Intravenous Tolerance Test Research Articles

Minimal Model-Derived Insulin Sensitivity Index Underestimates Insulin Sensitivity in Black Americans.

OBJECTIVETo examine the ethnic differences in insulin sensitivity (SI) as measured by the minimal model approach (SI-MM) and the reference method, the euglycemic-hyperinsulinemic clamp (EHC).RESEARCH DESIGN AND METHODSIn a prospective study design, thirty Black Americans (BA) were age, sex, and BMI matched with non-Hispanic Whites (NHW). Participants underwent frequently sampled intravenous tolerance test (FSIVGTT) and EHC on 2 separate days during a single visit.RESULTSSI-MM values were significantly lower in BA when compared with NHW (0.035 ± 0.025 vs. 0.058 ± 0.036 [dL/min]/[μU/mL]; P = 0.003). However, there were no ethnic differences in SI measured by EHC (0.028 ± 0.012 vs. 0.035 ± 0.019 [dL/min]/[μU/mL]; P = 0.18).CONCLUSIONSSI-MM systematically underestimates SI in BA when compared with NHW. These findings suggest that studies inferring lower SI in BA based on FSIVGTT and SI-MM should be interpreted cautiously.

Evaluation of the combined glucose-insulin and intravenous glucose tolerance tests for insulin dysregulation diagnosis in donkeys.

Insulin dysregulation (ID) and donkey metabolic syndrome (DMS) are common in this species. Contrary to horses, diagnostic guidelines compiling insulin cut-offs values and dynamic testing interpretations have not been reported for this species. To evaluate resting serum insulin concentrations, the combined glucose-insulin test (CGIT) and the glucose intravenous tolerance test (IVGTT) for the diagnosis of DMS with ID suspicion. Diagnostic test comparison. Six of 80 mix-breed adult donkeys fulfilled the inclusion criteria for DMS based on history or clinical evidence of recurrent laminitis, body condition >6 and neck score >2 or baseline insulin and leptin concentrations >20µIU/mL and >12ng/mL respectively. CGIT and IVGTT were performed in all donkeys within a week and interpreted following guidelines reported for equine metabolic syndrome (EMS). Insulin and glucose curves were analysed, proxies calculated and correlations and multivariate analysis assessed. Following EMS guidelines, CGIT classified 2 (using glucose-positive phase duration) or 3 (using insulin concentration) and IVGTT classified 5 donkeys as ID. ID donkeys showed a lower glucose/insulin ratio, QUICKI and RISQI, and a higher insulin/glucose ratio, MIRG and HOMA-B%. Comparison of these tests with additional dynamic testing including a larger number of ID donkeys is necessary. This is the first study evaluating dynamic tests to assess ID/DMS in DMS-suspected donkeys. IVGTT detected more ID donkeys than CGIT. EMS recommendations could also be used for DMS diagnosis, although a baseline insulin cut-off value is needed.

Dynamical analysis of fractional-order of IVGTT glucose–insulin interaction

Abstract This paper proposes a fractional-order model of glucose–insulin interaction. In Caputo’s meaning, the fractional derivative is defined. This model arises in Bergman’s minimal model, used to describe blood glucose and insulin metabolism, after intravenous tolerance testing. We showed that the established model has existence, uniqueness, non-negativity, and boundedness of fractional-order model solutions. The model’s local and global stability was investigated. The parametric conditions under which a Hopf bifurcation occurs in the positive steady state for a proposed model are studied. Moreover, we present a numerical treatment for solving the proposed fractional model using the generalized Euler method (GEM). The model’s local stability and Hopf bifurcation of the proposed model in sense of the GEM are presented. Finally, numerical simulations of the model using the Adam–Bashforth–Moulton predictor corrector scheme and the GEM have been presented to support our analytical results.

