Acute Insulin Response To Glucose Research Articles

Effects of Exercise Training Intensity on Pancreatic β-Cell Function

OBJECTIVEInsulin resistance and β-cell dysfunction both are important contributors to the pathogenesis of type 2 diabetes. Exercise training improves insulin sensitivity, but its effects on β-cell function are less well studied.RESEARCH DESIGN AND METHODSSedentary, overweight adults were randomized to control or one of three 8-month exercise programs: 1) low amount/moderate intensity, 2) low amount/vigorous intensity, or 3) high amount/vigorous intensity. Of 387 randomized, 260 completed the study and 237 had complete data. Insulin sensitivity (Si), acute insulin response to glucose (AIRg), and the disposition index (DI = Si × AIRg) were modeled from an intravenous glucose tolerance test.RESULTSCompared with control subjects, all three training programs led to increases in DI. However, the moderate-intensity group experienced a significantly larger increase in DI than either of the vigorous-intensity groups and through a different mechanism. The high-amount/vigorous-intensity group improved Si and had a compensatory reduction in AIRg, whereas the moderate-intensity group had a similar improvement in Si but almost no reduction in AIRg. Importantly, the inactive control group experienced a significant increase in fasting glucose.CONCLUSIONSTo the extent that the DI accurately reflects β-cell function, we observed that both moderate- and vigorous-intensity exercise training improved β-cell function, albeit through distinct mechanisms. It is not clear which of these mechanisms is preferable for maintenance of metabolic health. While moderate-intensity exercise led to a larger improvement in DI, which may reflect a transition toward a more normal DI, longer-term investigations would be necessary to determine which was more effective at reducing diabetes risk.

Uncoupling protein 2 Ala55Val polymorphism is associated with a higher acute insulin response to glucose

Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) in pancreatic β-cells plays a crucial role in insulin production and secretion. We hypothesized that 2 UCP2 polymorphisms, a −55C/T (Ala55Val) substitution in exon 4 and an exon 8 insertion, would alter the acute insulin response to glucose (AIRg). Subjects were 155 African American (AA) and European American (EA) women. Body composition was determined by dual-energy x-ray absorptiometry. Insulin sensitivity and AIRg were measured with an intravenous glucose tolerance test and minimal modeling. To account for the confounding effects of population stratification, estimates of African admixture were obtained from approximately 35 ancestry-informative markers. Uncoupling protein 2 genotyping was conducted with gel electrophoresis. Information was analyzed using mixed linear models. A positive association between the −55C/T homozygous mutation and AIRg was identified in the total sample ( P < .01) and independently in EA women ( P = .02) but not AA women. The exon 8 insertion did not significantly affect AIRg. No interaction effects of the 2 polymorphisms on AIRg were noted. These results indicate that AIRg is associated with the −55C/T UCP2 homozygous mutation and that the presence of this mutation could alter postchallenge insulin concentration.

Triglyceride Concentration is Independently Associated with Variation in the LPL Gene in African American and European American Women

Objective: The regulation of triglyceride (TG) metabolism may be affected by many factors including: race/ethnicity, body composition, body fat distribution, insulin action, and the activity of the lipoprotein lipase (LPL) enzyme. This study was designed to identify the independent effects of body composition, body fat distribution, insulin action, and LPL genetic variation on TG and HDL-C concentration. Subjects: The study consisted of premenopausal European American (EA) (n=114) and African American (AA) (n=140) women. Measurements: Body composition was measured by dual-energy X-ray absorptiometry (DXA), intra-abdominal adipose tissue (IAAT) by computed tomography (CT), insulin sensitivity (SI) and the acute insulin response to glucose (AIRg) by intravenous glucose tolerance test, median household income by zip-code. An estimate of individual genetic admixture was obtained from the genotyping of 85 ancestry informative markers and used to control for population stratification. Multiple linear regression analyses were used to identify contributions of body composition, IAAT, SI, AIRg, African genetic admixture, and LPL polymorphisms to TG and HDL-C. Results: AA had lower TG and higher HDL-C than EA. African genetic admixture, IAAT, AIRg, SI, and RS285 were significantly and independently related to TG concentration. SI was the only independent contributor to HDL-C. RS1800590 was not associated with variation in TG or HDL. Conclusion: Triglyceride concentration appears to be multifactorial in origin and emanates in part from variance in LPL RS285. Future investigations are necessary to understand the mechanisms through which gene polymorphisms, body fat distribution, and insulin action influence the lipid profile.

