in none, impaired glucose tolerance in 4, and normal glucose tolerance in 10 recipients. Athough this was not a prospectively randomized trial, we conclude that the change of surgical technique from SVD to PVD did not lead to any substantial change in terms of glucose tolerance.

MATLAB-implemented estimation procedure for model-based assessment of hepatic insulin degradation from standard intravenous glucose tolerance test data

Present study provides a novel MATLAB-based parameter estimation procedure for individual assessment of hepatic insulin degradation (HID) process from standard frequently-sampled intravenous glucose tolerance test (FSIGTT) data. Direct access to the source code, offered by MATLAB, enabled us to design an optimization procedure based on the alternating use of Gauss-Newton's and Levenberg-Marquardt's algorithms, which assures the full convergence of the process and the containment of computational time. Reliability was tested by direct comparison with the application, in eighteen non-diabetic subjects, of well-known kinetic analysis software package SAAM II, and by application on different data. Agreement between MATLAB and SAAM II was warranted by intraclass correlation coefficients ≥0.73; no significant differences between corresponding mean parameter estimates and prediction of HID rate; and consistent residual analysis. Moreover, MATLAB optimization procedure resulted in a significant 51% reduction of CV% for the worst-estimated parameter by SAAM II and in maintaining all model-parameter CV% <20%. In conclusion, our MATLAB-based procedure was suggested as a suitable tool for the individual assessment of HID process.

Effect of Tacrolimus Versus Cyclosporine on Glucose Metabolism of Pancreas and Kidney Recipients in the Late (> 8 years) Posttransplant Period

Diabetogenic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare the glucose metabolism in type 1 diabetic kidney and pancreas recipients on tacrolimus (Tacro) versus cyclosporine-based (Cyclo) immunosuppression in the late posttransplant period. We examined 26 insulin-independent patients with stabile good renal function. They were at least 7 years after simultaneous pancreas and kidney transplantation and with unchanged immunosuppressive therapy for at least 6 years. The mean follow-up in Tacro (n = 13) and Cyclo (n = 13) groups were 9.7 ± 1.9 and 10.9 ± 1.3 years, respectively ( P = .08). Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA 1c), a standard intravenous glucose tolerance test (IVGTT) with coefficient of glucose assimilation (K G) calculation and trough Tacro/Cyclo levels were assessed. Insulin sensitivity and insulin secretion were evaluated using the homeostasis model assessment (HOMA-IR, HOMA-B). Total C-peptide and insulin secretions were calculated as areas under the curves (AUC) from the serum levels during the IVGTT. Tacro and Cyclo groups did not differ in age and body mass index. We did not find any significant difference in any examined parameters of glucose metabolism (fasting glycemia, insulin and C-peptide levels, HbA 1c, IVGTT with K G, HOMA-IR, HOMA-B, AUC of C-peptide and AUC of insulin; P > .05). Two patients in the Tacro group and none in the Cyclo group had K G <0.8%/min. Seven recipients in the Tacro group and eight in the Cyclo group had the normal glucose tolerance with K G ≥ 1.2%/min. Trough Tacro or Cyclo levels did not correlate with any of examined parameters. The use of different types of calcineurin inhibitors in type 1 diabetic pancreas and kidney recipients had no effect on glucose metabolism in the late posttransplant period.

Insulin sensitivity (Si) assessment in lean and overweight subjects using two different protocols and updated software

Background. The standard frequently-sampled intravenous glucose tolerance test (FSIVGTT) is an alternative procedure to the clamp technique for estimating the insulin sensitivity (Si) parameter. The goal of this study was to compare Si in lean and overweight individuals in addition to assessing intra-individual reproducibility using two different protocols and updated software. Methods. FSIVGTT was carried out in 14 lean (BMI ≤ 25 kg/m2) and 14 overweight (BMI>25 kg/m2) subjects using two different protocols; full (29 samples) and short (12 samples). For reproducibility assessment four normal subjects (triplicate on three and twice on one) were recruited to undergo the same procedure at 1-week intervals. Data analysis was performed using COMAL and Minmod Millennium software. Results. Mean Si (10−4min−1[pmol/l]−1) values were significantly different between lean and overweight subjects (p < 0.001) but not between the two protocols using both software packages. For the full and short protocols, Si values were more closely related in lean versus overweight subjects using either COMAL (r = 0.98, p < 0.001), (r = 0.89, p < 0.001) or Minmod Millennium (r = 0.99, p < 0.001), (r = 0.85, p < 0.001) software respectively. The intra-individual reproducibility (%CV) of Si (COMAL) in full versus short protocol was 18.3 ± 11.1% and 13.7 ± 1.9% respectively. Reproducibility values for Si (Minmod Millenium) in full versus short protocols were 14.3 ± 3.8 and 14.9 ± 1.9% respectively. Conclusions. Si can be assessed accurately by a short protocol FSIVGTT in normal individuals. The short protocol may give less acceptable results for insulin sensitivity in individuals who have normal glucose tolerance but high BMI.

