Minimal Model Analysis Research Articles

Optimisation of the frequently sampled intravenous glucose tolerance test to reduce urinary glucose spilling in horses

The frequently sampled i.v. glucose tolerance test (FSIGTT) is used to evaluate glucose and insulin dynamics in horses, but it has not been determined whether urinary glucose spilling (UGS) affects results. UGS occurs in horses during the FSIGTT and this problem can be minimised by adjusting the dextrose and insulin dosages used. Six mature mares were included in this study. In the first phase, 6 FSIGTT procedures were performed in each horse to evaluate 6 different dextrose dosages. Six different insulin dosages were evaluated during the second phase of the study after administration of 300 mg/kg bwt dextrose. Area under the glucose (AUCg) and insulin (AUCi) curves were calculated and minimal model analyses performed. UGS was measured in the third and fourth phases of the study during the combined glucose insulin test and established FSIGTT. A new FSIGTT was developed and evaluated. Positive linear effects of dextrose dosage on AUCg, AUCi and acute insulin response to glucose were detected, with AUCg reaching a plateau at doses > or =200 mg/kg bwt. Insulin dosage had an inverse linear effect on AUCg, but other values remained unaffected. UGS occurred during all 3 tests and was the highest for the established FSIGTT and the lowest for the new FSIGTT. The type of FSIGTT performed did not affect minimal model results. Results indicate that the dextrose dosage of 300 mg/kg bwt used in the established FSIGTT is too high. UGS can be reduced by lowering the dextrose dosage to 100 mg/kg bwt. A new FSIGTT involving the administration of 100 mg/kg bwt dextrose followed by 20 mu/kg bwt insulin 20 min later is recommended for use in horses because this test provides adequate data for minimal model analysis while minimising UGS.

Type 2 diabetes mellitus with pancreatic β cell dysfunction in 3 horses confirmed with minimal model analysis

Type 2 diabetes mellitus (T2DM) is diagnosed rarely in equine practice although it may be under-recognised. A greater awareness of the condition and therapeutic considerations would be to the benefit of such cases presenting in practice. More investigation into the pharmacological management of these cases is needed. Three cases of diabetes mellitus were investigated using a specific test for insulin sensitivity and pancreatic beta cell function in order to define accurately and characterise the existence of T2DM in all 3 subjects. The insulin-modified frequently sampled i.v. glucose tolerance test was performed in each case and the data so obtained were subject to minimal model analysis of insulin-glucose dynamics. Cases were then monitored following treatment using a combination of dietary modification, metformin, glibenclamide and pergolide. Marked insulin resistance was identified in each case and, furthermore, severe pancreatic beta cell dysfunction was present therefore classifying each case as end stage T2DM. Treatment was nevertheless associated with restoration of normoglycaemia in all cases. T2DM in horses may be more common than generally considered.In some cases individuals may respond to therapy aimed at restoring insulin sensitivity and pancreatic function. Drugs used in other species for the treatment of T2DM have not yet been adequately tested in horses. T2DM should be considered as an important differential diagnosis in mature to elderly horses and ponies suffering from weight loss, polydipsia and polyuria. Clinicians should be encouraged to offer treatment and management advice when such cases are encountered.

An empirical index of insulin sensitivity from short IVGTT: validation against the minimal model and glucose clamp indices in patients with different clinical characteristics

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 (S(I)) and the mean glucose infusion rate (clamp) (M). A calculated S(I) (CS(I)) predictor, CS(I) = Alpha X K(G)/(DeltaAUC(INS)/T), was suggested, based on the calculation of the rate of glucose disappearance K(G) and the suprabasal AUC of insulin concentration DeltaAUC(INS) over T = 40 min. For all the participants, alpha was assumed equal to the regression line slope between K(G)/(DeltaAUC(INS)/T) and S(I) in control participants. CS(I) and S(I) showed high correlation (R(2) = 0.68-0.96) and regression line slopes of approximately one in the majority of groups. CS(I) tended to overestimate S(I) in type 2 diabetic participants, but results were more reliable when CS(I) was computed with insulin-modified rather than regular IVGTT. CS(I) showed behaviours similar to S(I) as regards relationships with BMI, acute insulin response and sex. CS(I) 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 CS(I) is that it allows analysis of IVGTT datasets with samples limited to 1 h.

