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The measurement of metabolites during intravenous or nutritional challenges may improve the identification of novel metabolic signatures which are not detectable in the fasting state. Here, we comprehensively characterized the plasma metabolomics response to five defined challenge tests and explored their use to identify interactions with the FTO rs9939609 obesity risk genotype. Fifty-six non-diabetic male participants of the KORA S4/F4 cohort, including 25 homozygous carriers of the FTO risk allele (AA genotype) and 31 carriers of the TT genotype were recruited. Challenges comprised an oral glucose tolerance test, a standardized high-fat high-carbohydrate meal and a lipid tolerance test, as well as an intravenous glucose tolerance test and a euglycemic hyperinsulinemic clamp. Blood was sampled for biochemical and metabolomics measurement before and during the challenges. Plasma samples were analyzed using a mass spectrometry-based metabolomics approach targeting 163 metabolites. Linear mixed-effects models and cluster analysis were performed. In both genotype groups, we observed significant challenge-induced changes for all major metabolite classes (amino acids, hexose, acylcarnitines, phosphatidylcholines, lysophosphatidylcholines and sphingomyelins, with corrected p-values ranging from 0.05 to 6.7E−37), which clustered in five distinct metabolic response profiles. Our data contribute to the understanding of plasma metabolomics response to diverse metabolic challenges, including previously unreported metabolite changes in response to intravenous challenges. The FTO genotype had only minor effects on the metabolite fluxes after standardized metabolic challenges. [ABSTRACT FROM AUTHOR]

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

Based on glucose kinetics minimal model (GKMM) interpretation of frequently sampled intravenous glucose tolerance test (FSIGTT), the aim was to broaden the characterization of insulin-mediated glucose disposal in hypertension by aid of a dynamic insulin sensitivity index, $$ S_{\text{I}}^{\text{D}} $$, and the related efficiency, $$ \eta = S_{\text{I}}^{\text{D}} /S_{\text{I}} , $$ of the metabolic system to convert the maximal individual response capacity, measured by S, into an effective insulin control on glucose. The C-peptide minimal model (CPMM) was used to interpret the role of β-cell function. Plasma glucose, insulin, and C-peptide concentrations were measured, during a 5-h FSIGTT, in eighteen normoglycemic individuals: ten hypertensive patients (H-group) and eight normotensive subjects (N-group) with no metabolic syndrome. Compared to our N-group, the H-group showed a significant ( P < 0.05) reduction of both S (56%) and $$ S_{\text{I}}^{\text{D}} $$ (50%), no significant change of η, a significant increase of both the first-phase β-cell responsiveness to glucose (105%) and total insulin secretion (55%), and no significant change in disposition indexes, defined as the product of insulin sensitivity (either S and $$ S_{\text{I}}^{\text{D}} $$) and β-cell responsiveness. These findings suggest that, in spite of no change of efficiency, insulin resistance in normoglycemic hypertensive patients is primarily compensated by an increase in first-phase insulin secretion to preserve glucose tolerance to intravenous glucose load. [ABSTRACT FROM AUTHOR]

Background:Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity.Objective:To study the effect of dietary supplementation with PS on cholesterol and glucose metabolism in humans.Methods:Twelve men with the metabolic syndrome (MetS) (according to the International Diabetes Federation (IDF) criteria; age 51±2 years (mean±s.e.m.); body mass index (BMI) 32±1 kg/m2) were randomly assigned to 4 weeks of PS (500 mg twice daily) and 4 weeks of placebo (P) in a double-blind cross-over study, with a 4-week wash-out period between both interventions. At the end of each intervention anthropometric measures and serum lipids were measured and an intravenous glucose tolerance test (IVGTT) was performed.Results:Phytosphingosine did not affect body weight and fat mass compared with P. PS decreased serum total cholesterol (5.1±0.3 (PS) vs 5.4±0.3 (P) mmol/l; P<0.05) and low-density lipoprotein (LDL)-cholesterol levels (3.1±0.3 (PS) vs 3.4±0.3 (P) mmol/l; P<0.05), whereas it did not alter serum triglyceride and high-density lipoprotein (HDL)-cholesterol levels. In addition, PS lowered fasting plasma glucose levels (6.2±0.3 (PS) vs 6.5±0.3 (P) mmol/l; P<0.05). PS increased the glucose disappearance rate (K-value) by 9.9% during the IVGTT (0.91±0.06 (PS) vs 0.82±0.05 (P) %/min; P<0.05) at similar insulin levels, compared with P, thus implying enhanced insulin sensitivity. PS induced only minor gastrointestinal side effects.Conclusion:Dietary supplementation of PS decreases plasma cholesterol levels and enhances insulin sensitivity in men with the MetS. [ABSTRACT FROM AUTHOR]