A genome-wide association scan for acute insulin response to glucose in Hispanic-Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS FS).

This study sought to identify genes and regions in the human genome that are associated with the acute insulin response to glucose (AIRg), an important predictor of type 2 diabetes, in Hispanic-American participants from the Insulin Resistance Atherosclerosis Family Study (IRAS FS). A two-stage genome-wide association scan (GWAS) was performed in IRAS FS Hispanic-American samples. In the first stage, 317K single nucleotide polymorphisms (SNPs) were assessed in 229 Hispanic-American DNA samples from 34 families from San Antonio, TX, USA. SNPs with the most significant associations with AIRg were genotyped in the entire set of IRAS FS Hispanic-American samples (n = 1,190). In chromosomal regions with evidence of association, additional SNPs were genotyped to capture variation in genes. No individual SNP achieved genome-wide levels of significance (p < 5 x 10(-7)); however, two regions (chromosomes 6p21 and 20p11) had multiple highly ranked SNPs that were associated with AIRg. Additional genotyping in these regions supported the initial evidence of variants contributing to variation in AIRg. One region resides in a gene desert between PXT1 and KCTD20 on 6p21, while the region on 20p11 has several viable candidate genes (ENTPD6, PYGB, GINS1 and RP4-691N24.1). A GWAS in Hispanic-American samples identified several candidate genes and loci that may be associated with AIRg. These associations explain a small component of variation in AIRg. The genes identified are involved in phosphorylation and ion transport, and provide preliminary evidence that these processes are important in beta cell response.

Racial differences in adolescent endothelial function and insulin secretion

African‐American (AA) adults have increased mortality and morbidity from cardiovascular disease. The mechanisms for this likely have their origins in childhood and adolescence. It is therefore crucial that we understand racial differences in this age group. Several studies have indicated that AA adolescents (adol) are insulin resistant compared to Caucasians (Ca). Because insulin resistance has been linked to increased cardiovascular risk and specifically to endothelial dysfunction, we studied endothelial function (EF) differences between AA and Ca adol. Endothelial dysfunction is one of the earliest precursors of cardiovascular disease. We found that post upper arm occlusion forearm blood flow was significantly lower in AA than in Ca adol indicating impaired EF. This impairment was primarily present in obese subjects. Interestingly, insulin sensitivity was not different between groups, but the acute insulin response to glucose (AIRG) in AA was over twice as high as that in Ca. EF was negatively correlated to the AIRG in the whole group and in AA, but not Ca. It, also, negatively correlated with triglycerides in AA. Future research will determine mechanisms for the differences and could potentially focus on intercellular insulin signaling, lipid metabolism, and specific genetic polymorphisms. This will allow the development of treatments to decrease cardiovascular disease in AA.

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.

Physical Fitness, Activity, and Insulin Dynamics in Early Pubertal Children

The objectives of this study were to identify the independent effect of physical activity and fitness on insulin dynamics in a cohort of European-, African-, and Hispanic-American children (n = 215) age 7-12 years and to determine if racial/ethnic in insulin dynamics could be statistically explained by racial/ethnic differences in physical activity or fitness. An intravenous glucose tolerance test and minimal modeling were used to derive the insulin sensitivity index (SI) and acute insulin response to glucose (AIRg). Fitness was assessed as VO2-170 and physical activity by accelerometer. Multiple regression models were tested for contributions of fitness and physical activity to SI and AIRg. Fitness was a stronger predictor of SI and AIRg than physical activity regardless of ethnicity; racial/ethnic differences in insulin dynamics were not accounted for by differences in fitness and/or physical activity.