Evaluation of different methods for assessment of insulin sensitivity in Göttingen minipigs: introduction of a new, simpler method

The use of animal models in diabetes research requires reliable tests for evaluation of insulin sensitivity and beta-cell function. Minipigs are being increasingly used in metabolic research, and the aim of this study was to compare different tests and indexes for evaluation of insulin sensitivity and beta-cell function in Göttingen minipigs. Hyperinsulinemic, isoglycemic clamp, intravenous (IVGTT) and oral glucose tolerance tests (OGTT), and a modified insulin tolerance test were performed in minipigs fed either low- or high-energy diet. Furthermore, the reproducibility of IVGTT-derived parameters was assessed. Previously described insulin sensitivity indexes [steady-state glucose infusion rate/glucose concentration/insulin concentration from clamp (M/G/I); oral glucose insulin sensitivity (OGIS) and ISI(comp) from OGTT; S(I) from minimal model analysis of IVGTT; and quantitative insulin sensitivity check index from fasting values] were calculated together with an insulin sensitivity index from the modified insulin tolerance test (ISI(ITT)) and a new simple index (S2) derived from the first 30 min of the IVGTT. beta-Cell function was assessed from the IVGTT and the OGTT. Reproducibility of the IVGTT-derived parameters was calculated as median intraindividual coefficient of variation (CV%).M/G/I correlated significantly only with S2 (P < 0.05, r = 0.54). S2 furthermore correlated with S(I) (P < 0.001, r = 0.81), ISI(ITT) (P < 0.001, r = 0.57), and the two indexes from OGTT, ISI(comp) (P < 0.001, r = 0.78) and OGIS (p < 0.05, r = 0.48). No correlation was found between beta-cell function indexes from OGTT and IVGTT. The median CV% of the new S2 index was 13. In conclusion, the new simple index of insulin sensitivity, S2, was revealed to be useful for evaluation of insulin sensitivity in pigs.

Insulin resistance, beta cell dysfunction and visceral adiposity as predictors of incident diabetes: the Insulin Resistance Atherosclerosis Study (IRAS) Family study.

Central obesity, insulin resistance and beta cell dysfunction are independent risk factors for incident type 2 diabetes, although few studies have used detailed measures of these disorders. Our objective was to study the association of directly measured visceral and subcutaneous adipose tissue (VAT, SAT), insulin sensitivity (S (I)) and the acute insulin response (AIR) with incident type 2 diabetes. Participants were 1,230 Hispanic-Americans and African-Americans in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study who were free of type 2 diabetes at baseline (2000-2002). S (I) and AIR were determined from frequently sampled IVGTTs with minimal model analysis. VAT and SAT were determined by computed tomography. Impaired fasting glucose and type 2 diabetes were defined according to American Diabetes Association criteria. Incident type 2 diabetes was diagnosed in 90 participants after 5 years. After adjustment for age, sex, ethnicity, centre, impaired fasting glucose, triacylglycerol, HDL-cholesterol and systolic BP, both S(I) and AIR were inversely associated with type 2 diabetes (S (I), OR 0.53, 95% CI 0.39-0.73; AIR, OR 0.22, 95% CI 0.14-0.34 per SD; both p < 0.001), while both VAT and SAT were positively associated with type 2 diabetes (VAT, OR 1.68, 95% CI 1.22-2.33; SAT, OR 1.49, 95% CI 1.13-1.99; both p < 0.01). In a model including all four factors, S (I) and AIR (S (I), OR 0.55, 95% CI 0.37-0.80; AIR, OR 0.21, 95% CI 0.13-0.33; both p < 0.01) were significant predictors of type 2 diabetes, although associations with VAT and SAT were no longer significant. A significant sex x VAT interaction indicated a stronger association of VAT with type 2 diabetes in women than in men. Insulin resistance, beta cell dysfunction and VAT predicted incident type 2 diabetes, with evidence of a stronger association of VAT with type 2 diabetes among women.