Insulin hypersecretion may be an independent predictor of progression to type 2 diabetes. Identifying genes affecting insulin hypersecretion are important in understanding disease progression. We have previously shown that diabetes-susceptible DBA/2 mice congenitally display high insulin secretion. We studied this model to map and identify the gene(s) responsible for this trait. Intravenous glucose tolerance tests followed by a genome-wide scan were performed on 171 (C57BL/6 × DBA/2) × C57BL/6 backcross mice. A quantitative trait locus, designated hyperinsulin production-1 (Hip1), was mapped with a logarithm of odds score of 7.7 to a region on chromosome 13. Production of congenic mice confirmed that Hip1 influenced the insulin hypersecretion trait. By studying appropriate recombinant inbred mouse strains, the Hip1 locus was further localised to a 2 Mb interval, which contained only nine genes. Expression analysis showed that the only gene differentially expressed in islets isolated from the parental strains was Nnt, which encodes the mitochondrial proton pump, nicotinamide nucleotide transhydrogenase (NNT). We also found in five mouse strains a positive correlation ( r 2 = 0.90, p < 0.01) between NNT activity and first-phase insulin secretion, emphasising the importance of this enzyme in beta cell function. Furthermore, of these five strains, only those with high NNT activity are known to exhibit severe diabetes after becoming obese. Insulin hypersecretion is associated with increased Nnt expression. We suggest that NNT must play an important role in beta cell function and that its effect on the high insulin secretory capacity of the DBA/2 mouse may predispose beta cells of these mice to failure. [ABSTRACT FROM AUTHOR]

Presents a study that compared the dose-dependent effects of sevoflurane and isoflurane anesthesia on glucose tolerance in humans. Method of the study; Results and discussion; Conclusion.

Aims/hypothesis: Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable. Methods: Here we report successful islet transplantation in a cohort of 15 patients with Type I diabetes who were followed for at least 1 year after islet transplantation, after having already received kidney allografts because of end-stage nephropathy. Results: C-peptide after transplantation was higher than 0.17 nmol/l in all 15 recipients, reflecting the absence of primary non-function. Insulin requirement was reduced by over 50 % in all but one patient, and insulin independence was achieved in 10 (66 %) recipients, five of whom now have stable, prolonged insulin independence, well controlled fasting glycaemia, a substantial first-phase and normal second-phase response to glucose, normal insulin sensitivity (HOMA analyses) and HbA1 c of under 6.2 % (33, 26, 18, 13 and 12 months after transplantation respectively). Of importance for patient management, an assessment of fasting blood glucose and proinsulin values following overnight withdrawal of insulin administration one month after transplantation was a potent predictor of insulin independence, and could be used to decide patients who should have further islet preparations. Conclusion/interpretation: These findings support the use of islet transplantation as a cure for Type I diabetes in patients with severe complications. [Diabetologia (2002) 45: 77–84] [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We compared four methods to assess their accuracy in measuring insulin secretion during an intravenous glucose tolerance test in patients with Type II (non-insulin-dependent) diabetes mellitus and with varying beta-cell function and matched control subjects. Methods: Eight control subjects and eight Type II diabetic patients underwent an intravenous glucose tolerance test with tolbutamide and an intravenous bolus injection of C-peptide to assess C-peptide kinetics. Insulin secretion rates were determined by the Eaton deconvolution (reference method), the Insulin SECretion method (ISEC) based on population kinetic parameters as well as one-compartment and two-compartment versions of the combined model of insulin and C-peptide kinetics. To allow a comparison of the accuracy of the four methods, fasting rates and amounts of insulin secreted during the first phase (0–10 min) and the second phase (10–180 min) were calculated. Results: All secretion responses from the ISEC method were strongly correlated to those obtained by the Eaton deconvolution method (r = 0.83–0.92). The one-compartment combined model, however, showed a high correlation to the reference method only for the first-phase insulin response (r = 0.78). The two-compartment combined model failed to provide reliable estimates of insulin secretion in three of the control subjects and in two patients with Type II diabetes. The four methods were accurate with respect to mean basal and first-phase secretion response. The one-compartment and two-compartment combined models were less accurate in measuring the second-phase response. Conclusion/interpretation: The ISEC method can be applied to normal, obese or Type II diabetic patients. In patients with deviating kinetics of C-peptide the Eaton deconvolution method is the method of choice while the one-compartment combined model is suitable for measuring only the first-phase insulin secretion. [Diabetologia (2001) 44: 1339–1348] [ABSTRACT FROM AUTHOR]