A Caputo (discretization) fractional-order model of glucose-insulin interaction: numerical solution and comparisons with experimental data

In this paper, we investigate a (discretization) Caputo fractional glucose-insulin model qualitatively with incommensurate orders that appear in Bergman's minimal model. After intravenous tolerance testing, the model is used to characterize the blood insulin and glucose metabolism. We also prove that the presented model possesses existence, uniqueness, non-negative, and boundedness solution. We also proceed a systematical studies on the stability of the (discretization) Caputo fractional. Comparisons between the results of the fractional-order, the integer order and the measured real data obtained from patients are presented. These comparisons is shown that the presented Caputo fractional order model is better representative of the system than its integer order form. Numerical solutions of the Caputo fractional model are obtained by using the method of Adams-Bashforth-Moulton type to handle the fractional derivatives. Also, numerical simulations of the discretization fractional derivative order model are used to support the analytical results.

1888-P: Impaired Insulin Clearance Relates to Increased Liver Fat Content in Recent-Onset Type 2 Diabetes and to Impaired Glucose Control in Recent-Onset Type 1 Diabetes

Hepatic insulin metabolism in patients with newly diagnosed diabetes is not yet understood. Insulin clearance seems to be decreased in patients with obesity, visceral adiposity and type 2 diabetes (T2D), but data compared to glucose tolerant humans have been inconclusive. To this end, persons with type 1 diabetes (T1D; n=124) or type 2 diabetes (T2D; n=401) and glucose-tolerant humans (CON; n=245) underwent hyperinsulinemic-euglycemic clamps to assess insulin sensitivity (IS) and whole-body insulin clearance (ICWBIC, ml x kg-1 x min-1). Hepatic insulin clearance was also calculated from the ratio of the areas under the curve of plasma C-peptide and insulin (0-60 min) during intravenous glucose-tolerance test (IVGTT, 0-60 min) and mixed meal tolerance test (MMTT, 0-180 min). Hepatocellular lipid content (HCL) was measured by 1H-magnetic resonance spectroscopy. Analyses were adjusted for age, sex and BMI. In T1D, ICIVGTT (1.71±1.1 vs. 2.3±0.3 and 3.2±0.3, all p<0.05) as well as ICMMT (1.6±0.7 vs. 2.0±0.4 and 2.1±0.3, all p<0.05) were lowest compared to T2D and CON respectively and correlated negatively with HbA1c (r=-0.242 and r=-0.279, both p<0.05). In T2D, ICIVGTT was positively correlated with HbA1c (r=0.178, p<0.05) as well as with IS (r=0.242, p<0.05). T2D patients with hepatic steatosis (n=73) had lower ICIVGTT, ICWBIC as well as ICMMT (2.2±0.31 vs. 2.4±0.31, 1.4±0.4 vs. 1.5±0.4 and 1.9 ±0.3 vs. 2.1±0.2 respectively, (i.e., differences of 8%, 9% and 7%, all p<0.05) compared to T2D without steatosis (n=53). CON with steatosis also had lower ICIVGTT (n=103, 2.1±0.2 vs. 2.3±0.35, p<0.05). ICMMT positively correlated with IS (r=0.338 and r=0.187, both p<0.05) in T1D and T2D, but not in CON. In conclusion, glycemic control likely impairs insulin clearance particularly in T1D patients, whereas steatosis affects insulin clearance in T2D and in glucose tolerant humans. Disclosure S. Antoniou: None. O.P. Zaharia: None. K. Strassburger: None. Y. Karusheva: None. K. Bodis: None. Y. Kupriyanova: None. V. Burkart: None. K. Muessig: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. J. Szendroedi: None.

Fasting Plasma Glucose Indicates Reversibility of Acute Insulin Response after Short-Term Intensive Insulin Therapy in Patients with Type 2 Diabetes of Various Duration

Objective: In patients with early type 2 diabetes, short-term intensive insulin therapy (SIIT) reverses ß cell dysfunction measured by acute insulin response (AIR). However, the complicated procedures limit large-scale use of AIR. Also unclear is whether SIIT is effective in patients with longer duration. This study is performed to assess fasting indicators estimating recovery of AIR after SIIT for type 2 diabetes of various duration. Research Design and Methods: Patients with type 2 diabetes (n=62) who had poor glycemic control were enrolled. Near-nomoglycaemia was achieved and maintained for 7 days with insulin pump. AIR was measured by intravenous tolerance tests before and after SIIT. Results: Both fasting plasma glucose (FPG, 12.0 ± 3.0 vs. 7.71± 1.6 mmol/L, P<0.001) and 2h-postprandial glucose (17.3 ± 5.2 vs. 11.5 ± 3.7 mmol/L, P<0.001) decreased significantly after SIIT. AIR was improved from -16.7 (-117.4, 52.4) pmol/L·min to 178.7 (31.8, 390.7) pmol/L·min (P<0.001). Increase of AIR (?AIR)was observed in all disease duration categories (329.2±380.6, 312.8±347.8, and 123.8 ±186.3 pmol/L·min for patients with disease duration of <2 years, 2-6 years, and >6 years respectively, P=0.10). AIR was almost absent when FPG was over 10 mmol/L. However, when FPG after SIIT was less than 10 mmol/L it was negatively associated with AIR (R= -0.53, P<0.001) and ?AIR (R= -0.52, P<0.001). In multivariate analysis, AIR after the therapy and ?AIR could be estimated as follows: Estimated AIR (pmol/L·min) = 447.6 × baseline fasting C peptide (nmol/L) - 138.0× FPG after SIIT (mmol/L) + 925.2 (R2=0.42); estimated ?AIR (pmol/L·min) = 401.4 × baseline fasting C peptide (nmol/L) - 136.8 × FPG after SIIT (mmol/L) -357.6 × HDL-C after SIIT (mmol/L) + 1380.0(R2=0.50). Conclusions: Recovery of AIR could be obtained in patients with various duration of type 2 diabetes, and it could be estimated conveniently by FPG and other fasting indicators. Disclosure L. Liu: None. S. Yang: None. J. Liu: None. L. Hai: None. J. Liu: None. Y. Li: None.

The Solution of Modified Fractional Bergman’s Minimal Blood Glucose-Insulin Model

In the present paper, we use analytical techniques to solve fractional nonlinear differential equations systems that arise in Bergman’s minimal model, used to describe blood glucose and insulin metabolism, after intravenous tolerance testing. We also discuss the stability and uniqueness of the solution.

Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers

Background and aimsConsumption of foods that modulate inflammatory stress in genetically-prone individuals may influence development of cardiometabolic diseases. Isoflavones in soy-derived foods function as phytoestrogens, have antioxidant and anti-inflammatory activity, inhibit protein-tyrosine kinase activity, and may be atheroprotective. We examined the relationship between soy food consumption and inflammatory responses to endotoxemia, postprandial responses to oral lipid tolerance test (OLTT), and insulin sensitivity from frequently sampled intravenous tolerance tests (FSIGTT). Methods and resultsWe administered low-dose endotoxin (LPS 1 ng/kg) to induce transient endotoxemia in young, healthy volunteers (N = 215) of African (AA), and European (EA) ancestry as part of the GENE Study. We further supported these findings in two independent samples: the MECHE Study and NHANES. Soy food consumption was a significant predictor of peak cytokine response following LPS. Individuals with moderate-high (>1.48 mg/day, N = 65) vs. low-no (<1.48 mg/day, N = 150) isoflavone consumption had significantly higher tumor necrosis factor alpha (TNFα) post-LPS (AUC, P = 0.009). Further, high-isoflavone consumers were protected against inflammation-induced decline in insulin sensitivity (SI) in GENE. We observed significant differences by soy consumption in the interferon gamma (IFNγ) response to OLTT, and the insulin response to OGTT in MECHE, as well as significantly lower fasting insulin, and 2-hour glucose post-OGTT in EA NHANES subjects. ConclusionWe demonstrate that soy consumption may influence inflammatory and metabolic responses. In research of nutritional exposures, measuring evoked phenotypes may be more informative than describing resting characteristics.The GENE Study was registered under NCT00953667 and the MECHE Study under NCT01172951, both at clinicaltrials.gov.

Abstract 367: Insulin Resistance is Associated with Increased Sympathetic Activity and Decreased Baroreflex Function in Obese African American Women

Obesity has a greater detrimental impact on the health of African American (AA) women than any other racial or gender group. Nearly 80% of AA women are overweight or obese and have higher incidence of insulin resistance compared to Caucasian women. The sympathetic nervous system (SNS) is increased in obesity and previous studies have reported that it may contribute to insulin resistance. However, most of these studies were performed in Caucasians. Thus, the contribution of the SNS to insulin resistance in African Americans remains unknown.The aim of this study was to determine if sympathetic activity is increased in obese AA women with insulin resistance. A total of 35 obese AA women with metabolic syndrome were studied (age 43±9 years, body mass index 38.7±5.5 Kg/m 2 , percentage body fat 48±4). Insulin sensitivity (SI) was evaluated by frequently sampled intravenous tolerance test and analyzed with Bergman's minimal model (MINMOD). Measurement of sympathetic regulation of vasomotor tone and baroreflex gain were determined with baroreflex-cross spectral analysis. Our results showed that SI was directly associated with baroreflex sensitivity, Figure. Subjects with insulin resistance (SI&lt;3) had lower baroreflex sensitivity compared with those with normal SI (6.2±2.8 vs 10.4±4.5 ms/mm Hg, P=0.009). Subjects with insulin resistance tended to have elevated sympathetic activity as measured by low frequency variability of systolic blood pressure (LF SBP ; 5.9±3.4 vs 3.7±2.0 mm Hg 2 , P=0.057). In conclusion, insulin resistance is associated with decreased baroreflex gain and increased sympathetic activity in obese AA women.

Energy substrate utilization in the common brushtailed possum (Trichosurus vulpecula) using intravenous tolerance tests

The aim of this study was to investigate the energy substrate requirements of the common brushtailed possum (Trichosurus vulpecula) using intravenous tolerance tests for glucose, alanine, and propionate in five adult male and female animals under standardized conditions. Significant differences (p<0.01) were observed for fasting blood glucose values between males (6.3±0.16 mmol L(-1)) and females (4.8±0.13 mmol L(-1)), and males had a significantly (p<0.001) increased response to glucose. All animals returned to fasting glucose levels within 120 min after the glucose challenge. No significant change in blood glucose levels was observed for either the alanine or propionate tolerance tests (p>0.05). However, following propionate administration, there was a highly significant (p<0.001) decrease in blood lactate concentrations over 120 min. There was no evidence of ketone formation using β-hydroxybutyrate as a biomarker during any of the tests, indicating that there was no significant switch to lipolysis. In conclusion, the study provides new information on energy substrate utilization in this species and has identified that a gluconeogenic response normally identified in other species is not apparent in the common brushtailed possum.

A novel minimal model to describe NEFA kinetics following an intravenous glucose challenge

Dynamics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification if we are to understand the etiology of such diseases as type 1 and 2 diabetes, as well as metabolic syndrome and obesity, or if we are to elucidate the mechanism of action of various interventions. We present a new compartmental model that employs the pattern of plasma glucose concentrations in healthy young adults to predict dynamic changes that occur in plasma NEFA concentrations during either a glucose-only intravenous glucose tolerance test, or an insulin-modified intravenous tolerance test, or a modified protocol during which variable-rate glucose infusions were administered to prevent plasma glucose from declining below 100 mg/dl. The model described all of the major features of NEFA response to an intravenous glucose tolerance test, including an initial latency phase, a phase during which plasma NEFA concentrations plummet to a nadir, and a rebound phase during which plasma NEFA concentrations may rise to a plateau concentration, which may be substantially higher than the initial basal NEFA concentration. This model is consistent with physiological processes and provides seven adjustable parameters that can be used to quantify NEFA production (lipolysis) and utilization (oxidation). When tested on data from the scientific literature, the range in estimated rate of lipolysis was 24-36 micromol.l(-1).min(-1) and for NEFA oxidation rate was 25-54 micromol.l(-1).min(-1). All model parameters were well identified and had coefficients of variation < 15% of their estimated values. It is concluded that this model is suitable to describe NEFA kinetics in human subjects.

Mathematical Beta Cell Model for Insulin Secretion following IVGTT and OGTT

Evaluation of beta cell function is conducted by a variety of glucose tolerance tests and evaluated by a number of different models with less than perfect consistency among results obtained from different tests. We formulated a new approximation of the distributed threshold model for insulin secretion in order to approach a model for quantifying beta cell function, not only for one, but for several different experiments. Data was obtained from 40 subjects that had both an oral glucose tolerance test (OGTT) and an intravenous tolerance test (IVGTT) performed. Parameter estimates from the two experimental protocols demonstrate similarity, reproducibility, and indications of prognostic relevance. Useful first phase indexes comprise the steady state amount of ready releasable insulin A0 and the rate of redistribution krd, where both yield a considerable correlation (both r=0.67) between IVGTT and OGTT estimates. For the IVGTT, A0 correlates well (r=0.96) with the 10 min area under the curve of insulin above baseline, whereas krd represents a new and possibly more fundamental first phase index. For the useful second phase index gamma, a correlation of 0.75 was found between IVGTT and OGTT estimates.

STATA: a statistical analysis system for examining biomedical data.

STATA is a statistical analysis program developed by STATA Corporation, College Station, TX. In addition to supporting a very extensive array of statistical tools, STATA incorporates a critical complement of data management and graphics facilities as well. As demonstrated in another article in this volume (Boston et al., 2002), STATA fits very well into the kinetic analysis suite of tools. In that paper, we show how some preliminary analyses of intravenous tolerance test (IVGTT) data leading to estimates of key parameters and their errors in the minimal model (see Bergman and Bowden, 1981) could easily be performed with STATA. We also demonstrate the transfer of some WinSAAM Population Management Results from WinSAAM to STATA for further appraisal as well as for graphical display. Here we will present aspects of the organization, operation, use, and availability of STATA.

Unique effect of visceral fat on insulin sensitivity in obese Hispanic children with a family history of type 2 diabetes.

This study aimed to establish whether total fat or central fat was related to measures of insulin in obese Hispanic children with a family history of type 2 diabetes. Subjects were 32 children aged 8-13 years. Visceral fat and subcutaneous abdominal fat were determined by magnetic resonance imaging at the umbilicus and total body fat was determined by dual-energy X-ray absorptiometry. Insulin sensitivity (S(i)) and acute insulin response (AIR) were determined by frequently sampled intravenous tolerance test with minimal modeling. Mean fasting glucose and insulin, S(i), and AIR (+/- SD) were 5.3 +/- 0.3 mmol/l, 206 +/- 105 pmol/l, 11.8 +/- 5.7 [x 10(-4) min(-1)/(pmol/l)], and 17,175 +/- 9,695 (pmol/l x 10 min), respectively. In multivariate regression analysis, total fat mass was independently and positively related to fasting insulin (P < 0.01) and negatively related to S(i) (P < 0.05) but was not related to AIR. Visceral fat was independently and positively related to fasting insulin (P < 0.05) and AIR (P < 0.01) and negatively related to S(i) (P < 0.001). -These findings support the hypothesis that specific accumulation of visceral fat in addition to overall adiposity in Hispanic children increases the risk of type 2 diabetes.

A dynamic model to analyse intravenous glucose and insulin tolerance tests performed on dairy cows.

A dynamic model was developed to assess insulin sensitivity and pancreatic response in lactating dairy cows. The model is based on a simultaneous analysis of insulin and glucose intravenous tolerance tests. It comprises five compartments corresponding to insulin in portal-hepatic plasma, and insulin or glucose in both systemic plasma and in interstitial fluid. Insulin secretion rate is a sigmoidal function of glucose in plasma. Insulin is cleared from hepatic plasma and from the interstitial fluid. The glucose entry rate is constant and glucose utilization rate is a sigmoidal function of insulin in the interstitial fluid. Six parameters were estimated: two for insulin secretion rate, two for insulin clearance, one for glucose entry rate and one for glucose utilization rate. After integration of the functions, the model yielded a relative estimate of the quantities of insulin secreted and cleared, as well as the glucose entering and utilized during each test. Using an experimental dataset composed of ten pairs of tolerance tests, the explained variations for plasma insulin and glucose concentrations were 96.0 and 98.3 % and standard errors of estimates were 0.032 nmol/l and 0.14 mmol/l respectively. Except in the early stages after injection, residual errors were low. A Jackknife analysis showed that the estimated parameters exhibited low statistical bias. This model simplifies the interpretation of both tests through a simulation based on six common parameters. Compared to a classical analysis of tolerance tests, it may improve the analysis of modifications in the key functions regulating glucose homeostasis in ruminants.

A comparison of the plasma fructose concentrations in dogs and cats and changes in the fructose concentrations in dogs following intravenous administration of fructose.

The plasma concentrations of fructose, glucose, free fatty acids (FFA) and triglycerides (TG) were measured in dogs and cats. Changes in these concentrations were investigated in dogs by an intravenous fructose tolerance test (IVFTT) at a dose of 0.1 g/kg body weight. Fructose concentrations in the plasma of dogs were significantly higher than those of cats. There was no significant difference in plasma glucose concentrations between dogs and cats. Plasma FFA concentrations decreased and TG concentrations increased after feeding in both dogs and cats. During the IVFTT, the plasma fructose concentrations in the dogs increased rapidly to a peak by 2 min and then decreased to half of the peak by 5 min after the administration of fructose. Administration of fructose resulted in an increase in the plasma TG concentrations and reduced plasma FFA concentrations in the dogs. Only 4%, of the administered fructose was detected in the urine of dogs following IVFTT. Plasma fructose was considered to be rapidly absorbed and metabolized in both dogs and cats. However, as with glucose metabolism, there appear to be some differences in fructose metabolism between dogs and cats.

Effect of glipizide GITS on insulin sensitivity, glycemic indices, and abdominal fat composition in NIDDM

Glipizide in a once daily formulation utilizing the gastrointestinal therapeutic system (GITS) has been shown in preliminary studies to improve insulin sensitivity as assessed with meal tolerance testing. To evaluate the ability of glipizide GITS to specifically improve clinical insulin sensitivity in vivo, a double–blind, placebo-controlled trial randomized 40 NIDDM subjects to either glipizide GITS or placebo. The study was designed to evaluate NIDDM subjects whose fasting blood glucose was <190 mg% and Ghb <11% to avoid the adverse effects of hyperglycemia on insulin resistance and secretion. After screening, oral hypoglycemic agents were discontinued for one month, at which time a meal tolerance test with glucose and insulin response, glycated hemoglobin, and fructosamine were obtained. Insulin sensitivity (SI) and glucose effectiveness (Sg) were determined with a 4–h frequently sampled intravenous tolerance test (modified minimal model – 3rd phase insulin infusion) at baseline. Specific abdominal fat depots were quantitated by MRI scans. Patients were then randomized to receive placebo or active drug and all parameters were repeated at 1, 2, 5, and 8 months after randomization. Glipizide GITS significantly improved meal tolerance, reduced glycated blood proteins, and increased insulin sensitivity (P < .001). No change was seen for SG. There was no significant change in abdominal fat distribution during the trial. Glipizide GITS is effective in lowering glucose tolerance and improving insulin sensitivity without an increase in fasting insulin, weight gain, or change in abdominal fat composition. Drug Dev. Res. 44:1–7, 1998. © 1998 Wiley-Liss, Inc.

Retrograde versus antegrade cannulation in the intravenous glucose tolerance test

To investigate whether drawing blood from a retrogradely cannulated hand vein rather than an antegradely cannulated arm vein improves reproducibility in the intravenous tolerance test (IVGTT) we compared these two methods directly by drawing blood from the two sites on the same arm simultaneously. We found no difference in intrasubject coefficients of variation for the measurement of insulin response to glucose (21.5% vs. 22.5%) or insulin sensitivity (22.8 vs. 24.7%) for these two methods. However, the values for insulin response to glucose were significantly increased when blood was drawn from the hand site (410.1 vs. 328.7 pM, P < 0.05). In addition, the failure rate for studies using the retrogradely cannulated hand vein was significantly increased (5% of arm veins vs. 20% of hand veins cannulated, P < 0.05) particularly in female subjects. In conclusion, drawing blood samples from a retrogradely cannulated hand vein appears to have no effect on the reproducibility of the intravenous glucose tolerance test. The acute insulin response to glucose obtained from samples drawn in this manner is, however, significantly increased and this should be borne in mind when comparing results from centers using these different methods.

The effects of hormonal replacement therapy on insulin sensitivity in surgically postmenopausal cynomolgus monkeys (Macaca fascicularis)

Our purpose was to evaluate the effect of hormone replacement therapy on insulin resistance in postmenopausal cynomolgus monkeys (Macaca fascicularis). We studied 37 surgically postmenopausal cynomolgus monkeys that were fed a moderately atherogenic diet for 12 weeks with either no treatment (control), conjugated equine estrogens, medroxyprogesterone acetate, combination conjugated equine estrogens and medroxyprogesterone acetate, or tamoxifen. Insulin sensitivity and glucose effectiveness were determined by the frequent-sampling intravenous tolerance test by means of the minimal model analysis. There were no differences in body weight, total plasma cholesterol, or body fat distribution between control and conjugated equine estrogens, medroxyprogesterone acetate, or combination treatment groups. However, compared with control animals (insulin sensitivity = 5.9 +2- 1.2 x 10(-4) min-1 microU-1 ml) or conjugated equine estrogens treatment (6.3 +/- 1.1 x 10(-4) min-1 microU-1 ml) insulin sensitivity was significantly decreased in animals treated with medroxyprogesterone acetate (2.9 +/- 0.4 x 10(-4) min-1 microU-1 ml, p < 0.001) or conjugated equine estrogens and medroxyprogesterone acetate (2.8 +/- 0.6 x 10(-4) min-1 microU-1 ml, p < 0.001). Although insulin sensitivity was shown to be decreased in the tamoxifen-treated animals (insulin sensitivity = 4.6 +/- 0.6 x 10(-4) min-1 microU -1 ml), the difference was not statistically significant compared with the control or conjugated equine estrogens-treated animals. No significant differences were seen for glucose effectiveness comparing control animals (glucose effectiveness = 0.043 +/- 0.006 min-1) to animals treated with medroxyprogesterone acetate (glucose effectiveness = 0.046 +/- 0.009 min-1), conjugated equine estrogens and medroxyprogesterone acetate (0.048 +/- 0.008 min-1) or tamoxifen (0.039 +/- 0.006 min-1). These results suggest that progestins alone or in combination with estrogens can induce insulin resistance in postmenopausal monkeys while having no effect on plasma lipid concentrations or glucose effectiveness.

Glutathione peroxidase in blood of diabetic and nondiabetic BB rats

The activity of glutathione peroxidase (GPX), an antioxidant selenoenzyme (EC.1.11.1.9.), was investigated in blood of BB rats developing spontaneous diabetes mellitus. The activity of the enzyme was significantly higher in the 4th and 5th inbred generation (G(4-5)) of BB rats as compared with their counterparts of lower degree of inbreeding (G(1-3)). Overt diabetes (actual blood glucose over 10 mM) appeared only in 8 out of 25 G(5) animals but oral and intravenous glucose tolerance tests revealed a gradual worsening of glucose metabolism already in rats with lower degree of inbreeding. No difference in GPX activity was found between diabetic and nondiabetic members of G(5) group. In the whole group of 69 rats positive correlation was found between the blood GPX activity and the age, weight and actual blood glucose value of the rats and negative correlation between GPX and the P/F value (ratio of peak blood glucose after intravenous tolerance test and fasting blood glucose). In the diabetic animals the enzyme activity showed inverse relationships with every measured or calculated parameter of glucose metabolism. Our findings indicate a relationship between age and blood GPX activity of BB rats and suggest the possibility of deleterious effect of elevated blood glucose level on the blood GPX activity after development of overt diabetes.