Search

Objective Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. Methods We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. Results In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. Conclusions Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.

We have recently established a method utilizing the natural abundance of [13C] polysaccharide enabling measurement of enrichment of [13C] glucose in healthy humans. We now compare complex carb (CC) meal with a single tracer infusion of [6,6-2H2] glucose at -120 min to the established simple carb (SC) triple tracer protocol with infusion of [6,6-2H2] glucose at -120 min and [2-13C] glucose at 0 min with meal ingested at time 0. Six type 2 diabetes subjects (4M, age 65±6 y; BMI 33±4 kg/m2; HbA1c 50±10 mM/mol) were studied in random order with SC labeled with [1-13C] glucose and CC meal with sorghum grain. All meals had ~75 g carbohydrates with matched macronutrient content. Steele’s non-steady state equations were used to calculate glucose fluxes: rates of meal glucose appearance (Rameal), glucose disappearance (Rd) and endogenous glucose production (EGP) (Results in Fig1). Glucose, insulin and C-peptide concentrations achieved as well as iAUC of Rameal and Rd were significantly lower with CC than SC meal (p Disclosure Y. R. Yadav: None. A. Asfa: None. F. Ruchi: None. A. Weaver: None. C. M. Amarasekarage: None. C. Lane: None. A. Basu: None. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D. Disclosure Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Japanese women have substantially lower BMI than women in other developed countries and the prevalence of underweight (BMI In conclusion, the present study suggested that main cause of hyperglycemia in underweight women with IGT was decreased Rd. In addition, decreased insulin secretion may partly contribute to the decreased Rd in those IGT subjects. Disclosure R. Suzuki: None. Y. Tamura: None. Y. Someya: None. H. Kaga: None. D. Sugimoto: None. S. Kadowaki: None. S. Kakehi: None. K. Takeno: None. T. Funayama: None. Y. Furukawa: None. J. Sato: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Novartis Pharmaceuticals Corporation, Sanofi, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd.. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

The model-based assessment of insulin sensitivity in Zucker rat from Intravenous Glucose Tolerance Test (IVGTT) data is a common procedure. The minimal model methodology provides a very reliable assessment but requires specific competence for running the model. The aim of this study was presenting calculated SI (CSI), as a surrogate index for the simple assessment of insulin sensitivity in the Zucker Rat from IVGTT data. To this aim 25 Zucker Lean Rats (ZLR) and 25 Zucker Fatty Rats (ZFR) were considered. Reference insulin sensitivity (SI) was estimated in each rat through the minimal model methodology. CSI is defined as the ratio between the rate of glucose disappearance (KG) and the mean supra-basal area under the insulin curve during the test (ΔAUCINS), corrected by the proportionality term, α. Regression analysis between SI and KG/ΔAUCINS was performed to identify the α coefficient. Results showed as the computed value of CSI presented a high correlation (r = 0.89, R-square = 0.80 and p < 0.0001, slope ≈1) with SI. Mean value of CSI over the whole population was not significantly different from correspondent SI value (p = 0.17). CSI is able to detect the wellknown reduction of insulin sensitivity in the ZFR group (1.0±0.1 vs. 5.0±0.7 min-1/μU·ml-1, p < 0.001), in accordance with the results provided by SI. In conclusion, the present study proposes CSI, as a suitable empiric index for a simple and reliable assessment of insulin sensitivity in Zucker rat and able to provide the same quantitative information of modelbased SI.

Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) stimulate insulin secretion. They are both released after meal ingestion, and therefore they might cooperate in their actions. However, whether there is a cooperative action of the two incretins is not known. This study therefore investigated the effects on insulin secretion and glucose disappearance of GLP‐1 and GIP when given together with intravenous glucose both alone and in combination in mice. Four different doses were used (0.003, 0.03, 0.3 and 3.0 nmol/kg), which ranged from subthreshold to maximal doses to stimulate first‐phase insulin secretion as evident from initial dose–response studies. It was found that at 0.03 nmol/kg and higher doses, glucose‐stimulated insulin secretion was augmented by both incretins. When they were given in combination, no further increase was observed, indicating no synergistic effect. Also, glucose disappearance rate was increased by 0.03 and 3.0 nmol/kg of the two incretins, both when they were given alone and in combination with, again, no synergy. Finally, glucose effectiveness (an index of noninsulin‐mediated processes) was enhanced by the two incretins, in particular GIP. We also found that insulin‐dependent and insulin‐independent mechanisms contributed 38% and 62%, respectively, to glucose tolerance after glucose alone; with GIP, the contribution by noninsulin‐dependent processes was remarkably dominant and with GLP‐1, insulin‐dependent processes were prevailing. In conclusion, GIP and GLP‐1 stimulate insulin secretion and glucose effectiveness in mice with no synergistic action, but with a dissociated contributory effector on glucose disposal: with GLP‐1 being more active on insulin‐dependent processes and GIP more active on noninsulin‐dependent processes.