Aims/ hypothesis. Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. Methods. Normal ( n = 7), impaired glucose tolerant ( n = 8) and Type II (non-insulin-dependent) diabetic subjects ( n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio – DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. Results. Reciprocal fasting plasma insulin (FPI–1), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI–1, HOMA %S, 2-h CIGMA %S and SI FSIVGTT intercorrelated more than 90 % of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. Conclusion/ interpretation. The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative. [Diabetologia (1999) 42: 678–687] [ABSTRACT FROM AUTHOR]

Studies in seven patients with moderate hypertension were done to explore the effect of the non-selective beta-receptor blocking agent penbutolol on blood glucose and plasma insulin levels under fasting conditions, and following a glucose load. Oral penbutolol 20-30 mg, twice daily for 3-8 months, produced no change in fasting levels of blood glucose and plasma insulin, or in the blood glucose response following an oral or iv glucose load. The initial insulin response to intravenous glucose was similar before and during penbutolol treatment. The total integrated insulin response following iv glucose increased slightly during treatment when measured from insulin zero level, but was unaltered when calculated from the initial basal insulin level. Following oral glucose the total integrated insulin response was not affected by treatment with penbutolol. [ABSTRACT FROM AUTHOR]

Glucose clamp experiments have shown that patients with reactive postprandial hypoglycaemia (PRH) frequently have an increased glucose disposal, but the relative involvement of insulin sensitivity (SI) and glucose effectiveness (Sg) in this process remains unknown. The minimal model approach was used to compare 13 patients in whom moderate reactive hypoglycaemia (<3.3 mmol) had been previously diagnosed and 13 matched controls. The intravenous glucose tolerance test (IVGTT, 0.5 g/kg glucose IV) with 0.02 U/kg insulin given at the 19th min and frequent sampling over 180 min shows that PRH patients exhibit a higher glucose tolerance coefficient Kg (2.99±0.26 vs 2.19±0.12; P<0.02), higher SI [22.9±6.4 vs 7.18±0.14 min/(μU/ml) · 10; P<0.01] and higher Sg (3.84±0.35 vs 2.92±0.79 min · 10; P<0.05). The increase in Sg is explained by an increase in its component basal insulin effectiveness (BIE: 1.2±0.27 min · 10 in PRH subjects vs 0.58±0.07; P<0.05) rather than an increase in Sg at zero insulin. The increase in BIE results from the high values of SI. In 4 PRH subjects SI and Sg were within the normal range, and the increase in Kg evidenced in the 9 others was explained by an increase in SI alone in 3 cases, in Sg alone in 1 case, and both SI and Sg in 5 cases. Thus, in sedentary subjects, the previously reported rise in tissue glucose assimilation is mainly explained by an increased insulin-mediated glucose disposal rather than non-insulin-mediated glucose disposal. [ABSTRACT FROM AUTHOR]