Effects Of Exercise During Pregnancy On Maternal Insulin Sensitivity And Offspring Growth

Epidemiological studies have demonstrated a relationship between abnormal fetal growth and increased risk of childhood obesity and later adult disease. Previous studies have suggested that the maternal metabolic environment, in particular a reduction in maternal insulin sensitivity, contributes significantly to fetal growth. Regular aerobic exercise may therefore influence offspring size by regulating appropriate nutrient supply to the fetus, through an effect on maternal insulin sensitivity. PURPOSE: To determine the effects of regular exercise during pregnancy on maternal insulin sensitivity, potential hormonal regulators of fetal growth, neonatal and offspring size. METHODS: Healthy nulliparous women (30±4 yrs, BMI 25.5±4 kg/m2) were randomized to either a monitored stationary cycling program (n=47) or control (n=37) from 20 weeks gestation to term. Maternal insulin sensitivity was assessed at 19 and 35 weeks using minimal model analysis of the frequently sampled intravenous glucose tolerance test. Neonatal auxology was assessed within 48 hours of delivery and at one year. RESULTS: Offspring of exercisers had lower birth weights (Z-score control 0.24±0.8; exercise 0.19±0.9; p=0.03) and BMI at birth (Z-score control 0.40±0.9; exercise -0.01±0.04; p=0.04). The reduction in maternal insulin sensitivity with advancing gestation was not affected by exercise (p=0.45), and was unrelated to offspring birth size. However, exercise offspring had lower cord serum IGF-II (p=0.04) and a trend towards lower IGF-I (p=0.08), supporting an effect of exercise on endocrine regulation of fetal growth. Offspring size at one year remained lower in the exercise group, although not statistically significant due to reduced sample size at follow-up (BMI Z-score control -0.09±1.1; exercise -0.40±1.1; p=0.26). CONCLUSIONS: Regular exercise resulted in lower birth weights and leaner neonatal offspring with preliminary follow-up data suggesting a persistent effect at 1 year. However, exercise effects on offspring growth occurred independently of alterations in insulin sensitivity or markers of the maternal environment and unlike previous studies, maternal insulin sensitivity was not predictive of offspring birth size.

Variation in IGF2BP2 Interacts With Adiposity to Alter Insulin Sensitivity in Mexican Americans

Genome-wide association studies showed variation in insulin-like growth factor-2 binding protein 2 (IGF2BP2) to be associated with type 2 diabetes mellitus (T2DM). We examined a 20-kb region of IGF2BP2 for association with T2DM-related quantitative traits in Mexican American families of a proband with gestational diabetes mellitus (GDM) from the BetaGene study. We genotyped 14 single-nucleotide polymorphisms (SNPs) in 717 individuals from 146 families phenotyped by oral glucose tolerance test (OGTT), intravenous glucose tolerance tests (IVGTTs) with minimal model analysis, and dual-energy X-ray absorptiometry scan for percent body fat. Three SNPs and one SNP combination that captured the majority of the variation in the region were tested for association with T2DM-related quantitative traits using a variance components framework. After correction for multiple testing, rs11705701 showed association with percent body fat (P(ACT) = 0.041) with body fat decreasing approximately 1.5-2% per copy of the A allele. We next tested whether the interaction between rs11705701 and body fat was associated with T2DM-relative quantitative traits. rs11705701 was significantly associated with insulin sensitivity (Bonferroni P = 0.028) and marginally associated with OGTT 2-h insulin (Bonferroni P = 0.066) and disposition index (DI) (Bonferroni P = 0.072). We conclude that rs11705701 in IGF2BP2 is associated with body fat and this effect on body fat influences insulin resistance which may contribute to T2DM risk.