The aim of this experiment was to evaluate the impact of selection for greater muscling on whole body insulin responsiveness in cattle, as reflected by greater uptake of glucose in response to constant insulin infusion and greater glucose disappearance following an intravenous glucose tolerance test. This study used 18-month-old steers from an Angus herd visually assessed and selected for divergence in muscling over 15 years. Eleven high-muscled (High), 10 low-muscled (Low) and 3 high-muscled steers, which were heterozygous for a myostatin polymorphism (High(Het)), were infused with insulin using the hyperinsulineamic-euglyceamic clamp technique. Insulin was constantly infused at two levels, 0.6 mu IU/kg per min and 6.0 mu IU/kg per min. Glucose was concurrently infused to maintain euglyceamia and the steady state glucose infusion rate (SSGIR) indicated insulin responsiveness. An intravenous glucose tolerance test was also administered at 200 mg/kg live weight. Sixteen blood samples were collected from each animal between -30 and 130 min relative to the administration of intravenous glucose, plasma glucose and insulin concentration was determined in order to analyse insulin secretion and glucose disappearance. Insulin-like growth factor-1 (IGF-1) was also measured in basal plasma samples. At the low insulin infusion rate of 0.6 mU/kg per min, the SSGIR was 73% higher for the High muscling genotype animals when compared to the Low (P < 0.05). At the high insulin infusion rate of 6.0 mU/kg per min, these differences were proportionately less with the High and the High(Het) genotypes having only 27% and 34% higher SSGIR (P < 0.05) than the Low-muscled genotype. The High-muscled cattle also had 30% higher plasma IGF-1 concentrations compared to the Low-muscled cattle. There was no effect of muscling genotype on basal insulin or basal glucose concentrations, glucose disappearance or insulin secretion following an intravenous glucose tolerance test. The increased whole body insulin responsiveness in combination with higher IGF-1 concentrations in the High-muscled steers is likely to initiate a greater level of protein synthesis, which may partially explain the increased muscle accretion in these animals.

Carbohydrate drink can increase work capacity by maintaining power output or speed or prolonging the time to fatigue at a fixed workload. Literature is available on fluid intake content and exercise performance. No study has been undertaken till now on fluid intake patterns during high intensity exercise in heat. Therefore the present study is devised to fill this gap and to design an appropriate fluid volume intake pattern during high intensity exercise in hot environmental condition. 15 moderately trained men participated in the study. Each subject was given two different intake patterns of carbohydrate drink in two exercise sessions conducted on different days. A gap of seven days was kept between two exercise sessions. Total amount of fluid intake by the subjects in each session is 1000ml. During the experiment ambient temperature was kept constant at 35 C. Parameters evaluated were blood glucose concentration during and o after the high intensity exercise, time to exhaustion and mental concentration. Findings of the present study revealed that when carbohydrate ingestion was done in large quantities before exercise, the rate of glucose disappearance was significantly (t = 10.34, p

Aims: The effects of chronic alcohol consumption (8 weeks) on glucose kinetics, in the absence (water, 4 g/kg) and presence of an acute ethanol dose (4 g/kg), were examined in 48 h fasted male and female Wistar rats. Methods: Primed continuous infusions of (6- 3 H)- and (U- 14 C)glucose were employed to assess rates of glucose appearance (Ra), glucose disappearance (Rd), and apparent glucose carbon recycling. Results: After injecting the male and female controls with water, there were no significant alterations in glucose kinetics. Compared to controls, chronic alcohol-fed female animals (injected with water) demonstrated significantly lower: glucose Ra, blood glucose concentration, and apparent glucose carbon recycling for a majority of the experimental period. In separate groups injected with ethanol, the glucose Ra fell by 31% for male rats fed the control diet (MC), 43% for male rats fed the ethanol diet (ME), 29% for female rats fed the control diet (FC), and 42% for female rats fed the ethanol diet (FE). Further, compared to controls (MC and FC), the blood glucose concentration was significantly lower prior to and following the ethanol injection for FE. In addition, FE animals had significantly lower rates of glucose Ra and glucose carbon recycling compared to controls prior to and after the ethanol injection. ME animals demonstrated similar declines in glucose Ra (compared to FE), but only after the ethanol injection. Conversely, ME were able to match the decrease in glucose Ra with comparable declines in glucose Rd resulting in blood glucose concentrations that did not differ from controls. Conclusions: Chronic alcohol consumption results in sex differences in whole-body glucose production and glucose regulation.