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-2H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Clb), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Clb/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 ± 0.6 vs 0.76 ± 0.18 ml · min–1· m–2· pmol/l–1, p < 0.02; ISI: 0.40 ± 0.06 vs 0.13 ± 0.05 ml · min–1· m–2· pmol/l–1, p < 0.02; Cl600: 333 ± 47 vs 137 ± 26 ml · min–1· m–2, p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 ± 169 vs 606 ± 123 μmol · min–1· m–2, NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 ± 15 vs 12 ± 7 pmol · min–1· m–2· mmol/l–1, p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects ( n = 4), PSIb was inversely correlated with BSI ( r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion. [Diabetologia (1998) 41: 1029–1039] [ABSTRACT FROM AUTHOR]

Gestational diabetes affects 2-3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2-3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6, 6-H]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose K) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16±0.11 vs 1.78±0.23%/min; p<0.05) and post-partum (1.47±0.22 vs 2.59±0.43%/min; p<0.05) and increased significantly in the control women after delivery ( p<0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes ( p<0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased ( p<0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2±42.7 pmol/kg) compared with post-partum values (58.3±25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5±9.3 pmol/kg) and after delivery (57.7±15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose. [ABSTRACT FROM AUTHOR]

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A 'whole' or 'mixed' pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell 'selective' ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the 'mixed' pattern in only three. None of this group had detectable 37k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the 'whole' or 'mixed' ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration. [ABSTRACT FROM AUTHOR]

First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a M 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high ( n=6) and low ( n=30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies. In contrast, of the six subjects with progressively declining Beta-cell function who are therefore at high risk, two of whom have already developed Type 1 diabetes, two (33%) were positive for insulin autoantibodies, four (67%) were islet cell antibody positive, while all six (100%) were positive for 64K antibodies. We conclude that antibodies to the M 64,000 islet protein correlate with progressive Beta-cell dysfunction more closely than either islet cell antibodies or insulin autoantibodies, but can sometimes be present in individuals whose Beta-cell function remains stable over several years. [ABSTRACT FROM AUTHOR]

In this study we have investigated blood glucose and serum free insulin response to glucose and to arginine orally or intravenously, 3 months and 3 years after a successful segmental, neoprene-injected, pancreas transplantation. Serum insulin responses to different secretagogues were normal 3 months after transplantation; they remained normal up to 3 years after transplantation. [ABSTRACT FROM AUTHOR]

A controlled trial of oral nicotinamide to prevent the onset of diabetes mellitus in high risk children was conducted in two centres. The selection criteria were age less than 16 years, islet cell antibody ≥80 IUs, and first phase insulin release < 5th percentile. All of eight untreated control subjects have developed diabetes, whereas only 1 of 14 treated children has diabetes to date. This data suggests that nicotinamide has an effect in preventing Type 1 (insulin-dependent) diabetes and that randomized controlled studies are now indicated. [ABSTRACT FROM AUTHOR]

We have followed-up 35 islet cell antibody-positive first degree relatives of patients with Type 1 (insulin-dependent) diabetes mellitus for an average of 1,300 days with sequential intravenous glucose tolerance tests. At the time of analysis and manuscript submission approximately half (18 of 35) had developed diabetes during follow-up. At initial intravenous glucose tolerance test, 11 had a 1+3 min insulin secretion below the first percentile of insulin secretion compared to 225 similarly studied normal control subjects. Six islet cell antibody positive relatives on follow-up developed an intravenous glucose tolerance test less than the first percentile. Fifteen out of 17 (88%) of these islet cell antibody positive relatives with secretion ever found to be below the first percentile are now overtly diabetic (positive predictive value=88%) and insulin-treated, while only 3 of 18 (17%) without an intravenous glucose tolerance test demonstrating loss of first phase insulin secretion have progressed to diabetes (with approximately 1,300 days of follow-up for both groups relative risk or odds ratio with intravenous glucose p<0.001). tolerance test ever below vs never below the first percentile=38, Intravenous glucose tolerance test response below the first percentile preceded diabetes by an average of 656 days. Even when first phase insulin secretion is below the first percentile, the absolute value of 1+3 min insulin above basal insulin correlates with the time to development of diabetes ( r=0.586, p<0.001). With our current duration of follow-up, the negative predictive value (intravenous glucose tolerance test never below the first percentile) is 83%, and overall accuracy 86%. Incidence rates of diabetes development amongst our islet cell antibody positive relatives with follow-up while intravenous glucose tolerance test is below the first percentile is 0.48 per year (15 conversions to diabetes amongst 17 relatives in 30.8 patient years of follow-up) vs 0.05 per year (three diabetic patients in 55.5 patient years) with intravenous glucose tolerance test greater than the first percentile. [ABSTRACT FROM AUTHOR]

To determine the reproducibility of the first phase insulin response to intravenous glucose, ten normal subjects underwent two intravenous glucose tolerance tests separated by at least two weeks. Intravenous dextrose (0.3 g/kg) was administered over 2 min by continuous infusion and arterialised-venous samples were taken from a retrogradely cannulated hand vein in the opposite arm. Within subjects, median coefficient of variation for the 3 min insulin was 4.0% (range 1.2-24.3%) and median coefficient of variation for the 0-10 min area was 6.7% (range 1.7-18.8%). These coefficients of variation are close to those of the assay itself (< 10%). Despite this, between subject responses varied by greater than sixfold. In conclusion, contrary to previous reports the intravenous glucose tolerance test is highly reproducible. This makes it a very valuable tool for further studies of the pathogenesis of diabetes. [ABSTRACT FROM AUTHOR]

Using the decay phase of the glucose response during an intravenous tolbutamide test, a minimal model of glucose dynamics was used to calculate a value for an 'index of insulin sensitivity'. This index describes the efficiency of insulin in accelerating the instantaneous rate of glucose disposal, and provides a measure of insulin resistance. The validity of estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test have been assessed with reference to estimates of this index derived from the intravenous glucose tolerance test for which the model was originally designed. There were three studies: (A) estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test in a group of normal, healthy men and women were compared with results obtained in a comparable group of subjects using the intravenous glucose tolerance test. The two methods gave estimates of the index of insulin sensitivity that were identical; (B) A group of patients taking methandienone, an anabolic steroid previously shown to cause marked insulin resistance, were tested whilst taking the steroid and either before, or at least two months after treatment. Each patient was tested by both intravenous tolbutamide test and intravenous glucose tolerance test on both occasions. Estimates of the index of insulin sensitivity from intravenous glucose tolerance or intravenous tolbutamide procedures both on and off treatment were significantly correlated (off treatment: r,= 0.71, n=9, p<0.05; on treatment: r=0.69, n=9, p<0.05); (C) A group of patients undergoing investigations for suspected disturbances in carbohydrate metabolism was studied, each patient having had both an intravenous tolbutamide and intravenous glucose tolerance test. The group studied included patients in whom a degree of insulin resistance would be expected. Estimates of the index of insulin sensitivity from the two methods were closely correlated ( r=0.95, n=25, p<0.001). This strong, identical correlation obtained between the intravenous glucose tolerance and intravenous tolbutamide tolerance estimates of index of insulin sensitivity in studies B and C over a wide range of values [intravenous tolbutamide tolerance test: 0.11-1.07 minU 1; intravenous glucose tolerance test: 0.12-1.06 minU1]. This suggests that the intravenous tolbutamide estimates of index of insulin sensitivity are closely comparable to those derived from intravenous glucose tolerance test over a broad range of insulin sensitivities. We suggest that the use of intravenous tolbutamide to induce a dynamic change in insulin-glucose relationships, and mathematical modelling of those dynamics, can provide a valuable, quantitative measure of insulin sensitivity in a variety of clinical situations. [ABSTRACT FROM AUTHOR]

The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees of β-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient β-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and β-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (R = 0.88, p < 0.0001), the fasting insulin concentration (R = 0.81, p < 0.0001), and the hyperglycaemic clamp, (R = 0.69, p < 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient β-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (R = 0.61, p < 0.01) and with the estimate from the intravenous glucose tolerance test (R = 0.64, p < 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for β-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. [ABSTRACT FROM AUTHOR]

In an attempt to study pancreatic A cell function at an early stage of pancreatic diabetes secondary to chronic pancreatitis, both intravenous glucose (0.5 g/kg) and insulin (0.5 U/kg) tolerance tests were performed on seven dogs with pancreatolithiasis and seven normal control dogs. Experimental pancreatolithiasis was produced 12 months after incomplete ligation of the greater pancreatic duct. Impaired glucose tolerance and reduced plasma insulin response to an intravenous glucose load were observed in the calcified group. Pancreatic release of glucagon to insulin-induced hypoglycaemia was diminished, but suppressive response of the hormone to glucose-induced hyperglycaemia was well preserved. These data suggest that the A cell response to hypoglycaemia may be impaired earlier than that to hyperglycaemia in pancreatic diabetes secondary to pancreatolithiasis. [ABSTRACT FROM AUTHOR]

Insulin and high density lipoproteins are considered to play a role in the development of atherosclerosis. In order to study whether there was a relationship between endogenous plasma insulin response and high density lipoproteins, an acute intravenous glucose tolerance test (0.5 g glucose/kg body weight) was performed in 94 healthy men, aged 20-49 years. Cholesterol and triglyceride levels were measured in very low density lipoproteins, low density lipoproteins and high density lipoproteins isolated from fasting serum by preparative ultracentrifugation. The subjects were divided into quartiles according to their fasting and post-glucose load plasma insulin and high density lipoprotein cholesterol levels. The results obtained in the subjects of the upper quartiles were compared with the results obtained in the subjects of the lower quartiles. The mean glucose disappearance rates were within the normal range and did not differ between the upper and lower quartiles. Subjects with high fasting plasma insulin had lower high density lipoprotein cholesterol levels (1.11±0.34 mmol/l, p=0.01) than men with low fasting plasma insulin (1.40±0.37 mmol/l). Higher mean post-glucose plasma insulin was associated with lower high density lipoprotein cholesterol levels (1.18±0.32 mmol/l, p<0.05) and increased high density lipoprotein triglyceride levels (0.14±0.07 mmol/l, p<0.01) when compared with the men with low post-glucose plasma insulin (1.40±0.36 mmol/l and 0.09±0.03 mmol/l respectively). These observations reflect the close relationship between endogenous insulin and lipoprotein metabolism. [ABSTRACT FROM AUTHOR]

The relationship between the pre-stimulus glucose level and immunoreactive insulin responses to a glucose challenge (20-g IV) was studied in normal subjects. When the steady-state pre-stimulus glucose concentration was lowered by a 0.33 mU· kg· min insulin infusion or raised by a 900mg/ min glucose infusion, no effect on first phase insulin secretion (mean Δ 3-5 min insulin level) was observed. In contrast, the second phase response (10-60 min insulin area after glucose pulse) to intravenous glucose fell during insulin infusion and increased during the glucose infusion. Overall, a linear relationship was found between the change of pre-stimulus glucose level from the control to that during the insulin or glucose infusion and the change in second phase response ( r=0.65, n = 14, p<0.02). The effect of tolbutamide infusion (7 mg·m· min) when compared with saline control was to increase both first phase (+54 ±13 mU/1, n=8, p <0.001, mean±SEM) and second phase (+972±256mU · mur · 1, P<0.01) insulinsecretion. It is concluded that the first phase response to a glucose pulse is independent of the steady-state pre-stimulus glucose concentration and is directly enhanced by tolbutamide; in contrast, second phase is related to both the steady-state pre-stimulus glucose level and tolbutamide. These findings suggest that changes in basal or pre-stimulus plasma glucose during therapy with sulphonylurea drugs may be expected to influence the second phase insulin responses to glucose challenge. [ABSTRACT FROM AUTHOR]

To study insulin response and insulin sensitivity a glucose infusion test was devised. Twenty normal non-pregnant and twenty normal pregnant women had an intravenous glucose tolerance test followed by a glucose infusion test. In a normal pregnant group at 38-40 weeks gestation (n=20) the plasma insulin response was found to be 3.7 times greater than that observed in a normal non-pregnant group (n=20), while in the normal pregnant group the insulin sensitivity index was only 18 per cent of that observed in the non-pregnant group. Intravenous glucose tolerance in the non-pregnant women was observed to correlate with the insulin sensitivity index (r=0.61, p<0.05) but in the pregnant women it correlated with the insulin response (r=0.66, p<0.01). These findings support the hypothesis that in the non-pregnant state intravenous glucose tolerance may be primarily related to insulin sensitivity while during pregnancy it may be related to the degree of compensatory hyperinsulinism. [ABSTRACT FROM AUTHOR]