Insulin Response in Relation to Insulin Sensitivity

OBJECTIVEThe purpose of this study was to characterize differences in the acute insulin response to glucose (AIRg) relative to insulin sensitivity (SI) in black and white premenopausal normoglycemic South African women matched for body fatness.RESEARCH DESIGN AND METHODSCross-sectional analysis including 57 black and white South African women matched for BMI, SI, AIRg, and the disposition index (AIRg × SI) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography.RESULTSSI was significantly lower (4.4 ± 0.8 vs. 9.4 ± 0.8 and 2.9 ± 0.8 vs. 6.0 ± 0. 8 × 10−5 min−1/[pmol/l], P < 0.001) and AIRg was significantly higher (1,028 ± 255 vs. 352 ± 246 and 1,968 ± 229 vs. 469 ± 246 pmol/l, P < 0.001), despite similar body fatness (30.9 ± 1.4 vs. 29.7 ± 1.3 and 46.8 ± 1.2 vs. 44.4 ± 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of β-cell function, was not different between ethnic groups (3,811 ± 538 vs. 2,966 ± 518 and 3,646 ± 485 vs. 2,353 ± 518 × 10−5 min, P = 0.10). Similar results were obtained for the OGTT-derived measures.CONCLUSIONSBlack South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate β-cell response for the level of insulin sensitivity.

Effects of low-dose oligofructose treatment administered via nasogastric intubation on induction of laminitis and associated alterations in glucose and insulin dynamics in horses

To ascertain whether laminitis can be induced via administration of oligofructose (OF) at doses of 5.0 and 7.5 g/kg in horses and to assess glucose and insulin dynamics before and after treatment. 19 adult horses. Horses were fed OF (1.0 g/kg) mixed with oats for 6 days. Oligofructose at doses of 5.0 and 7.5 g/kg was then mixed with 4 L of water and administered (0 hours) to 8 (group A) and 4 (group B) horses, respectively, via nasogastric intubation; 8 horses received water alone. One horse in group A that did not develop laminitis was subsequently treated again and included in group B. Before and at intervals after treatment, resting plasma glucose and serum insulin concentrations were measured and frequently sampled IV glucose tolerance tests were performed. Area under the glucose curve (AUCg) and area under the insulin curve (AUCi) were calculated, and minimal model analyses were performed. 3 of 8 horses in group A and all 4 horses in group B developed laminitis. Significant treatment-time effects were detected for resting plasma glucose concentrations and AUCg. Among horses in group A, mean AUCg values at 24 and 48 hours were 34% and 32% higher, respectively, than the mean value at 24 hours. Treatment groups did not differ significantly with respect to resting serum insulin concentration, AUCi, or minimal model analysis results. In horses, laminitis can be induced and glucose dynamics altered via nasogastric administration of 5.0 g of OF/kg. An alteration in insulin dynamics was not detected following treatment with OF.

Bayesian and non-Bayesian analysis of mixed-effects PK/PD models based on differential equations

Compartmental analysis is used to model dynamic biological systems and widely applied to study the kinetics of drugs in the body. We used compartmental mixed-effects modeling, which quantifies the between- and within-subject variability, to analyze population data based on a pharmacokinetic model where predictions were obtained from a solution of a system of ordinary differential equations (ODEs). Non-Bayesian software (nlmeODE in R, or, NLINMIX with ODEs in SAS) and Bayesian software (WBDiff in WinBUGS) enabled the mixed-effect analysis of complicated systems of ODEs with and without a closed-form solution. Our aim was to use simulation data and real data from the glucose-insulin minimal model study to illustrate the applicability of Bayesian and non-Bayesian methods for compartmental analysis of population data. Our results indicated that the two methods are numerically stable and provided accurate parameter estimates for the simulation data based on the standard PK/PD model. However, in the analysis of glucose-insulin minimal model, the Bayesian method was preferred, since it provided a satisfactory solution (statistically) to the minimal model without approximation by linearization required by the non-Bayesian algorithm.

First-Phase Insulin Secretion Restoration and Differential Response to Glucose Load Depending on the Route of Administration in Type 2 Diabetic Subjects After Bariatric Surgery

OBJECTIVE—The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery.RESEARCH DESIGN AND METHODS—Peripheral insulin sensitivity and β-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured.RESULTS—The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 ± 816 to 577 ± 155 pmol · l−1 · min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 ± 24.4 to 424.4 ± 64.3 pmol · l−1 · min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration.CONCLUSIONS—Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.