The effects of dietary manipulation and exercise on weight loss and related indices of health in horses

Obesity is considered a risk factor for laminitis, insulin resistance and other medical problems in horses. The objective of this study was to test the hypothesis that a feeding and exercise programme would induce weight loss and affect indices of health in overweight horses. Twenty-three overweight (BCS 6.5–9.0) QH and TB horses were assigned to three groups: calorie restriction (DIET), calorie restriction plus exercise (DIETX) and a control group at weight maintenance (CON). Measurements included body weight, body condition score, rump fat thickness, glucose, insulin, leptin, non-esterified fatty acids (NEFA) and triglycerides. Frequently sampled intravenous glucose tolerance tests measured insulin sensitivity (SI), glucose effectiveness and acute insulin response to glucose (AIRg). Disposition index (DI) was calculated. DIETX underwent a fitness test (graded exercise test) on a treadmill before and after the experimental period, and performed a standardized submaximal exercise regimen in an Equi-ciser™. Horses in the DIETX group lost more weight (P &lt; 0.01) than DIET or CON. DIET also lost more weight versus CON (P &lt; 0.05). All groups had decreases (P &lt; 0.05) in BCS, with DIETX and DIET exhibiting the largest decreases. DIET and DIETX decreased (P &lt; 0.05) in rump fat thickness. Cortisol decreased (P &lt; 0.05) in DIET, and NEFA decreased in DIETX pre- versus post-weight loss. There were decreases (P &lt; 0.05) in leptin and AIRg in DIET and DIETX pre- versus post-weight loss. DI was decreased (P &lt; 0.05) in DIET and CON. SI was decreased (P &lt; 0.05) only in CON. Calorie restriction and calorie restriction plus exercise programmes were successful in achieving weight loss in overweight horses. Indices of obesity, physiological stress and fat metabolism can be significantly altered with calorie control and exercise.

Relationships between reported macronutrient intake and insulin dynamics in a multi-ethnic cohort of early pubertal children.

Racial/ethnic differences in the pediatric population in insulin dynamics have been documented. Additionally, girls tend to be more insulin resistant than boys. Although the mechanism driving these differences is unclear, diet may be a contributor. The objective of this study was to evaluate the contribution of reported macronutrient intake on insulin dynamics and determine if diet composition may account for racial/ethnic and sex differences in insulin response/action. Participants were 250 African- (n=84), European- (n=105), or Hispanic-American (n=61) children 7-12 years, pubertal stage < or =3. An intravenous glucose tolerance test was used to derive the insulin sensitivity index and acute insulin response to glucose (AIRg) diet by two 24 h recalls, and body composition by dual-energy x-ray absorptiometry (DXA). Reported energy intake from fat was positively related to fasting insulin (P < 0.05) and AIRg (P=0.05). Reported energy from carbohydrate was inversely associated with fasting insulin (P < 0.05), and reported energy from protein was inversely associated with AIRg (P < 0.05). The interaction terms between ethnicity and diet, and sex and diet were not significant for any outcome variables. Dietary intake influences insulin dynamics; however, the racial/ethnic and sex differences in insulin dynamics in this population are not accounted for by macronutrient intake. Pubertal status is likely to play a role in the interaction between diet, race/ethnicity, sex and insulin dynamics. Longitudinal studies are needed to determine if the contribution of diet to insulin dynamics strengthens with reproductive maturation.