In 14 normal subjects, treatment with acetylsalicylic acid (ASA, 3.2 g daily for 3 days) a well known inhibitor of prostaglandin synthesis, caused a slight but significant decrease (p<0.05) in basal plasma glucose levels; by contrast, basal insulin rose from 5±1 to 8±1 μU/ml (p<0.01) after ASA. Pretreatment with ASA augmented the early insulin response to a standard IV glucose tolerance test (25 g) in 7 normal subjects (p<0.05 at 2 min; p<0.02 at 5 min; p<0.01 at 10 min). No significant changes were detected in the rate of glucose utilization. 7 additional subjects received a standard arginine test without and with ASA pretreatment. Arginine stimulated insulin levels were increased after ASA (p<0.01 at 15 min; p<0.05 at 30 min; p<0.05 at 45 min), whereas glucose values were lower than under basal conditions at all times, with significant differences at 105 (p<0.02) and 120 (p<0.05) min. A possible role of prostaglandins upon the insulin responses to glucose and arginine is discussed. [ABSTRACT FROM AUTHOR]

Early insulin responses were measured after a high dose (50 g/1.73 m) of rapidly injected glucose in 31 subjects who had repeatedly shown 'lagstorage' curves in the OGTT, in 24 controls and in 19 mild maturity-onset diabetics. Division between controls and diabetics was virtually complete, when the insulin responses were expressed as 'insulindgenic index' $$\left( {\frac{{\Delta insulin}}{{\Delta glucose}}} \right)$$ Twenty out of 31 patients with lag curves showed normal early insulin responses and 11 patients showed diabetic responses. In patients with lag curves, presence of obesity, and absence of family history of diabetes were associated with normal insulin responses. It is concluded that the finding of a lag curve is of little consequence in obese persons but, when in conjunction with a genetic background of diabetes, is suggestive of diabetes. [ABSTRACT FROM AUTHOR]

The purpose of the study was to evaluate and compare the most commonly used criteria for the interpretation of the oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and the intravenous tolbutamide test (IVTT) and to establish the criteria that give the highest degree of diagnostic agreement. The highest degree of diagnostic agreement was obtained with the following limits: a) blood glucose > or ≤ 120 mg/100 ml within 2 1/2 h after a 100 g OGTT together with b) a k-value of > or ≤ 1.05 as a limit for a 25 g IVGTT and c) a 30 min blood glucose level as percentage of fasting of > or ≤ 77 as limit for a 1 g IVTT. Using these criteria the three tests deemed the same subjects either diabetic or nondiabetic in about 2/3 of the cases. The best correlation between the blood glucose values of the OGTT and the k-values of the IVGTT and the 30 min values of the IVTT was obtained using the blood glucose concentrations of the last part of the OGTT. The 2 and the 3 hr values were however equal to the 2 1/2 hr values with regard to the degree of correlation with the values of the intravenous test. The results indicated that the diagnostic disagreement reported previously between the three tests may partly be due to the use of blood glucose values in the first part of the OGTT for the classification of the test and partly due to the screening limits chosen for interpretation of the three test. [ABSTRACT FROM AUTHOR]

Copyright of Acta Diabetologica Latina is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Acta Diabetologica Latina is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Diabetologia is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Diabetologia is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Diabetologia is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Most reports investigating the hormonal and metabolic effects of bariatric surgery studied obese subjects after partial weight loss only. Nevertheless, all studies showed significant improvements of insulin secretion, action, clearance and inhibition of its own secretion, although the parallel kinetics of all these changes remained questionable. Using the intravenous glucose tolerance test, we demonstrated a full normalization of insulin secretion, action on glucose metabolism and clearance in eight obese women who recovered and maintained ideal body weight following gastroplasty. Reciprocal changes were observed between postglucose acute insulin secretion and insulin-mediated glucose disposal so that the so-called disposition index (product of these two variables) remained unchanged after vs before gastroplasty in those individuals with normal glucose tolerance. These favourable results should encourage obtaining a drastic and sustained weight loss in patients with severe obesity at risk of developing type II diabetes.International Journal of Obesity (2004) 28, 821-823. doi:10.1038/sj.ijo.0802632 Published online 30 March 2004 [ABSTRACT FROM AUTHOR]