Alterations in Glucose Disposal in Sleep-disordered Breathing

It is well established that sleep-disordered breathing (SDB) is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. However, data on whether SDB alters in vivo kinetics of glucose and insulin are lacking. The primary goal of this study was to use the frequently sampled intravenous glucose tolerance test (FSIVGTT) in subjects with and without SDB to model the in vivo kinetics of glucose and insulin. Minimal model analysis of the FSIVGTT data was used to derive parameters of insulin sensitivity, glucose effectiveness (a measure of the ability of glucose to mediate its own disposal), and pancreatic beta-cell function. A total of 118 nondiabetic subjects underwent polysomnography, the FSIVGTT, and body composition measurements including determination of percent body fat. Compared with normal subjects (apnea-hypopnea index < 5 events/h), those with mild, moderate, and severe SDB displayed a 26.7, 36.5 and 43.7% reduction in insulin sensitivity, respectively, independent of age, sex, race, and percent body fat. The disposition index, an integrated measure of pancreatic beta-cell function, was also reduced in patients with moderate to severe SDB. The decrease in insulin sensitivity and the disposition index were correlated with the average degree of oxyhemoglobin desaturation. In contrast, glucose effectiveness was negatively correlated with the frequency of respiratory event-related arousals. The results of this study suggest that, independent of adiposity, SDB is associated with impairments in insulin sensitivity, glucose effectiveness, and pancreatic beta-cell function. Collectively, these defects may increase the risk of glucose intolerance and type 2 diabetes mellitus in SDB.

361 POSTER FGFR4 Y367C: Contributes to a constitutively active FGFR4 and tumour aggressiveness in breast cancer cell line

Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs.Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection.Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus.The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.

Impact of Menstrual Cycle Phase on Insulin Sensitivity Measures and Fasting Lipids

There is evidence to suggest that insulin sensitivity may vary in response to changes in sex hormone levels. However, the results of human studies designed to investigate changes in insulin sensitivity through the menstrual cycle have proved inconclusive. The aims of this study were to 1) evaluate the impact of menstrual cycle phase on insulin sensitivity measures and 2) determine the variability of insulin sensitivity measures within the same menstrual cycle phase. A controlled observational study of 13 healthy premenopausal women, not taking any hormone preparation and having regular menstrual cycles, was conducted. Insulin sensitivity (Si) and glucose effectiveness (Sg) were measured using an intravenous glucose tolerance test (IVGTT) with minimal model analysis. Additional surrogate measures of insulin sensitivity were calculated (homoeostasis model for insulin resistance [HOMA IR], quantitative insulin-to-glucose check index [QUICKI] and revised QUICKI [rQUICKI]), as well as plasma lipids. Each woman was tested in the luteal and follicular phases of her menstrual cycle, and duplicate measures were taken in one phase of the cycle. No significant differences in insulin sensitivity (measured by the IVGTT or surrogate markers) or plasma lipids were reported between the two phases of the menstrual cycle or between duplicate measures within the same phase. It was concluded that variability in measures of insulin sensitivity were similar within and between menstrual phases.

Co-associations between insulin sensitivity and measures of liver function, subclinical inflammation, and hematology

Clustering of risk factors for coronary heart disease and diabetes is well established, particularly in relation to insulin resistance. To determine whether evaluation of risk factor clustering will contribute to risk assessment, it is first necessary to discriminate co-association between risk factors from correlation. We undertook this in a large homogenous group, using a sophisticated measure of insulin sensitivity and a broad range of risk factors. Cross-sectional analysis of an occupational cohort using regression and factor analyses was performed. Subjects were 472 apparently healthy white men. The main outcome measures were insulin sensitivity, S I, by minimal model analysis of the intravenous glucose tolerance test plus liver function and hematologic variables, including the inflammation indices, leukocyte count, and erythrocyte sedimentation rate. The S I correlated independently with serum γ-glutamyl transferase (GGT), aspartate transaminase, and alkaline phosphatase activities; blood pressure; leukocyte count; and erythrocyte sedimentation rate ( P < .01). On factor analysis, the factor that explained the greatest proportion of the variance (56.7%) included, in decreasing order of factor loading, triglycerides, S I (negative), body mass index, high-density lipoprotein cholesterol (negative), insulin, uric acid, and GGT activity (loadings >0.40). Mean arterial pressure was not a feature (loading 0.29), neither were indices of subclinical inflammation. In apparently healthy men, blood pressure and indices of subclinical inflammation do not cluster with other insulin resistance–related risk factors, despite correlating with insulin sensitivity. In contrast, both GGT activity and uric acid concentrations correlated with insulin sensitivity and co-associated with insulin resistance–related risk factors and are therefore components of a true risk factor cluster.