Insulin sensitivity and first-phase insulin secretion in obese Chinese with hyperglycemia in 30 and/or 60 min during glucose tolerance tests

The purpose of this study was to investigate insulin sensitivity and first-phase insulin secretion in obesity with hyperglycemia in 30 and/or 60 min during oral glucose tolerance (OGTT, glucose > or = 11.1 mmol/l, post-loading hyperglycemia, PLH) in Chinese population. A total of 196 nondiabetic subjects were included in the present study, among them 99 had normal glucose tolerance (NGT, subdivided into 32 lean NGT and 67 obese NGT), 74 had obesity with impaired glucose tolerance (IGT) and 23 had obesity with PLH. A standard 75-g oral glucose tolerance test was performed after fasting and at 30 min, 1, 2 and 3 h. Insulin sensitivity index (S(I)) was assessed by the Bergman's minimal model method with frequently sampled intravenous glucose tolerance test (FSIGTT), insulin secretion was determined by acute insulin response to glucose (AIRg). The disposition index (DI), the product of AIRg and S(I) was used to determine whether AIRg was adequate to compensate for insulin resistance. S(I) was significantly equally lower in three obese subgroups. AIRg was significantly increased in obese NGT as compared with lean NGT controls, and reduced to the same extent in IGT and PLH subjects. There was no significant difference among lean NGT, IGT and PLH subjects. DI value was reduced from obese NGT individuals, IGT and PLH subjects had a similar lower level of DI. In conclusion, our present results demonstrated that the pathophysiological basis of obese subjects with PLH were clearly insulin resistance and defective in first-phase insulin secretion as that in IGT subjects in Chinese population.

Longitudinal Analysis of the Insulin-Like Growth Factor System in African-American and European American Children and Adolescents

IGF-I and its binding proteins influence growth, development, and disease risk. Studies have revealed ethnic variations in the IGF system. This longitudinal study was undertaken to test the hypothesis that the ethnic differences in the IGF system exist throughout the pubertal transition, and these differences are mediated at least in part by inherent differences in insulin dynamics. This was a longitudinal study. Annual evaluations were conducted for pubertal maturation, body composition, acute insulin response to glucose (AIRg), and reproductive-endocrine profile. Hormones and binding proteins were determined using standard assays, the AIRg during a frequently sampled iv glucose tolerance test, and body composition by dual-energy x-ray absorptiometry. Mixed model analyses were used to identify and characterize ethnic differences in the IGF system across the pubertal transition after adjusting for ethnicity, sex, age, maturation status, body composition, and reproductive hormones, and to identify the contribution of insulin to IGF binding protein (IGFBP)-1. Subjects included African-American (AA) and European American children (n = 162 at baseline) aged 7-16 yr, evaluated across the pubertal transition. Annual data on IGF-I, IGFBP-1, and IGFBP-3 were examined. IGF-I was higher in AA children at pubertal stage 1 only (P < 0.001). However, IGFBP-3 and IGFBP-1 concentrations were lower in AAs through much of puberty (P < 0.05). The lower IGFBP-1 of AAs was in part explained by greater AIRg. Our data suggest that the higher IGF-I and lower IGFBP-1 and IGFBP-3 levels in AAs as compared with European Americans during puberty suggest potential ethnic differences in circulating bioavailable IGF-I. In addition, higher AIRg in AAs may lead to greater bioavailable IGF-I. Whether these differences in the IGF system account for disparities in disease risk warrants further investigation.

Obesity, body composition and metabolic disturbances in polycystic ovary syndrome