Nicotinamide has been given both before and after clinical onset of Type 1 (insulin-dependent) diabetes mellitus in an attempt to prolong beta-cell survival. Nicotinic acid, structurally similar to nicotinamide, induces insulin resistance and increases insulin secretion in healthy individuals. It is not known if nicotinamide has similar effects. Since insulin secretion, as measured by the acute insulin response to intravenous glucose, is used to predict diabetes and to monitor therapy, the effects of nicotinamide must be established before trials in individuals at high risk of progression to Type 1 diabetes can be interpreted. Intravenous tolerance tests were performed according to the ICARUS standard protocol in 10 healthy, adult subjects (age 32±5.7 years) before and after 14 days of treatment with nicotinamide 25 mg · kg · day. The acute insulin response after nicotinamide did not differ from the control study, whether measured as the incremental 0-10 min insulin area (278±142 vs 298±130mU · l · 10 min) or as the 1±3 min insulin level (78±39 vs 81±44 mU/l). The late insulin response was equally unaffected, as were basal insulin (5.2±1.6 vs 5.6±2.1 mU/l) and glucose (5.0±0.4 vs 4.9±0.2 mmol/l) levels and glucose disposal rates (1.98±0.88 vs 2.04±0.68%/min). Nicotinamide does not affect insulin secretion and glucose kinetics in normal subjects, confirming its suitability for trials designed to delay or prevent the onset of Type 1 diabetes. [ABSTRACT FROM AUTHOR]

The presence of islet amyloid polypeptide in amyloid within pancreatic islet cells in Type 2 (non-insulin-dependent) diabetes, and its reported inhibition of glucose uptake by skeletal muscle in vitro, has prompted speculation concerning its role in the pathogenesis of diabetes. We investigated the effect of infused synthetic amidated human islet amyloid polypeptide (mol. wt. 3904, confirmed by mass spectroscopy) on intravenous glucose tolerance. Seven healthy, non-obese volunteers (age±SD, 27±4 years) were infused over 50 min with normal (0.9%) saline or islet amyloid polypeptide at 50 pmol·kg·min. After 20 min, a bolus of 0.5 g/kg glucose was given within 1 min and blood sampling continued for up to 60 min. Circulating concentrations of islet amyloid polypeptide reached at steady state were 1130±90 pmol/l. The calculated half-life was 11.8±0.9 min, metabolic clearance rate 5.7±0.6 ml·kg·min and apparent distribution space therefore 94±12 ml/kg. However, islet amyloid polypeptide was found to have no effect on the peak value reached, or the total area under the curve for plasma glucose, insulin or glucagon following intravenous glucose. This study suggests circulating islet amyloid polypeptide may not be an important influence on intravenous glucose tolerance in man. [ABSTRACT FROM AUTHOR]

Insulin secretion after oral (100 g) and i.v. glucose (0.33 g/kg b.w.) was studied in 14 patients with 21-trisomy (Down's syndrome) and in 18 normal subjects. Plasma immunoreactive insulin (IRI), fasting and at predetermined time intervals during each glucose load, was measured by a double antibody method (Hales-Randle). Tolerance to oral glucose in Down's patients was found to be normal though a flat, late peaked glycaemic response was characteristic of the group. Fasting IRI and insulin levels after oral glucose in patients did not significantly differ from those in the normal group. After i.v. glucose, the patients showed a slower decline of the blood sugar, maintaining significantly higher levels than the normals at 30, 40, 50 and 60 min after the glucose load. However, the peripheral glucose uptake expressed by the K index (Conard) did not significantly differ from the normal despite the lower K values in the patients. Insulin release after i.v. glucose showed some differences between both groups. - The present study cannot support a causal relationship between D.M. and the 21-trisomy through an altered insulin secretion. [ABSTRACT FROM AUTHOR]