To determine whether regulation of fasting endogenous glucose production (EGP) and glucose disappearance (Rd) are both abnormal in people with type 2 diabetes, EGP and Rd were measured in 7 “severe” (SD), 9 “mild” (MD), and 12 nondiabetic (ND) subjects (12.7 ± 0.6 vs. 8.1 ± 0.4 vs. 5.1 ± 0.4 mmol/l) after an overnight fast and during a hyperglycemic pancreatic clamp. Fasting insulin was higher in both the SD and MD than ND subjects, whereas fasting glucagon only was increased ( P < 0.05) in SD. Fasting EGP, glycogenolysis, gluconeogenesis, and Rd all were increased ( P < 0.05) in SD but did not differ in MD or ND. On the other hand, when glucose (∼11 mmol/l), insulin (∼72 pmol/l), and glucagon (∼140 pg/ml) concentrations were raised to values similar to those observed in the severe diabetic subjects, EGP was higher ( P < 0.001) and Rd lower ( P < 0.01) in both SD and MD than in ND. The higher EGP in the SD and MD than ND during the clamp was the result of increased ( P < 0.05) rates of glycogenolysis (4.2 ± 1.7 vs. 3.5 ± 1.0 vs. 0.0 ± 0.8 μmol·kg−1·min−1), since gluconeogenesis did not differ among groups. We conclude that neither glucose production nor disappearance is appropriate for the prevailing glucose and insulin concentrations in people with mild or severe diabetes. Both increased rates of gluconeogenesis (likely because of higher glucagon concentrations) and lack of suppression of glycogenolysis contribute to excessive glucose production in type 2 diabetics.

The minimal model of glucose disappearance (MINMOD version 3; MM3) and both the one-compartment (1CMM) and the two-compartment (2CMM) minimal models were used to analyze stable isotope-labeled intravenous glucose tolerance test (IVGTT) data from year 10 of a study of the effect of dietary restriction (DR) in male rhesus monkeys. Adult monkeys were energy restricted (R; n = 12) on a semipurified diet to ∼70% of control (C) intake (ad libitum-fed monkeys; n = 12). Under ketamine anesthesia, fasting insulin levels were greater among C monkeys. Insulin sensitivity estimates from all models were greater in R than C monkeys, whereas glucose effectiveness estimates were not consistently greater in R monkeys. Fasting plasma glucose as well as hepatic glucose production and clearance rates did not differ between groups. Body fat, in part, statistically mediated the effect of DR to enhance insulin sensitivity indexes. Precision of estimation and intermodel relationships among insulin sensitivity and glucose effectiveness estimates were in the ranges of those reported previously for humans and dogs, suggesting that the models may provide valid estimates for rhesus monkeys as well. The observed insulin sensitivity indexes from all models, elevated among R vs. C monkeys, may be explained, at least in part, by the difference in body fat content between these groups after chronic DR.

Intravenous glucose tolerance tests (IVGTT) were performed on 30 anesthetized, captive Sumatran (Pongo pygmaeus abeli), Bornean (P. p. pygmaeus), and hybrid (P. p. ablie x P. p. pygmaeus) orangutans, and fasted blood samples were taken from two additional juvenile orangutans in 11 U.S. zoos from 1989 to 1997. The age range of animals was 3.5 to 40.5 years. Plasma and serum samples were assayed for glucose and insulin concentrations. Glucose disappearance rate (KG), an index of glucose tolerance, was calculated, as were the early (acute) and second phase insulin responses to administered glucose. The mean ± SE (and median) fasting glucose and insulin concentrations were 113 ± 16 mg/dL (90 mg/dL) and 45 ± 7 μU/mL (27 μU/mL), respectively. Two animals previously suspected to be diabetic were easily identified by their markedly elevated fasting glucose concentrations (380 and 562 mg/dL) and relatively low fasted insulin concentrations (21 and 14 μU/mL); their insulin responses during the IVGTTs were also low or non-detectable. Without these diabetics, the mean ± SE (median) fasting glucose concentration was 92 ± 18 mg/dL (89 mg/dL). Two animals, ages 18 and 40, were identified as potentially pre-diabetic based on age, adiposity, elevated fasted glucose (116 and 137 mg/dL, respectively), and elevated fasted insulin concentrations (114 and 217 μU/mL, respectively). In addition, nearly half of the animals of varying ages, all sub-species and both sexes exhibited delayed or attenuated acute insulin responses during the IVGTTs, resulting in lower KG (P < 0.04) and suggesting propensity for glucose intolerance in captive orangutans. Glucose and insulin concentrations and insulin responses to glucose did not differ between females on hormonal contraception regimes and those not receiving treatment. Zoo Biol 19:193–208, 2000. © 2000 Wiley-Liss, Inc.

The minimal model is widely used to evaluate insulin action on glucose disappearance from frequently sampled intravenous glucose tolerance tests (FSIGT). The common protocols are a regular (rFSIGT, single injection of 0.3 g/kg of glucose) and an insulin-modified test (mFSIGT, with an additional insulin administration at 20 min). This study compared the insulin sensitivity index (SI) and glucose effectiveness (SG) obtained in the same individual (16 normal subjects) with the two tests. SI was 7.11 ± 0.80 10−4 ⋅ min−1 ⋅ μU−1 ⋅ ml in rFSIGT and 6.96 ± 0.83 in mFSIGT ( P = 0.656), regression r = 0.92, P < 0.0001; SG was 0.0260 ± 0.0028 min−1 and 0.0357 ± 0.0052, respectively, statistically different ( P = 0.013) but still with a good regression ( r = 0.66, P = 0.0051). SG and insulin amount during the early period correlated ( r = 0.6, P = 0.015 in rFSIGT and r = 0.76, P = 0.0006 in mFSIGT). In summary, both FSIGTs with minimal model analysis provide the same SI, which is a very robust index. SG was different by 28% due probably to the relationship between SG and the amount of circulating insulin. In studies comparing groups, the simpler rFSIGT can still be used with the advantage of accounting for endogenous insulin, thus offering the possibility of direct inferences on the β-cell activity.

International audience; A new control model for T1DM is designed with the aim to represent accurately the plasma glucose-insulin dynamics. It is in the form of a nonlinear system of three timecontinuous state equations. The model includes two successive remote compartments for plasma insulin, accounting for a slow and a fast dynamics. The modeling of the action of the insulin on the glucose disappearance is in an original nonlinear form. This new model is identified and validated using data from the adult subjects of the UVa T1DM simulator training database. The parametric identification of the model provides in each case an accurate representation of the glucose-insulin dynamics of the subjects.

Many, but not all, adult rhesus monkeys spontaneously develop significant increases in body fat mass, and many, but not all, progress to develop overt adult-onset type II diabetes. The purpose of this study was to determine whether both an increase in body fat and onset of diabetes could be simultaneously prevented through long-term maintenance of stable normal adult body weight by caloric titration. Eight adult male monkeys were provided a complete normal chow diet, but with daily amounts restricted and titrated on a weekly basis to maintain a constant body weight (weight-stabilized group). This regimen has been continued for 5–9 yr (mean ± SD of 7 ± 0.5 yr) with monkeys attaining the age of 17.9 ± 0.6 yr and with maintenance of normal body fat (17.7 ± 1.8%). The age-matched ad libitum fed group (18.1 ± 0.2 yr of age) consisted of 19 monkeys maintained under identical laboratory conditions and diet, but with food available ad libitum. Results showed weight-stabilized monkeys weighed significantly < ad libitum fed monkeys (10.4 ± 0.2 vs. 16.1 ± 0.7 kg, respectively, P < 0.05) and had significantly better glucose tolerance as measured by Kglucose (glucose disappearance rate) (3.9 ± 0.3 vs. 2.4 ± 0.2, P ± 0.05). Of the 19 ad libitum fed age-matched monkeys, 4 were overtly diabetic, and 6 others had significantly reduced glucose tolerance. Hyperinsulinemia did not develop in the weight-stabilized group, and β-cell response to glucose remained normal; both were significantly different from the exaggerated levels of the ad libitum fed group (P < 0.05). This form of obesity-associated type II diabetes and impaired glucose tolerance, thus, appears to be completely prevented or onset indefinitely delayed by sustained caloric restriction and maintenance of normal body composition.

The short insulin tolerance test is a simple method of estimating insulin resistance by measuring the rate of fall of blood glucose following the intravenous administration of insulin. To determine its reproducibility, 18 healthy subjects underwent duplicate insulin tolerance tests separated by at least 1 week. Intravenous insulin (0.05 units kg-1) was administered into an antecubital vein and arterialized venous samples were obtained from a retrogradely cannulated vein on the dorsum of the hand on the same side. The test was terminated with an intravenous glucose injection 15 min after the administration of insulin. The mean whole blood glucose concentration fell from 4.6 mmol l-1 to 2.8 mmol l-1 while plasma insulin concentrations rose to supraphysiological levels and declined exponentially. The glucose disappearance rate (Kitt) calculated from the slope of the fall in log transformed blood glucose between 3 and 15 min after insulin injection ranged from 2.1 to 6.5 (mean 4.4) % min-1 during the first visit and 1.7 to 7.4 (mean 4.4) % min-1 during the second. The ratio of the within-subject to between-subject variance of the test was 0.24, the within-subject coefficient of variation was 13% and the between-subject coefficient of variation 26%. The short insulin tolerance test is reproducible and could be used to measure insulin resistance in large-scale epidemiological studies.