Insulin Sensitivity, Food Intake, and Cravings with Premenstrual Syndrome: A Pilot Study

The objective of this pilot study was to evaluate possible differences in insulin sensitivity, food intake, and cravings between the follicular and luteal phases of the menstrual cycle in women with premenstrual syndrome (PMS). Subjects were screened for PMS using the Penn Daily Symptom Rating (DSR) scale. Each subject had two overnight admissions (once in each cycle phase) to the Hospital of the University of Pennsylvania. They performed 3-day diet histories prior to each hospitalization. After admission, subjects received dinner and a snack, then were fasted until morning, when they underwent a frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity was determined by Minimal Model analysis. Blinded analysis of diet histories and inpatient food intake was performed by a registered dietitian. There was no difference found in insulin sensitivity between cycle phases (n = 7). There were also no differences in proportions of macronutrients or total kilocalories by cycle phase, despite a marked difference in food cravings between cycle phase, with increased food cravings noted in the luteal phase (p = 0.002). Total DSR symptom scores decreased from a mean of 186 (+/-29.0) in the luteal phase to 16.6 (+/-14.2) in the follicular phase. Women in this study consumed relatively high proportions of carbohydrates (55%-64%) in both cycle phases measured. These findings reinforce the suggestion that although the symptom complaints of PMS are primarily confined to the luteal phase, the neuroendocrine background for this disorder may be consistent across menstrual cycle phases.

In vivo and in vitro studies of GAD-antibody positive subjects with Type 2 diabetes: A distinct sub-phenotype

The purpose of this study was to determine if immune mechanisms in GAD positive patients’ contribute to the pathogenesis of a specific sub-type of Type 2 diabetes. GAD positive ( n = 8) and GAD negative ( n = 8) subjects diagnosed with Type 2 diabetes were matched for age, gender, body mass index, duration of diabetes and glycaemic control. All subjects underwent an insulin-modified frequently sampled intravenous glucose tolerance test to measure insulin sensitivity and insulin secretory function with minimal model analysis. In addition, BRIN-BD11 clonal β-cells were supplemented with patients’ sera to determine basal and alanine-stimulated insulin secretion and terminal complement complex (TCC) formation. Both groups were severely insulin resistant (0.56 ± 0.17 vs. 0.99 ± 0.33 10 −4 min −1/(μU ml −1) for GADneg and GADpos, respectively) but the GAD negative subjects had a higher basal (87 ± 11 vs. 58 ± 14 pmol l −1, p < 0.05) and glucose-stimulated insulin secretion (ΔAUCins 0.96 ± 0.12 vs. 0.60 ± 0.12 pmol/(l −1 min), p < 0.05). In vivo measures of insulin secretion were negatively correlated with TCC formation, independent of antibody status. In conclusion, GAD positive subjects initially diagnosed with Type 2 diabetes are unable to compensate for insulin resistance due to more pronounced β-cell impairment. TCC formation may be partly responsible for the insulin secretory dysfunction associated with this specific sub-type of Type 2 diabetes.

Alternative Methods of Insulin Sensitivity Assessment in Obese Children and Adolescents

To validate fasting indexes against minimal model analysis (MMOD) of the frequently sampled intravenous glucose tolerance test (FSIVGTT) in an obese pediatric population. FSIVGTT-MMOD results were compared with homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin with the sample stratified by sex, puberty, and sensitivity index (S(i)) median in 191 children (82 males and 109 females, 13.9 +/- 2.9 years of age, BMI 36.9 +/- 6.2 kg/m(2), BMI SD score 6.1 +/- 1.6). Across pubertal groups, correlation coefficients between S(i) and HOMA-IR ranged from -0.43 to -0.78 in males and from -0.53 to -0.57 in females (age and BMI adjusted, P < 0.05 in all instances). Similar results were seen for fasting insulin. In females, the relationship was significantly weaker in more-insulin-resistant subjects. The validity of fasting indexes in explaining S(i) was sex dependent, varied with pubertal stage, and in females was influenced by degree of insulin sensitivity. In obese pediatric populations, we generally discourage the use of fasting indexes, although the validity varies within subgroups.

Effects of an intravenous endotoxin challenge on glucose and insulin dynamics in horses

To evaluate the effects of endotoxin administered IV on glucose and insulin dynamics in horses. 16 healthy adult mares. Each week of a 2-week randomized crossover study, each horse received an IV injection (duration, 30 minutes) of Escherichia coli O55:B5 lipopolysaccharide (LPS) in 60 mL of sterile saline (0.9% NaCl) solution (20 ng/kg) or sterile saline solution alone (control treatment). Frequently sampled IV glucose tolerance test procedures were performed at 24 hours before (baseline) and 24 and 48 hours after injection; glucose and insulin dynamics were assessed via minimal model analysis. 13 of 16 horses had a clinical response to LPS, which was characterized by mild colic and leukopenia. Before treatment, mean +/- SD insulin sensitivity was 2.9 +/- 1.9 x 10(4) L x min(1) x mU(1); this significantly decreased to 0.9 +/- 0.9 x 10(4) L x min(1) x mU(1) 24 hours after treatment (69% reduction) and was 1.5 +/- 0.9 x 10(4) L x min(1) x mU(1) 48 hours after treatment. At baseline, mean +/- SD acute insulin response to glucose was 520 +/- 196 mU x min x L(1); this significantly increased to 938 +/- 620 mU x min x L(1) (80% increase) and 755 +/- 400 mU x min x L(1) (45% increase) at 24 and 48 hours after LPS treatment, respectively. Compared with baseline values, insulin sensitivity was decreased for 24 hours after IV injection of LPS, and affected horses had a compensatory pancreatic response. These disturbances in glucose and insulin dynamics may contribute to development of laminitis in horses.

Effects of long-term oral administration of levothyroxine sodium on glucose dynamics in healthy adult horses

To determine the effects of long-term oral administration of levothyroxine sodium (L-T(4)) on glucose dynamics in adult euthyroid horses. 6 healthy adult mares. Horses received L-T(4) (48 mg/d) orally for 48 weeks. Frequently sampled IV glucose tolerance test procedures were performed on 3 occasions (24-hour intervals) before and at 16, 32, and 48 weeks during the treatment period. Data were assessed via minimal model analysis. The repeatability of measurements was evaluated. During treatment, body weight decreased significantly from the pretreatment value; mean +/- SD weight was 49 +/- 14 kg, 43 +/- 7 kg, and 25 +/- 18 kg less than the pretreatment value at weeks 16, 32, and 48, respectively. Compared with pretreatment findings, 1.8-, 2.4-, and 1.9-fold increases in mean insulin sensitivity (SI) were detected at weeks 16, 32, and 48, respectively; SI was negatively correlated with body weight (r = -0.42; P < 0.001). During treatment, glucose effectiveness increased and the acute insulin response to glucose decreased. Overall mean within-horse coefficients of variation were 5% and 29% for plasma glucose and serum insulin concentrations, respectively, and 33%, 26%, and 23% for SI, glucose effectiveness, and the acute insulin response to glucose, respectively. Long-term administration of L-T(4) was associated with weight loss and increased SI in adult euthyroid horses, although other factors may have confounded results. Levothyroxine sodium may be useful for the treatment of obesity and insulin resistance in horses, but further studies are required.