We determined the impact of polycystic ovary syndrome (PCOS) and obesity on glucose and lipid metabolism and beta-cell function in women with PCOS. In 35 women with PCOS (17 lean, lean PCOS and 18 obese, obese PCOS) and 25 control women (9 lean, lean controls and 16 obese, obese controls), beta-cell function was evaluated by the first-phase insulin response after intravenous glucose, acute insulin response to glucose (AIRg); insulin sensitivity, determined as insulin sensitivity index (ISI), was evaluated by the euglycemic hyperinsulinemic clamp. Indirect calorimetry was used for the assessment of glucose and lipid oxidation. Body composition was estimated by dual X-ray absorptiometry scan. When adjusted for obesity, PCOS was associated with higher 2-h glucose levels (P < 0.05), higher trunk/periphery fat ratio (P < 0.001), lower ISI (P < 0.001), lower insulin-stimulated glucose oxidation (GOX 2) (P < 0.05) and lower non-oxidative glucose metabolism (P < 0.05), but a normal AIRg compared with control women. Lean women with PCOS had lower ISI (P < 0.001), GOX-2 (P < 0.05) and higher trunk/periphery fat ratio (P < 0.05) than lean control women. In obese women with PCOS, ISI was reduced with 25% compared with obese control women, whereas trunk/peripheral fat ratio did not differ. AIRg was increased in obese groups compared with lean groups (P < 0.05), but was, in all groups, appropriate for the ambient action of insulin. PCOS is associated with a low ISI, which in lean women with PCOS may partly be explained by higher trunk/peripheral fat ratio. AIRg was amplified by obesity, but was, in all groups, appropriate for prevailing insulin sensitivity, suggesting a normal beta-cell adaptation.

Associations among Insulin, Estrogen, and Fat Mass Gain over the Pubertal Transition in African-American and European-American Girls

Age at menarche (AgeM) is earlier in African-American (AA) than in European-American (EA) girls. Neither the physiological cause nor the health implications of this difference are known. We tested the hypotheses that higher insulin among AA vs. EA precipitates an earlier elevation of estradiol (E2), an associated earlier AgeM, and greater gain in body fat. The study was conducted at a university research laboratory and General Clinical Research Center. Subjects were 137 girls (57 AA and 80 EA) aged 7-15 yr. The study had a longitudinal design. Annual evaluations were conducted for body composition by dual-energy X-ray absorptiometry, acute insulin response to glucose (AIRg) by iv glucose tolerance test, and reproductive-endocrine profile. Multiple linear regression modeling and mixed model analyses were used to identify independent predictors of AgeM and E2 concentration at menarche. AgeM was significantly earlier in AA vs. EA (10.8 vs. 11.6 yr). Neither E2 nor insulin was a significant independent predictor of AgeM. AIRg was a significant predictor of E2 concentration. AA had higher E2 than EA (P < 0.01), and girls with higher AIRg had higher E2. Total fat increased with age in both EA and AA. However, among EA, the increase in fat mass was similar both before and after menarche (9.4%/yr before vs. 10.0%/yr after), whereas among AA, fat deposition nearly doubled after menarche (8.4%/yr before vs. 14.9%/yr after). Results did not support a direct cause-and-effect relationship between higher insulin, higher E2, and earlier AgeM in AA girls. However, the data suggested that higher insulin was associated with higher E2. Furthermore, reproductive maturation appeared to be associated with an acceleration of fat deposition among AA girls.

Differences in insulin resistance and pancreatic B‐cell function in obese subjects with isolated impaired glucose tolerance and isolated impaired fasting glucose

To investigate changes in insulin action and insulin secretion in obese subjects with different categories of impaired glucose regulation (IGR): impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and combined IFG/IGT (CGI). A total of 222 subjects underwent an oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test (FSIGTT); 100 had normal glucose tolerance (subdivided into 32 lean NGT, 68 obese NGT), and 122 were obese with IGR (82 IGT, 14 IFG and 26 CGI). The insulin sensitivity index (S(I)) was assessed by Bergman's minimal model method with FSIGTT; insulin secretion was determined by acute insulin response to glucose (AIRg). The disposition index (DI), the product of AIRg and S(I), was used to determine whether AIRg was adequate to compensate for insulin resistance. S(I) was similar in NGT and IGR obese subgroups. AIRg was significantly increased in obese NGT as compared with lean NGT, significantly reduced in IGT, and further reduced in IFG and CGI subjects as compared with obese NGT subgroups. DI was reduced in NGT obese individuals. Within the obese IGR subgroups, IFG and CGI subjects had even lower DI value than IGT subjects. Obese Chinese subjects with IGR have a similar degree of insulin resistance but differ in insulin secretion. Subjects with IFG and CGI have a more prominent deficiency in insulin secretion than subjects with IGT.