1. Modelling analysis of intravenous glucose tolerance test glucose and insulin concentrations can provide measures of insulin sensitivity and metabolism from a single straightforward procedure. However, little is known of the effects of blood arterialization on model-derived parameters. 2. Intravenous glucose tolerance tests were carried out on 18 subjects, with measurement of glucose and insulin concentrations in simultaneously sampled non-arterialized and arterialized blood. Blood oxygen saturation, partial pressure of CO2 and pH were measured on both non-arterialized and arterialized blood during the intravenous glucose tolerance test. Using the minimal models of glucose disappearance and post-hepatic insulin delivery, measures of insulin sensitivity, glucose-dependent glucose disposal, firstand second-phase post-hepatic insulin responsiveness to glucose and plasma insulin elimination rate were derived from intravenous glucose tolerance test glucose and insulin concentrations in both arterialized and non-arterialized blood. 3. During the intravenous glucose tolerance test mean blood oxygen saturation was 6.7% higher, partial pressure of CO2 was 0.3 kPa lower and pH was 0.015 higher in arterialized than non-arterialized blood. Mean parameter values did not differ when derived from measurements made on non-arterialized and arterialized blood. Model-derived parameters were not related to the degree of arterialization, although there was some consistent variation with sampling site for parameters of glucose-dependent glucose disposal (Sg), first-phase post-hepatic insulin responsiveness (φ1) and insulin elimination (ni). 4. Measurements made on non-arterialized blood are suitable for analyses employing the minimal models of glucose disappearance and post-hepatic insulin delivery. Imprecision in some parameters may be diminished by adherence to a single sampling site.

The intravenous glucose tolerance test, IVGTT, has been used to evaluate patients in whom abnormalities in carbohydrate metabolism and diabetes mellitus are suspected. IVGTT, if analyzed using “minimal models”, or discrete-time methods, provides information on the sensitivity of glucose disappearance to insulin and on pancreatic sensitivity to glucose, information that cannot be obtained from direct analysis of the dynamic response alone. In a preliminary study, data obtained by intravenously injecting 18-FDG in four subjects was analyzed using a discrete-time model. The experimental details, the results and their implications will be discussed.

The glycaemic index (GI) is a food-scoring index based on blood glucose response (GR). The conventional orthodoxy of GI evolves around the concept of blood glucose appearance rate and factors associated with it. However, blood glucose concentration is a function of both the rate of glucose appearance into the systemic circulation and the rate of glucose disappearance. Irrespective of the concept of GI, the availability of insulin and the rate of energy expenditure (EE) have been shown to influence blood glucose concentration. Potassium (K) is strongly implicated with insulin secretion in addition to stimulating EE (2) . The aim of this research was to investigate the impact of K-induced EE on GR.

Minimal model analysis for insulin sensitivity has been validated against the glucose clamp and is an accepted method for estimating insulin sensitivity from IVGTT. However minimal model analysis requires a 3 h test and relevant expertise to run the mathematical model. The aim of this study was to suggest a simple predictor of minimal model analysis index using only 1 h IVGTT. We studied participants with different clinical characteristics who underwent 3 h regular (n = 336) or insulin-modified (n = 160) IVGTT, or 1 h IVGTT and euglycaemic–hyperinsulinaemic clamp (n = 247). Measures of insulin sensitivity were insulin sensitivity index estimated by minimal model analysis (SI) and the mean glucose infusion rate (clamp) (M). A calculated SI (CSI) predictor, $${\text{CS}}_{{\text{I}}} = {\text{ $ \alpha $ }} \times {K_{\text G} } \mathord{\left/ {\vphantom {{K_{G} } {{\left( {{\Delta {\text{AUC}}_{{{\text{INS}}}} } \mathord{\left/ {\vphantom {{\Delta {\text{AUC}}_{{{\text{INS}}}} } T}} \right. \kern-\nulldelimiterspace} T} \right)}}}} \right. \kern-\nulldelimiterspace} {{\left( {{\Delta {\text{AUC}}_{{{\text{INS}}}} } \mathord{\left/ {\vphantom {{\Delta {\text{AUC}}_{{{\text{INS}}}} } T}} \right. \kern-\nulldelimiterspace} T} \right)}}$$ , was suggested, based on the calculation of the rate of glucose disappearance K G and the suprabasal AUC of insulin concentration ΔAUCINS over T = 40 min. For all the participants, α was assumed equal to the regression line slope between K G/(ΔAUCINS/T) and SI in control participants. CSI and SI showed high correlation (R 2 = 0.68–0.96) and regression line slopes of approximately one in the majority of groups. CSI tended to overestimate SI in type 2 diabetic participants, but results were more reliable when CSI was computed with insulin-modified rather than regular IVGTT. CSI showed behaviours similar to SI as regards relationships with BMI, acute insulin response and sex. CSI showed good correlation with M (R 2 = 0.82). A short test can achieve a good approximation of minimal model analysis and clamp insulin sensitivity. The importance of a method such as CSI is that it allows analysis of IVGTT datasets with samples limited to 1 h.

In this chapter we evaluate the ability of the minimal model of glucose disappearance to describe experimental data collected from 9 diabetic patients controlled subcutaneously by an insulin pump. Two versions of the minimal model are used: the nonlinear classic minimal model developed by Bergman et al. (MM) and the linear approximation proposed by Fernandez et al. (LMM). All data windows (n = 13) show residuals that are correlated for both the LMM and MM (p-value 0.05). This study confirms that the minimal model of glucose disappearance, either the classic or linear version, is unable to describe the observed experimental data possibly as a result of the physiological constraints imposed by the minimal model approach on the system dynamics, together with possible errors derived from the unmeasured insulin dynamics. Further testing on more complex models should be performed.

UNLABELLED Virtually no information is available on glucose fluxes during a meal or glucose ingestion in adolescents. AIM To use a triple tracer approach to measure rates of appearance of ingested glucose (Ra(ogtt)), endogenous glucose production (EGP) and glucose disappearance (Rd) following an oral glucose bolus in adolescents. METHODS Eleven adolescents (4 M/7 F, 15 +/- 1 yr; 67.3 +/- 4.7 kg; 24 +/-2 kg/m2) underwent a frequent sampled oral glucose tolerance test (OGTT) (labelled with [6,6-2H2]glucose) combined with intravenous infusion of [1-(13)C]glucose and [U-(13)C6]glucose following an overnight fast. Formulas were developed to estimate glucose fluxes using one- or two-compartment models. RESULTS During the 7 h following the OGTT bolus, 9.8 +/- 2.3% of the ingested glucose was extracted by the liver, EGP was suppressed by 45 +/- 4% and Rd increased by 21 +/- 5%. CONCLUSIONS The triple tracer method provided accurate assessment of Ra(ogtt), EGP and Rd fluxes during an OGTT in adolescents. Thus, this method might provide novel insight on postprandial glucose fluxes in children/adolescents under various conditions.

In this study, intravenous glucose tolerance tests were performed in a group of insulin-dependent diabetic subjects who had no residual insulin secretion. Under these circumstances, it was possible to measure directly glucose-mediated glucose disappearance in response to intravenous glucose administration. Two models, the minimal model of unlabeled glucose kinetics and a linear two-compartment model, were identified from the observed plasma glucose data. The performances of those two models were compared on the basis of goodness-of-fit criteria and of practical identifiability. The results suggest the inadequacy of the minimal model to describe glucose-mediated glucose disappearance after glucose administration. In contrast, the considered two-compartment model was able to account for the observed glucose-mediated glucose dynamics. The two-compartment model exhibited a better performance, because it considers not only the effect of glucose per se on glucose production and glucose uptake, but also the glucose exchange dynamics between vascular and extravascular spaces.

In the identification of physiological systems it is often of practical interest knowing which time intervals during experiments provide most information on specific model parameters. This problem is usually approached using parameter sensitivities of model outputs. However, this kind of analysis does not provide always a correct answer, especially if strong correlation among the parameters is present. For this reason, the authors consider in this paper alternative approaches based on information-theoretic criteria. They use as a case study the widely used minimal model of glucose disappearance. Their results demonstrate the usefulness of one particular approach for defining the relevant time intervals for the identification of specific parameters.

In order to directly measure glucose-mediated effects on glucose disappearance, intravenous glucose tolerance tests were performed in insulin-dependent diabetic subjects without dynamic insulin response after glucose administration. Two models, the minimal model of unlabeled glucose kinetics and a linear two-compartment model, were identified from glucose data. The performances of those two models were compared on the basis of goodness-of-fit criteria and of practical identifiability. The results suggest the inadequacy of the the minimal model to describe glucose-mediated glucose disappearance after glucose administration. The considered two-compartment model seems to be sufficiently complex to account for the observed glucose-mediated glucose dynamics.

Troglitazone (T) and d-chiroinositol (DCI) have been reported to improve insulin resistance associated with obesity and NIDDM. We tested whether these compounds counteract the insulin antagonistic effects of recombinant human GH. Male Wistar rats were allocated to 4 different treatment groups, rhGH (n=8), rhGH+T (n=7), rhGH+DCI (n=8) and control (saline, n=8). rhGH (2 IU/100 g/day) was injected sc twice daily for 2 days. T and DCI were given (20 mg/day) po for 5 days preceding and 2 days along with rhGH. Euglycemic hyperinsulinemic clamp studies were done to assess the hepatic glucose output (HGO) and glucose disappearance rate (GDR). Fasting plasma glucose, insulin, serum FFA and basal HGO were similar in all 4 treatment groups. During the hyperinsulinemic clamp which raised plasma insulin levels to 7.2 +/- 0.4 ng/ml, HGO was suppressed in the control and rhGH+T treated rats but not in the rats treated with rhGH and rhGH+DCI. GDR decreased in the rats which received rhGH (18.1 +/- 5.8 vs 30.3 +/- 5.2 mg/kg/min) compared to the control rats. The rats given either T (24.7 +/- 2.7) or DCI (31.4 +/- 2.7) along with rhGH showed comparable GDR to the control rats. These results indicated that rhGH induced hepatic and peripheral insulin resistance. Troglitazone counteracted the insulin-antagonistic action of rhGH both in the liver and the peripheral tissues. DCI was effective in offsetting peripheral insulin resistance but without any effect on hepatic insulin resistance associated with rhGH treatment.

In this paper we analyze a mathematical model (called MINMOD) that describes the interactions between glucose and insulin in human subjects, in order to realize an adequate model for ill patients, suffering from Diabetes Mellitus (DM) Type 2. Our model has been tested on the basis of clinical data and it has correctly reproduced glucose and insulin reply and temporal evolution, according to experimental data test. This model could, in the future, contribute to predict glucose and insulin behavior in ill patients and suggest the adequate treatment.

During the last decade, there has been an increasing number of publications reporting concentrations of free dissociable insulin-like growth factor I (IGF-I) in serum or plasma. The goal for attempting to measure free IGF-I in a serum sample in vitro has been to obtain information about the bioactivity of IGF-I in target tissues, and thus relate a measurable parameter to biological responses such as longitudinal growth or glucose disappearance rate. In this review, the serum free IGF-I approach is placed into a physiological perspective. In addition, methodological aspects are discussed and suggestions for the validation of free IGF-I assays are presented.

The cardiovascular protective properties of hormone replacement therapy can be hampered when a progestin is used. Aim: To assess the effects of hormone replacement therapy with progestins on insulin sensitivity and lipid profile. Patients and methods: Twelve healthy postmenopausal women aged 45 to 55 years old were studied. Blood lipids and insulin sensitivity, determined using the insulin tolerance test, were measured at baseline and after three months of hormone replacement therapy using conjugated estrogens, 0.625 mg/day and medroxyprogesterone acetate, 5 mg/day. Results: The glucose disappearance constant was higher after the treatment period than at baseline (5.3±0.8 and 4.7±0.8%/min respectively, p = 0.005). Serum LDL cholesterol was also lower at the end of treatment period (124.5 ± 30.2 and 140±25.4 mg/dl respectively, p = 0.019). Conclusions: In this group of postmenopausal women, a period of three months of hormone replacement therapy with a progestin improved insulin sensitivity and lowered LDL cholesterol levels (Rev Méd Chile 2001; 129: 989-94)

Objective—To determine reference values and test variability for glucose tolerance tests (GTT), insulin tolerance tests (ITT), and insulin sensitivity tests (IST) in cats. Animals—32 clinically normal cats. Procedure—GTT, ITT, and IST were performed on consecutive days. Tolerance intervals (ie, reference values) were calculated as means ± 2.397 SD for plasma glucose and insulin concentrations, half-life of glucose (T1/2glucose), rate constants for glucose disappearance (Kglucose and Kitt), and insulin sensitivity index (SI). Tests were repeated after 6 weeks in 8 cats to determine test variability. Results—Reference values for T1/2glucose, Kglucose, and fasting plasma glucose and insulin concentrations during GTT were 45 to 74 minutes, 0.93 to 1.54 %/min, 37 to 104 mg/dl, and 2.8 to 20.6 µU/ml, respectively. Mean values did not differ between the 2 tests. Coefficients of variation for T1/2glucose, Kglucose, and fasting plasma glucose and insulin concentrations were 20, 20, 11, and 23%, respectively. Reference values for Kitt were 1.14 to 7.3%/min, and for SI were 0.57 to 10.99 × 10-4 min/µU/ml. Mean values did not differ between the 2 tests performed 6 weeks apart. Coefficients of variation for Kitt and SI were 60 and 47%, respectively. Conclusion and Clinical Relevance—GTT, ITT, and IST can be performed in cats, using standard protocols. Knowledge of reference values and test variability will enable researchers to better interpret test results for assessment of glucose tolerance, pancreatic β-cell function, and insulin sensitivity in cats. (Am J Vet Res 2001;62:630–636)

The effect of long-term strenuous resistance training on glucose effectiveness (SG) was examined by comparing 11 strength-trained and 20 sedentary males by a minimal model approach. Lean body mass (LBM) was measured by hydrostatic weighing. The LBM in strength-trained subjects (65.7 +/- 3.1 kg) was significantly larger than in sedentary subjects (56.6 +/- 1.2 kg, P < .01). The glucose disappearance constant ([KG] 3.07% +/- 0.45% min(-1)) and insulin sensitivity ([SI] 17.5 +/- 2.0 x 10(-5) x min(-1) x pmol/L(-1)) in strength-trained subjects were significantly higher than in sedentary subjects (2.06% +/- 0.14% x min(-1) and 10.3 +/- 1.2 x 10(-5) x min(-1) x pmol/L(-1), P < .05). SG in strength-trained subjects (0.024 +/- 0.003 min(-1)) was significantly higher than in sedentary subjects (0.018 +/- 0.001 min(-1), P < .05). These results thus suggest that the improved glucose tolerance in strength-trained subjects was due to increased SG and SI.

Equal volumes of teleost fish (tilapia), Lewis rat, or CD-1 mouse islets were transplanted under the kidney capsules of streptozotocin-diabetic athymic nude mice. Nonfasting blood glucose levels were monitored in recipient mice over a period of 30 days. Mean nonfasting blood glucose levels in recipients of tilapia ( n = 7), rat ( n = 8), and murine ( n = 8) islets were 78.8, 77.0, and 115 mg/dl, respectively. Mean blood glucose levels were significantly higher in recipients of murine islets than in recipients of fish and rat islets. After Day 30, intraperitoneal glucose tolerance tests were performed on recipient mice. Mean fasted blood glucose levels in mouse, rat, and fish islet recipients were 113.3, 89.8, and 72.7 mg/dl, respectively. All three groups of recipient mice had similar glucose tolerance profiles with mean glucose disappearance rates ( K values) between 4.3 and 5.7. Tilapia islet grafts resulted in a significantly lower baseline for blood glucose values than either rat or mouse islet grafts.

In this paper the domain of validity of the unlabelled and labelled minimal models of glucose disappearance is studied. Labelled intravenous glucose tolerance tests were performed in six normal subjects using 3-3H-glucose as the tracer. Insulin and unlabelled glucose data were analysed with the minimal model of glucose disappearance. The model provides estimates of glucose effectiveness (SG) and insulin sensitivity (SI) which measure the effects of glucose per se and insulin on both glucose production and disposal. Insulin and labelled glucose data were analysed with the labelled minimal model of tracer disappearance. Estimates of glucose effectiveness (SG*) and insulin sensitivity (SI*) which reflect disposal processes only were calculated. The results of the two minimal models suggest two areas of model error. Firstly, the relationships between labelled and unlabelled parameters contradict the theoretical expectation. Secondly, the time-course of hepatic glucose production is unrealistic. Possible sources of these inconsistencies are an inadequate description of the glucose and/or insulin effect upon hepatic glucose production, and the assumption that glucose kinetics are monocompartmental. The monocompartmental description of glucose kinetics may affect both model parameters and hepatic glucose production and this leads to a critical reexamination of the previously published validation studies in which the minimal model metabolic indices have been compared with the analogous indices measured during glucose clamp studies.

The approximations embedded in the single compartment description of glucose kinetics used in the minimal models are investigated using a model of the glucose-insulin system, to generate a high number of noisy synthetic data sets of glucose, tracer glucose and insulin plasma concentrations during an IVGTT, which are then analyzed with the minimal models of glucose and tracer glucose disappearance. The metabolic indices of glucose effectiveness and insulin sensitivity (liver+periphery and periphery) such obtained are compared with the “true” ones yielded by the model generating the data. Results show that (1) the minimal model glucose effectiveness is uncorre1ated with the corresponding simulationmodel index, (2) minimal model insulin sensitivity (liver+periphery) is well correlated with the simulation model insulin sensitivity, but severely underestimates it, (3) minimal model clearance rate is well correlated with the simulation model one, and (4) insulin sensitivity (periphery) estiDiated by the minimal model slightly underestimates the corresponding measure of the simulation model.

The influence of normal late pregnancy on insulin action and insulin secretion was studied in the Sprague-Dawley female rats. On 20th day after mating, intravenous glucose tolerance test(IVGTT) was performed in non pregnant control and pregnant rats. As results of IVGTT, glucose disappearance rate was not significantly different in both groups, but secretory response of insulin was significantly(p insulin/glucose - 5 min) was highly significantly (r=0.62, p-glucose incorporated into glycogen after IVGTT were significantly(p