Assessment of hepatic insulin degradation, in normoglycemic hypertensive patients, by minimal modelling of standard intravenous glucose tolerance test data

Role of hepatic insulin degradation in modulating insulin delivery to peripheral circulation, in insulin-resistant hypertensive patients, is not yet fully understood. This issue was investigated here by a novel application to hypertension of a previously proposed minimal modelling of insulin and C-peptide data, using population values for insulin and C-peptide kinetics parameters. Data, from frequently sampled intravenous glucose tolerance test (FSIGTT), were analysed in ten normoglycemic, hypertensive patients (H-group), compared with eight normoglycemic, normotensive subjects (N-group), matched for age, gender and body mass index. Minimal modelling of C-peptide and insulin data provided β-cell responsiveness to glucose perturbation (first, Φ 1, second, Φ 2, and basal, Φ b , phase), insulin secretion rate, ISR( t) and total pre-hepatic insulin secretion, TIS, as well as insulin delivery rate, IDR( t), and total insulin delivery, TID, into plasma, over 5-h test. Instantaneous normalized hepatic insulin degradation rate was computed as HIDR( t) = 1 − [ IDR( t)/ ISR( t)]. In our H-group, insulin sensitivity, S I , assessed by minimal model of glucose kinetics, showed a 56% reduction, which confirmed deterioration of insulin action in hypertension. This was associated with significant increase in Φ 1 (105%), TIS (55%) and TID (62%). No significant alterations were observed in other characteristic parameters of secretion and hepatic degradation of insulin, such that no significant difference was observed in HIDR( t) between our H and N groups. In conclusion, an increase of first phase and total insulin secretion occurring, in our H-group, in the presence of no alteration of hepatic insulin degradation, resulted in up-regulation of total insulin delivered to plasma ( TID) for insulin-resistance compensation.

A novel minimal model to describe non-esterified fatty acid kinetics in Holstein dairy cows

The dynamics of non-esterified fatty acid (NEFA) metabolism in lactating dairy cows requires quantification if we are to understand how dietary treatments and disease influence changes in body condition (adipose reserves) and the production of milk fat. We present here a novel compartmental model that employs the pattern of plasma glucose concentrations to predict the dynamic changes that occur in plasma NEFA concentrations during an intravenous glucose tolerance test (IVGTT) in lactating dairy cows. The model was developed using data obtained from ten early-lactation, Holstein-Friesian cows given a standard IVGTT. The model described all of the major features of the NEFA response to an IVGTT; it was consistent with physiological processes and provided a number of parameters that can be used to quantify NEFA production and utilization. For all of the individual cows, all model parameters were well identified and usually had CV<10% of their estimated values. In the model, elevated plasma glucose concentrations cause an increase in the level of glucose in a remote compartment, which in turn suppresses the rate of entry of NEFA to the plasma compartment. The means (+/-sd) for the five adjustable parameters of the model were: rate of entry of NEFA to the plasma pool (SFFA) 183+/-71 [micromol l-1 min-1], rate of removal (oxidation, sequestration in adipose tissue and uptake by the mammary gland for milk production) of NEFA from the plasma pool (KFFA) 0.140+/-0.047 [min-1], a threshold parameter (gs) representing a plasma glucose concentration above which elevated levels of plasma glucose result in entry of glucose into a 'remote' or inaccessible glucose compartment, 3.30+/-0.52 [mmol/l], a rate constant (K) describing the movement of plasma glucose (above gs) into a remote compartment 0.063+/-0.033 [min-1] and a parameter Phi which is a Michaelis Menten type affinity constant which modulates the extent to which remote glucose inhibits the provision of NEFA to the plasma pool, 0.812+/-0.276 [mmol/l]. It is concluded that the model is suitable to describe NEFA kinetics in lactating dairy cows and it may have application in other species.

Evaluation of a compartmental model to describe non-esterified fatty acid kinetics in Holstein dairy cows

The dynamics of non-esterified fatty acid (NEFA) metabolism in lactating dairy cows requires quantification if we are to understand how dietary treatments and disease influence changes in body condition (adipose reserves) and the production of milk fat. Recently, Thomaseth & Pavan (2003) presented a compartmental model (Thomaseth model), which employs the pattern of plasma insulin concentrations in humans to predict the dynamic changes that occur in the plasma concentrations of glucose and NEFA during an intravenous glucose tolerance test (IVGTT). The Thomaseth model, or at least a similar model, could have potential application to the field of energy metabolism in ruminants because it would enable the estimation of parameters that describe the rates of whole body disposition of glucose, and the production and utilization of NEFA. In this study we investigated the suitability of the Thomaseth model to describe NEFA and glucose kinetics in 10 lactating Holstein-Friesian cows given a standard IVGTT in early lactation. The Thomaseth model described the general pattern of the NEFA response and, in particular, described the downward-slope and nadir in NEFA concentrations reasonably well. However, it failed to describe the initial latency period (the period before NEFA concentrations decline precipitously), and it could not describe terminal 'rebound' plateau in NEFA concentration. Because of these inherent problems, the parameters of the Thomaseth model cannot be considered to provide accurate estimates of rates of NEFA production or utilization. It is concluded that the Thomaseth model is not suitable for describing NEFA kinetics in lactating dairy cows.

Metabolic Effect of Sirolimus Versus Mycophenolate Mofetil on Pancreatic Graft Function in the Early Posttransplant Period

Metabolic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare effects of tacrolimus-based immunosuppression in conjunction with sirolimus (RAPA) versus mycophenolate mofetil (MMF) on glucose metabolism in type 1 diabetic recipients following a simultaneous pancreas and kidney transplantation (SPK). We examined 30 insulin-independent patients after SPK with venous systemic drainage of the pancreatic graft. All recipients had good kidney graft function. Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA lc), standard intravenous glucose tolerance test (IVGTT), and trough RAPA levels were assessed in pancreas recipients before elective steroid withdrawal. Insulin sensitivity was evaluated using the homeostasis model assessment (HOMA-IR). The groups did not differ in age, BMI, posttransplant period, steroid daily dose, HbA lc, and fasting glycemia. We did not find any significant difference in the IVGTT response. Area under the curve of insulin levels during IVGTT and HOMA-IR were significantly lower in the RAPA group. Trough levels of RAPA had no significant impact on any of the examined parameters. Glucose tolerance measured with the use of IVGTT was similar in patients treated with RAPA and MMF. However, recipients on sirolimus treatment had significantly lower insulinemia during the test and consequently more favorable indices of insulin action as assessed by HOMA-IR.

An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission

Aims: To examine derived indices of β cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes...

Bayesian two-compartment and classic single-compartment minimal models: comparison on insulin modified IVGTT and effect of experiment reduction

Models describing plasma glucose and insulin concentration of an intravenous glucose tolerance test (IVGTT) allow a noninvasive cost-effective approach to estimate important indexes characterizing the efficiency of glucose-insulin control system, i.e., glucose effectiveness (S(G)) and insulin sensitivity (S(I)). To overcome some limitations of the classic single compartment minimal model (1CMM) of glucose kinetics , a two-compartment Bayesian minimal model (2CBMM) has been recently proposed for the standard IVGTT. This study aims to assess 2CBMM ability to describe the insulin-modified IVGTT (IM-IVGTT) which is the protocol of choice since it allows to study insulinopenic states. Both a full-length IM-IVGTT (240 min) as well as a reduced version (90 min) of it are studied. Results of the maximum a posteriori identification of IM-IVGTT (240 min) in 13 normals agree with those of standard IVGTT, i.e., a 42% decrease (P < 0.002) of S(G) and a 13% increase (P < 0.006) of S(I) with respect to ICMM. When identified from IM-IVGTT (90 min), 2CBMM not only provides S(G) and S(I) estimates 46% lower (P < 0.002) and 41% higher (P < 0.002) than 1CMM ones respectively, but also seems to overcome some limitations of the 240 min-based identification that probably arise because the minimal model is unable to properly account for the hyperglycemic hormonal response taking place in the second half of IM-IVGTT.

Measurement of insulin sensitivity indices using 13C-glucose and gas chromatography/combustion/isotope ratio mass spectrometry.

Important aspects of glucose metabolism can be quantified by using the minimal model of glucose kinetics to interpret the results of intravenous glucose tolerance tests. The power of this methodology can be greatly increased by the addition of stable isotopically labelled tracer to the glucose bolus dose. This allows the separation of glucose disposal from endogenous glucose production and also increases the precision of the estimates of the physiological parameters measured. Until now the tracer of choice has been deuteriated glucose and the analytical technique has been gas chromatography/mass spectrometry (GC/MS). The consequence of this choice is that nearly 2 g of labelled material are needed and this makes the test expensive. We have investigated the use of (13)C-labelled glucose as the tracer in combination with gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) as the analytical technique. This methodology offers superior analytical precision when compared with the conventional method and so the amount of tracer used, and hence the cost, can be reduced considerably. Healthy non-obese male volunteers were recruited for a standard intravenous glucose tolerance test (IVGTT) protocol but 6,6-(2)H-glucose and 1-(13)C-glucose were administered simultaneously. Tracer/tracee ratios were derived from isotope ratio measurements of plasma glucose using both GC/MS and GC/C/IRMS. The results of these determinations indicated that the two tracers behaved identically under the test protocol. The combination of these results with plasma glucose and insulin concentration data allowed determination of the minimal model parameters S*g and S*i. The parameter relating to insulin-assisted glucose disposal, S*i, was found to be the same in the two techniques, but this was not the case for the non-insulin-dependent parameter S*g.

Minimal model SG overestimation and SI underestimation: improved accuracy by a Bayesian two-compartment model.

The intravenous glucose tolerance test (IVGTT) single-compartment minimal model (1CMM) method has recently been shown to overestimate glucose effectiveness and underestimate insulin sensitivity. Undermodeling, i.e., use of single- instead of two-compartment description of glucose kinetics, has been advocated to explain these limitations. We describe a new two-compartment minimal model (2CMM) into which we incorporate certain available knowledge on glucose kinetics. 2CMM is numerically identified using a Bayesian approach. Twenty-two standard IVGTT (0.30 g/kg) in normal humans were analyzed. In six subjects, the clamp-based index of insulin sensitivity (ScI) was also measured. 2CMM glucose effectiveness (S2G) and insulin sensitivity (S2I) were, respectively, 60% lower (P < 0.0001) and 35% higher (P < 0.0001) than the corresponding 1CMM S1G and S1I indexes: 2.81 +/- 0.29 (SE) vs. S1G = 4.27 +/- 0.33 ml. min(-1). kg(-1) and S2I = 11.67 +/- 1.71 vs. S1I = 8.68 +/- 1.62 10(2) ml. min(-1). kg(-1) per microU/ml. S2I was not different from ScI = 12.61 +/- 2.13 10(2) ml. min(-1). kg(-1) per microU/ml (nonsignificant), whereas S1I was 60% lower (P < 0.02). In conclusion, a new 2CMM has been presented that improves the accuracy of glucose effectiveness and insulin sensitivity estimates of the classic 1CMM from a standard IVGTT in normal humans.

First-phase insulin release in normal children

Normal values for the first-phase insulin release during an intravenous glucose tolerance test are not yet well defined for children and adolescents. In this study, 69 normal subjects (aged 7 to 22 years) who had no family history of type I diabetes, a normal glycohemoglobin value, and a negative islet cell antibody test result underwent a standard intravenous glucose tolerance test. The mean (+/- SEM) first-phase insulin release increased with age and pubertal status: 7 to 10 years, 93 +/- 10.1 mIU/L; 11 to 15 years, 172.7 +/- 22.3 mIU/L; and 16 to 22 years, 163 +/- 28.5 mIU/L. The mean intraindividual variability in 11 subjects who underwent a second test was 23.6%. Acute stress, as estimated by observer assessment or by blood catecholamine levels, did not significantly correlate with first-phase insulin release. We conclude that first-phase insulin release is markedly lower in prepubertal children than in adolescents and young adults.

Androgen responses to acutely increased endogenous insulin levels in hyperandrogenic and normal cycling women

We examined androgen responses in hyperandrogenic (polycystic ovarian disease [PCOD]) and normal women after an acute endogenous insulin elevation. Standard intravenous glucose tolerance tests (IVGTTs), modified to include a tolbutamide injection 20 minutes after IVGTTs, were performed. Polycystic ovarian disease patients were studied in the untreated state, after 6 weeks of ovarian androgen suppression with leuprolide acetate, after a 6-week rest period, and after 6 weeks of antiandrogen therapy with spironolactone. Normal menstruating women were studied during the early follicular, midcycle, and luteal phases of a single cycle. An acute rise in insulin did not alter serum testosterone or androstenedione levels in PCOD or normal women. A significant rise in dehydroepiandrosterone sulfate after modified IVGTTs was found in both hyperandrogenic and normal cycling women. Although these results are not supportive of the theory that insulin acts on the ovary to stimulate androgen production, they may be because of the short time course of insulin elevation that occurs during an IVGTT.

Androgen responses to acutely increased endogenous insulin levels in hyperandrogenic and normal cycling women

We examined androgen responses in hyperandrogenic (polycystic ovarian disease [PCOD]) and normal women after an acute endogenous insulin elevation. Standard intravenous glucose tolerance tests (IVGTTs), modified to include a tolbutamide injection 20 minutes after IVGTTs, were performed. Polycystic ovarian disease patients were studied in the untreated state, after 6 weeks of ovarian androgen suppression with leuprolide acetate, after a 6-week rest period, and after 6 weeks of antiandrogen therapy with spironolactone. Normal menstruating women were studied during the early follicular, midcycle, and luteal phases of a single cycle. An acute rise in insulin did not alter serum testosterone or androstenedione levels in PCOD or normal women. A significant rise in dehydroepiandrosterone sulfate after modified IVGTTs was found in both hyperandrogenic and normal cycling women. Although these results are not supportive of the theory that insulin acts on the ovary to stimulate androgen production, they may be because of the short time course of insulin elevation that occurs during an IVGTT.

The insulin sensitivity index in nondiabetic man. Correlation between clamp-derived and IVGTT-derived values.

Although the minimal-model-based insulin sensitivity index (S1) can be estimated from the results of a simple 180-min intravenous glucose tolerance test (IVGTT), its relationship to widely accepted but technically more difficult clamp-based techniques has not been resolved in humans. Therefore we measured S1 by standard IVGTT, modified IVGTT, and clamp methods in 10 nondiabetic men with %IBW of 109 +/- 12 (mean +/- SD). In the euglycemic clamp studies, insulin was infused to bring insulin levels (IRI) from basal, 8 +/- 4 microU/ml, to plateaus of 21 +/- 5 and 35 +/- 6 microU/ml. S1[clamp], measured as the increase in glucose (G) clearance per increase in IRI [delta INF/(delta IRI X G)], averaged 0.29 +/- 0.09 ml/kg X min per microU/ml. In the IVGTT studies, 300 mg/kg G was given as an i.v. bolus, and G and IRI were measured for 180 min; in the modified (mod) IVGTT, tolbutamide (300-500 mg) was given i.v. 20 min after the G to observe the effect of an IRI peak on G removal after G level was free of initial "mixing" effects. The S1 estimated by computer did not differ significantly between standard [(6.9 +/- 3.4) X 10(-4) min-1 per microU/ml] and modified [(6.7 +/- 3.5) X 10(-4) min-1 per microU/ml] tests, indicating no bias due to the differing insulin patterns and levels. There was a strong positive correlation between S1 (mod IVGTT) and S1(clamp): r = 0.84; N = 10; P less than 0.002. The correlation between S1(standard IVGTT) and S1(clamp) was 0.54, suggesting the modified test is less "noisy." Nonetheless, in eight euglycemic women with a wider range of adiposity, S1(standard IVGTT) has been significantly correlated with %IBW (r = -0.72) and basal IRI (r = -0.84). The correlation between S1 measures by clamp and IVGTT methods provides one step toward validation of the minimal model for studies of insulin action in man.

Glucose intolerance in sarcoma patients.

Twenty-seven otherwise healthy patients with localized sarcoma were examined to determine if glucose intolerance can be detected before the appearance of clinical signs of cachexia. No patient had lost weight or demonstrated severe malnutrition. Fasting plasma samples for glucose, insulin, glucagon, and free fatty acids (FFA) were obtained, and a standard intravenous glucose tolerance test performed. Glucose disappearance rate (K) was calculated between 5 and 60 minutes. K levels were compared to those of normal controls and to those of patients with more extensive cancer (statistics obtained from the literature). Levels for K were compared to tumor volume measurements following surgery. Fasting glucose, insulin, and glucagon levels were normal. Fasting FFA levels were slightly elevated. K levels for sarcoma patients were significantly lower than in control patients (P = 0.04), and higher than in patients with advanced cancer (P less than 0.0001). The subset of patients who weighed less than the ideal had a significantly lower K level than did the rest of the sarcoma population. K levels correlated inversely with tumor volume (r = -0.34; P = 0.04). These data indicate that mild glucose intolerance (reduction in clearance of a glucose load) occurs early in untreated sarcoma patients, is most prevalent in patients who maintain less than the ideal weight, correlates with tumor burden, and occurs before other signs of cachexia appear.