Short-Term Exercise Improves β-Cell Function and Insulin Resistance in Older People with Impaired Glucose Tolerance

There is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Normal aging is associated with insulin resistance and impaired insulin secretion, with greater defects in people with IGT. Short-term exercise has been found to increase insulin sensitivity, but little is known about acute exercise effects on beta-cell function in older people with IGT. We assessed the effects of 7 consecutive days of supervised aerobic exercise (1 h/d at 60-70% heart rate reserve) in 12 sedentary older people with IGT. Screening included oral glucose tolerance test, stress/maximal O(2) uptake test, and dual-energy x-ray absorptiometry scan. Participants had a frequently sampled iv glucose tolerance test at baseline and 15-20 h after the seventh exercise session. Insulin sensitivity (S(I)), glucose disappearance constant (Kg, a measure of iv glucose tolerance), acute insulin response to glucose (AIRg), and disposition index (AIRg x S(I)), a measure of beta-cell function in relation to insulin resistance, were calculated. Exercise was well tolerated. Body weight, fasting glucose, fasting insulin, and iv glucose tolerance were unchanged with exercise. S(I) increased by 59%, AIRg decreased by 12%, and disposition index increased by 31%. There was no significant change in fasting lipid, catecholamine, leptin, or adiponectin levels. Short-term exercise not only improved insulin resistance but also significantly enhanced beta-cell function in older people with IGT. These effects of short-term exercise on beta-cell function cannot be explained by changes in body weight or circulating levels of lipids, leptin, adiponectin, or catecholamines.

The Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves β-Cell Function and Insulin Sensitivity in Subjects With Impaired Fasting Glucose

To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIR(g)) and insulin sensitivity index (S(I)) were determined and used to compute the disposition index (AIR(g) x S(I)) as a measure of beta-cell function. Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean +/- SEM AIR(g) increased from 224 +/- 44 to 286 +/- 52 pmol/l (P < 0.05), and S(I) improved from 2.8 +/- 0.5 to 3.5 +/- 0.5 x 10(-5) x min(-1) x pmol(-1) x l (P < 0.01), resulting in an increase in the disposition index from 688 +/- 180 to 1,164 +/- 318 x 10(-5)/min (P < 0.05). These effects were not sustained after washout. During the MTT, the incremental area under the glucose curve was significantly decreased after treatment (240 +/- 15 vs. 191 +/- 14 mmol x l(-1) x min(-1); P = 0.002), but this effect was not sustained after washout. The DPP-4 inhibitor vildagliptin improves insulin sensitivity and beta-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have beta-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects.

Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses

To determine effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. 6 adult Standardbreds. In a balanced crossover study, horses received dexamethasone (0.08 mg/ kg, IV, q 48 h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment) during a 21-day period. Horses underwent a 3-hour frequently sampled IV glucose tolerance test (FSIGT) 2 days after treatment. Minimal model analysis of glucose and insulin data from FSIGTs were used to estimate insulin sensitivity (Si), glucose effectiveness (Sg), acute insulin response to glucose (AIRg), and disposition index. Proxies for Si (reciprocal of the inverse square of basal insulin concentration [RISQI]) and beta-cell responsiveness (modified insulin-to-glucose ratio [MIRG]) were calculated from basal plasma glucose and serum insulin concentrations. Mean serum insulin concentration was significantly higher in dexamethasone-treated horses than control horses on days 7, 14, and 21. Similarly, mean plasma glucose concentration was higher in dexamethasone-treated horses on days 7, 14, and 21; this value differed significantly on day 14 but not on days 7 or 21. Minimal model analysis of FSIGT data revealed a significant decrease in Si and a significant increase in AIRg after dexamethasone treatment, with no change in Sg or disposition index. Mean RISQI was significantly lower, whereas MIRG was higher, in dexamethasone-treated horses than control horses on days 7, 14, and 21. The study revealed marked insulin resistance in healthy horses after 21 days of dexamethasone administration. Because insulin resistance has been associated with a predisposition to laminitis, a glucocorticoid-induced decrease in insulin sensitivity may increase risk for development of laminitis in some horses and ponies.

Impaired Endothelial Function in Healthy African-American Adolescents Compared with Caucasians

To determine whether African-American adolescents have endothelial dysfunction compared with Caucasians and whether differences are a result of differences in insulin sensitivity calculated from total glucose (S(I)) or secretion. Thirty-three Caucasian (13.6 +/- 2.6 years of age; body mass index [BMI] 21.6 +/- 4.4 kg/m2 mean +/- SD) and 25 African-American (13.3 +/- 2.9 years of age; BMI 24.0 +/- 4.4 kg/m2) adolescents were studied. Forearm blood flow (FBF; plethysmography) was measured before and after 5 minutes of arterial occlusion. S(I) and acute insulin response to glucose (AIRG) were measured using intravenous glucose tolerance tests and minimal modeling. Baseline FBF did not differ between races. Postocclusion FBF was lower in African-Americans (17.2 +/- 1.2 vs 22.6 +/- 1.2 mL/dL/minute, P = .006). AIRG was higher in African-Americans (6050 +/- 940 vs 2410 +/- 30 microU minute/mL, P = .001). Pubertal stage had no effect. S(I) did not differ by race or pubertal stage. In African-Americans, percent fall in FVR following arterial occlusion correlated (r = 0.67, P = .001) with log AIRG. No relationships were found between percent fall in FVR and S(I) in either race. African-American adolescents have decreased endothelial function. This may be a result of increased insulin secretion. Endothelial dysfunction in African-American adolescents may predispose to cardiovascular and type II diabetes.

Elements of the Metabolic Syndrome: Association with Insulin Sensitivity and Effects of Ethnicity

The objectives of the present study were, within a group of 322 healthy European American (EA) and African American (AA) women, to, (1) determine the extent to which insulin sensitivity (Si) was correlated with the elements of the metabolic syndrome using the third Adult Treatment Panel (ATP III) criteria; (2) determine if ethnicity affected the relationships between Si and the elements of the metabolic syndrome; and (3) determine the amount of variance in elements of the metabolic syndrome independently explained by fasting insulin, the acute insulin response to glucose (AIRg), and Si. Si and AIRg were assessed with a frequently-sampled intravenous glucose tolerance test and minimal modeling; total body fat with dual-energy x-ray absorptiometry; and intra-abdominal adipose tissue (IAAT) with computed tomography scanning. Among all women combined, Si was associated with fasting glucose (r = -0.18, p < 0.01), waist circumference (r = -0.36, p < 0.001), and high-density lipoprotein cholesteraol (HDL-C; r = 0.18, p < 0.01). However, the association of Si with elements of the metabolic syndrome other than fasting glucose and waist circumference differed with ethnicity; among EA, Si was correlated with triglycerides (r = -0.28, p < 0.01) and HDL-C (r = 0.29, p < 0.001), whereas among AA, Si tended to be correlated with systolic blood pressure (r = -0.17, p = 0.059). In multiple regression modeling, fasting insulin was independently related to more elements of the metabolic syndrome (fasting glucose, waist circumference, triglycerides, systolic and diastolic blood pressure) than were Si or AIRg (both related only to fasting glucose), after adjusting for ethnicity, age, and total fat or IAAT. Correlation of Si with elements of the metabolic syndrome differed with ethnic group. Fasting insulin, rather than Si, best predicted most elements of the metabolic syndrome.

Polymorphism in the Transcription Factor 7-Like 2 (TCF7L2) Gene Is Associated With Reduced Insulin Secretion in Nondiabetic Women

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7-57 years. Outcomes included BMI, percent body fat, insulin sensitivity (S(i)), acute insulin response to glucose (AIR(g)), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIR(g) adjusted for S(i) in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with S(i). The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower S(i) and higher AIR(g) observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes.