Acute Insulin Response To Glucose Research Articles

Effects of dietary fat on insulin secretion in subjects with the metabolic syndrome

Objective Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome. Design In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test. Results There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the high-fat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010). Conclusions The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

Oral Glucose Tolerance Testing Allows Better Prediction of Diabetes in Women with a History of Gestational Diabetes Mellitus.

BackgroundWe aimed to identify the postpartum metabolic factors that were associated with the development of diabetes in women with a history of gestational diabetes mellitus (GDM). In addition, we examined the role of the oral glucose tolerance test (OGTT) in the prediction of future diabetes.MethodsWe conducted a prospective study of 179 subjects who previously had GDM but did not have diabetes at 2 months postpartum. The initial postpartum examination including a 75-g OGTT and the frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed 12 months after delivery, and annual follow-up visits were made thereafter.ResultsThe insulinogenic index (IGI30) obtained from the OGTT was significantly correlated with the acute insulin response to glucose (AIRg) obtained from the FSIVGTT. The disposition indices obtained from the OGTT and FSIVGTT were also significantly correlated. Women who progressed to diabetes had a lower insulin secretory capacity including IGI30, AIRg, and disposition indices obtained from the FSIVGTT and OGTT compared with those who did not. However, the insulin sensitivity indices obtained from the OGTT and FSIVGTT did not differ between the two groups. Multivariate logistic regression analysis showed that the 2-hour glucose and disposition index obtained from the FSIVGTT were significant postpartum metabolic risk factors for the development of diabetes.ConclusionWe identified a crucial role of β-cell dysfunction in the development of diabetes in Korean women with previous GDM. The 2-hour glucose result from the OGTT is an independent predictor of future diabetes. Therefore, the OGTT is crucial for better prediction of future diabetes in Korean women with previous GDM.

Pathogenic Mechanisms of Prediabetes in Obese vs. Very Obese African American Women: Implications for Diabetes Prevention

BackgroundThe influence of obesity on the development of prediabetes among African American women (AAW) remains uncertain. Thus, we investigated whether the pathogenic mechanisms of prediabetes differ in obese (OB, BMI<35 kg/m2) and very obese (VOB, BMI>35 kg/m2) AAW. Subjects/MethodsWe recruited 26-OB and 41-VOB, AAW with prediabetes, mean age (46.3 ± 10.3 years), A1C (5.9 ± 0.4%) and BMI (38.3 ± 8.2 kg/m2). OGTT and FSIVGT were performed in each subject. Body composition (% body fat) was measured using DEXA. Si, Sg acute insulin response to glucose (AIRg) and disposition index (DI) were calculated using minimal model method. ResultsMean BMI (32.6 ± 1.9 vs. 42.8 ± 5.5 kg/m2) and %body fat (44.7 ± 2.0 vs. 49.6 ± 2.2%) were significantly (p = 0.0001) lower in OB vs VOB. Mean fasting and post-glucose challenge, (glucose, insulin, c-peptide) levels were significantly (p = 0.03–0.0001) lower in OB vs VOB. Mean Si and Sg was not different. Mean AIRg tended to be higher (808 ± 776 vs. 535 ± 443 (x min [uU/L] −1), p = 0.106) whereas DI was greater (1999 ± 1408 vs. 1511 ± 1033, (×10−2 x min−1), p = 0.01) in OB vs VOB subjects. ConclusionWe found that OB and VOB AAW had similar Si and Sg, but VOB showed attenuated AIRg and DI. These parameters should be considered when developing primary prevention programs in AAW with prediabetes.

Longitudinal Predictors of Insulin Sensitivity and Secretion during Puberty

All youth experience a transient reduction in Si during puberty, but little is known about the associated physiology. We previously demonstrated cross-sectionally that insulin-like growth factor 1 (IGF-1) and leptin are associated with Si early in puberty. We now aim to evaluate longitudinal predictors of Si and acute insulin response to glucose (AIRg) during puberty. Methods: Forty-five (47% female) normal-weight (mean BMI %ile 44±22%) ethnically mixed youth entered the study in early puberty (Tanner [T] 2-3). Study visits, including an IV glucose tolerance test (IVGTT), fasting laboratory studies, and DXA, were performed at T2-3, T4, and T5, based on breast development and testicular volume. Physical activity (PA) was assessed by the 3DPAR (3-Day PA Recall). Repeated measures models were used to test if changes over time in potential predictors (IGF-1, leptin, estradiol, total testosterone, dehydroepiandrosterone-sulfate, PA, and urinary gonadotropins) were associated with changes over time in the outcomes, with and without adjustment for sex and % body fat. Results: Si (p=0.04) decreased and AIRg increased (p=0.12) from T2/3-T5. IGF-1 and leptin were the only significant predictors of change in Si and AIRg over time. IGF-1 was associated with both Si (β=-0.016, p=0.0004) and AIRg (β=1.40, p=0.002), and remained so after adjusting for sex and % fat (p=0.0007 and 0.004, respectively). Leptin was associated with Si in univariate analysis (p=0.003) and with both Si (β=-0.238, p=0.003) and AIRg (β=38.4, p=0.043) after adjustment for sex and % fat. Conclusions: This is the first study to show a longitudinal relationship between leptin and Si and AIRg during puberty independent of sex and body fat, and confirms previous reports of associations between IGF-1 and Si and AIRg. These results suggest that leptin and IGF-1 may be driving factors for changes in Si and AIRg during puberty. Knowledge of normal pubertal metabolism may contribute to understanding of diseases of pubertal onset, such as type 2 diabetes. Disclosure M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp &amp; Dohme Corp.. L. Pyle: None. A.M. Hilkin: None. A. Johnson: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Daiichi Sankyo Company, Limited, Merck &amp; Co., Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Boehringer Ingelheim GmbH.

Effect of age and dietary carbohydrate profiles on glucose and insulin dynamics in horses.

Glucose and insulin dynamics may be different in adult and aged horses. To determine the effects of age and dietary carbohydrates on glucose and insulin dynamics in healthy horses. Balanced Latin square with four isocaloric diets: CONTROL (hay plus restricted-starch-and-sugar fortified pellets), STARCH (control plus kibbled corn), FIBER (control plus unmolassed sugar beet pulp/soybean hull pellets) and SUGAR (control plus dextrose powder). A total of 16 healthy Thoroughbreds and Standardbreds divided into two age groups: ADULT (8.8±2.9years; n=8) and AGED (20.6±2.1years; n=8). Following dietary adaptation, horses underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT), modified oral sugar test (OST) and dietary meal challenge. Outcome variables included: insulin sensitivity (SI), disposition index (DI), glucose effectiveness (Sg) and acute insulin response to glucose (AIRg) from the FSIGTT; peak glucose, peak insulin, time to peak, area under the curve for glucose (AUCg) and insulin (AUCi) from the OST and dietary meal challenge. Data were analyzed using multivariable linear mixed regression modelling. AIRg was higher in AGED (mean [95% confidence interval]; 582.0 [455.0-709.0]) vs. ADULT (358.0 [224.0-491.0]; P=0.03). ADULT and AGED horses had a higher SI on STARCH (adult: 3.3 [2.3-4.2]; aged: 2.8 [1.9-3.7]) and SUGAR (adult: 3.4 [2.5-4.3]; aged: 4.0 [3.1-4.9]) diets compared with CONTROL (adult: 2.0 [1.1-2.9], P=0.029 (starch), P=0.009 (sugar); aged: 1.4 [0.5-2.2], P=0.009 (starch), P < 0.001 (sugar)). Feeding a STARCH (adult: 21581.0 [15029.0-28133.0]; aged: 35205.0 [29194.0-41216.0]) or SUGAR (adult: 26050.0 [19885.0-32215.0]; aged: 25720.0 [19770.0-31670.0]) meal resulted in postprandial hyperinsulinaemia (AUCi). Study cohort contained two insulin-sensitive breeds and no insulin-resistant breeds. Age and diet should be considered when evaluating glucose and insulin dynamics.

Evaluation of a Reduced Sampling Schedule for Assessment of Pancreatic Beta‐Cell Function with the Intravenous Glucose Tolerance Test During a Dietary Intervention

Pancreatic beta‐cell function is a key determinant of glucose tolerance. The intravenous glucose tolerance test (IVGTT) can be used to assess both the insulin sensitivity index (Si) and the acute insulin response to glucose (AIRg). The disposition index (DI = Si × AIRg) reflects the adequacy of pancreatic beta‐cell response for the level of insulin sensitivity. The aim of this analysis was to compare the AIRg and DI values calculated using a reduced early test sampling schedule (t = 0, 5, 10 min), to those from the full sampling schedule (t = 0, 3, 5, 7, and 10 min). Participants included men (n = 8) and women (n = 16) with mean (SD) age 48.9 (9.9) y and body mass index 30.8 (4.9) kg/m2. Subjects consumed 0, 15, and 30 g/d high‐amylose resistant starch (RS) for 4 weeks each, in a double‐blind, randomized, crossover trial, and underwent a 180‐min IVGTT at the end of each treatment period. The Minmod Millenium program was used to derive Si. AIRg was calculated as the mean increment in plasma insulin during the first 10 min of the test for the full and reduced sampling schedules. The median (interquartile range) full schedule AIRg values during the control, 15, and 30 g/d RS conditions were 43 (29, 103), 47 (23, 67) and 44 (30, 94) mU/L, respectively. Mean (95% confidence interval) percentages of the full schedule values for the reduced schedule values were 82 (79–86), 87 (76–98) and 83 (80–85) for the control, 15 and 30 g/d RS conditions, respectively, all p &lt; 0.05 vs. the full schedule. Correlations between the AIRg and DI values from the two schedules during each RS condition were high (Pearson r values all ≥0.98, p &lt; 0.001). Thus, although AIRg and DI values cannot be directly compared between sampling schedules, the reduced sampling schedule accurately reflects relative AIRg and DI values, and may thus be a time and cost‐effective option when conducting the IVGTT in clinical and epidemiological studies.Support or Funding InformationIngredion Inc., Westchester, IL

Ethnic differences in glucose effectiveness and disposition index in overweight/obese African American and white women with prediabetes: A study of compensatory mechanisms.

Prediabetes, a major precursor of type 2 diabetes, varies among ethnic populations. Therefore, we compared the pathophysiologic mechanisms of prediabetes in overweight/obese African American (AA) and White American (WA) women. We recruited 95 women (67 AA, 28 WA) with prediabetes. Standard OGTT and FSIVGTT were performed in each subject. Insulin sensitivity (Si), glucose effectiveness (Sg), beta cell function (acute insulin response to glucose (AIRg) and disposition index (DI: Si×AIRg) were calculated using Bergman's Minmod. Mean BMI was greater in AA vs WA with prediabetes (38.3±8.2vs 34.6±8.5kg/m2, p=0.05). Mean fasting serum glucose, and insulin levels were lower in AA vs WA. Similarly, mean peak serum glucose levels were lower while peak insulin levels were higher at 30 and 60minutes in AA vs WA. In contrast, mean fasting and peak serum c-peptide levels at 60 and 90minutes were significantly lower in AA vs WA. Mean AIRg was higher but not significantly different in AA vs WA (633±520.92 vs 414.8±246.8, p=0.193). Although, Si (2.93±3.25vs 44 2.50±1.76 (×10-4×min-1 [μU/ml]-1), p=0.448) was not different, DI was significantly higher in AA vs WA (1381±1126 vs 901.9±477.1, p=0.01). In addition, mean Sg was significantly higher in AAvs WA (2.51±1.17 vs 1.97±0.723 (×10-2/min), p=0.02). We found that in overweight/obese prediabetic AA and WA women with similar Si, the mean Sg and DI were significantly higher in AA. We conclude that the pathophysiologic mechanisms of prediabetes differ in the overweight/obese AA and WA women.

GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS.

Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with known T2D loci implicated in insulin secretion. To test this hypothesis, single nucleotide polymorphisms (SNPs) nominally associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and previously associated with T2D in genome-wide association studies (GWAS) were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n=492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using GWAS data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n=2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction < 5×10-6) interactions were observed at several loci including DGKB (rs978989), CDK18 (rs12126276), CXCL12 (rs7921850), HCN1 (rs6895191), FAM98A (rs1900780), and MGMT (rs568530). Notable beta-cell GRS interactions included two SNPs at the DGKB locus (rs6976381; rs6962498). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.

The longitudinal effects of ambient air pollution exposure on obesity and risk factors for type 2 diabetes in Los Angeles Latino children

Introduction: Studies suggest that ambient (AAP: NO2, PM2.5, and O3) contributes to risk for obesity and type 2 diabetes. The objective of this study was to examine relationships between residential AAP, adiposity, and risk factors for type 2 diabetes over 13 years of follow-up. Methods: Overweight and obese Latino children (8-15 years) were enrolled between 2001–2013 from urban Los Angeles, California (n=317). Yearly data include body mass index (BMI), body fat percent, and abdominal adiposity. Metabolic testing provided fasting insulin and glucose, insulin sensitivity (SI), acute insulin response to glucose (AIRg), and disposition index (DI, an estimate of β-cell function). Individual residential AAP exposure was estimated from central site monitors. Linear mixed models were used to assess associations between AAP and longitudinal outcomes. Effects are reported for each SD increase in exposure. Results: NO2 and PM2.5 exposure was positively associated with BMI growth (p=0.04 and p=0.007, respectively) and an increase of approximately 1.7 and 2.6 BMI units at age 18 (p&lt;0.01 for both). NO2 and PM2.5 exposure was inversely associated with SI over follow-up (p=0.02 for both) and a 13.6% and 21% lower SI at age 18 (p=0.04 and p=0.01). PM2.5 exposure was positively associated with a 27.2% higher AIRg at age 18 (p=0.03). NO2 exposure was inversely associated with DI over follow-up (p=0.02) and a 13.7% lower DI at age 18 (p=0.04). Conclusions: This analysis provides the first longitudinal evidence of significant effects of NO2 and PM2.5 exposures on adiposity, glucose metabolism, and β-cell function in Latino children. These results identify AAP as a risk factor for obesity and type 2 diabetes-related pathophysiology in children.

Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans.

Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10−6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.

Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs.

A normal consequence of increased energy intake and insulin resistance is compensatory hyperinsulinaemia through increased insulin secretion and/or reduced insulin clearance. Failure of compensatory mechanisms plays a central role in the pathogenesis of type 2 diabetes mellitus; consequently, it is critical to identify in vivo signal(s) involved in hyperinsulinaemic compensation. We have previously reported that high-fat feeding leads to an increase in nocturnal NEFA concentration. We therefore designed this study to test the hypothesis that elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation for insulin resistance. Blood sampling was conducted in male dogs to determine 24 h profiles of NEFA at baseline and during high-fat feeding with and without acute nocturnal NEFA suppression using a partial A1 adenosine receptor agonist. High-fat feeding increased nocturnal NEFA and reduced insulin sensitivity, effects countered by an increase in acute insulin response to glucose (AIR(g)). Pharmacological NEFA inhibition after 8 weeks of high-fat feeding lowered NEFA to baseline levels and reduced AIR(g) with no effect on insulin sensitivity. A significant relationship emerged between nocturnal NEFA levels and AIR(g). This relationship indicates that the hyperinsulinaemic compensation induced in response to high-fat feeding was prevented when the nocturnal NEFA pattern was returned to baseline. Elevated nocturnal NEFA are an important signal for hyperinsulinaemic compensation during diet-induced insulin resistance.

An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.

Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of β-cell function in African American women

BackgroundThe TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians. However, there are conflicting data on TG/HDL-C ratio as a predictor of IR in African Americans. Compared to Caucasians, African Americans have lower TG levels and increased insulin levels despite a greater risk for diabetes. We hypothesized that the TG/HDL-C ratio is predictive of IR and/or β-cell function in African American (AA) women. MethodsNon-diabetic AA women (n=41) with a BMI>25kg/m2 underwent frequently sampled intravenous glucose tolerance test (FSIGTT). Insulin sensitivity (SI) and the acute insulin response to glucose (AIRg) were measured using minimal model and β-cell function was determined by disposition index (DI=SI*AIRg). IR was defined as the lowest tertile of SI (<1.8×10−4min−1/μU/ml) and inadequate β cell compensation was defined as the lowest tertile of DI (<900). Data were analyzed using logistic regression models and area under the receiver operating characteristic curve (AUC-ROC). An AUC-ROC>0.70 was defined as significant discrimination. ResultsThe mean (± SD) age was 38.5±11.3years, with BMI of 33.5±6.7kg/m2 and fasting glucose of 86.5±10.5mg/dL. The AUC-ROC for the prediction of DI<900 was 0.74 indicating that a higher TG/HDL-C ratio was associated with decreased DI. However, the AUC-ROC for prediction of IR or low AIRg (<335 μU/ml) was not significant. ConclusionThis study confirmed that the TG/HDL-C ratio is a poor predictor of IR in AA women. However, we did show an inverse association between the TG/HDL-C ratio and β-cell function, suggesting that this simple tool may effectively identify AA women at risk for DM2.

Decreased Insulin Secretion in Women with Previous Gestational Diabetes Mellitus

Objectives: Gestational diabetes mellitus (GDM) affects 2%–4% of the all pregnant women, and it is a major risk factor for development of type 2 DM. We performed this cross-sectional study to determine whether there were defects in insulin secretory capacity or insulin sensitivity in women with previous GDM. Methods: On 6–8 weeks after delivery, 75 g oral glucose tolerance test was performed in 36 women with previous GDM and 19 non-pregnant control women matched with age and weight. Intravenous glucose tolerance test was performed on 10–14 weeks after delivery. Insulin secretory capacity measured as the acute insulin response to glucose (AIRg) and insulin sensitivity as minimal model derived sensitivity index (SI) were obtained. AIRg×SI (β-cell disposition index) was used as an index of β-cell function. Results: Women with previous GDM were classified into normal glucose tolerance (postpartum-NGT, n=19) and impaired glucose tolerance (postpartum-IGT, n=17). Postpartum fasting glucose levels were significantly higher in postpartum-IGT compared to postpartum-NGT and control (P<0.05). AIRg×SI was significantly lower in postpartum-IGT compared to control (P<0.05). SI was lower in postpartum-NGT and postpartum-IGT compared to control, but the difference did not have the statistical significance. Frequency of parental history of type 2 diabetes was significantly greater in postpartum-IGT compared to postpartum-NGT (P<0.05). Conclusion: Women with previous GDM showed impaired insulin secretion although their glucose tolerance states were restored to normal. It suggests impaired early insulin secretion may be a major pathophysiologic factor for development of type 2 DM, and this defect may be genetically determined. (Ewha Med J 2015;38(1):30-35)

Effects of diet-induced weight loss on the cardiometabolic markers in obese African American and white women with prediabetes

Objective: The objective was to investigate the effects of a 6 month diet-induced weight loss (DIWL) on glucose homeostasis, cardiometabolic variables, and high density lipoproteins (HDL) associated functionality paraoxonase1 (PON1) enzyme in overweight/obese African American (AA) and White American (WA) women, with prediabetes. Methods: We recruited 108 obese women (67 AA and 41 WA) with prediabetes hemoglobin A 1 C (HbA 1 C; 5.7-6.4%). Metabolic studies, fasting cardiometabolic markers (lipids/lipoproteins, inflammatory markers), and PON1 were performed at 0, 3, and 6 months. Insulin sensitivity (Si), glucose effectiveness (Sg), acute insulin response to glucose (AIRg), and disposition index (DI) were obtained (Bergman's Minmod). The DIWL program consists of approximately 1200 kcal/day for 6 months. Results: The mean body mass index was greater in AA than WA (38 ± 8 vs. 34 ± 8 kg/m 2 ). DIWL resulted in a mean 7.5% and 10.3% (8kg vs. 10.3 kg) weight loss in AA versus WA. Mean fasting and 2 h serum glucose, insulin, and c-peptide levels decreased significantly during 3 and 6 versus 0 month. The mean Si, Sg, AIRg, and DI did not improve in either AA or WA. DIWL had no significant effect on the cardiometabolic markers or PON1 in the present study. Conclusions: We found ethnic differences in the magnitude of the weight loss. However, modest weight loss had no impact on the glucose homeostasis, cardiovascular markers, and HDL functionality in prediabetic AA and WA women.

Rapid Deterioration of Insulin Secretion in Obese Adolescents Preceding the Onset of Type 2 Diabetes

To identify pathophysiologic changes that lead to the onset of type 2 diabetes (T2DM) in adolescents. Obese adolescents with normal glucose tolerance (n = 41) were studied longitudinally over the course of 4 years with serial measure of the acute insulin response to glucose (AIRg) as well as proinsulin (PI) concentrations. Insulin resistance was estimated with the homeostatic model assessment of insulin resistance (HOMA-IR), the disposition index (DI) computed as AIRg × 1/HOMA-IR, and intravenous glucose tolerance estimated as the glucose disappearance constant. Four adolescents developed diabetes mellitus (DM) during the study, and the rest of the cohort remained nondiabetic. Baseline PI exceeded the IQR of the nondiabetic group in 3 of 4 subjects with DM, and all had >85% reduction from baseline AIRg, and DI, within 6 months of diagnosis. All the subjects with DM gained weight over the course of the study, but these changes paralleled those for the nondiabetic group. HOMA-IR increased substantially in 1 of the subjects with DM at the time of diagnosis but was comparable with baseline in the other 3. The DI and glucose disappearance constant of the subjects with DM was less than the 10th percentile of the nondiabetic group before and after diagnosis. Conversion from normal glucose tolerance to T2DM in adolescents can occur rapidly, and the onset of T2DM is heralded by a substantial decrease in AIRg and DI, as well as increased release of PI. These results support loss of β-cell function as the proximate step in the development of T2DM in this age group.

Activation of Innate Immunity Modulates Insulin Sensitivity, Glucose Effectiveness and Pancreatic β-Cell Function in Both African Ancestry and European Ancestry Healthy Humans

ObjectiveInsulin resistance is a risk factor for type 2 diabetes, and is associated with inflammatory cardiometabolic disease. Given differences between African ancestry (AA) and European ancestry (EA) in the epidemiology of type 2 diabetes as well as in response to inflammatory stress, we investigated potential race differences in glucose homeostasis responses during experimental endotoxemia in humans. MethodsHealthy volunteers (age 18–45years, BMI 18–30kg/m2, 47% female, African-ancestry (AA, n=42) and European-ancestry (EA, n=106)) were recruited as part of the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study. Subjects underwent an inpatient endotoxin challenge (1ng/kg LPS) and two frequently-sampled intravenous glucose tolerance tests (FSIGTT). Insulin and glucose values obtained during FSIGTT pre- and 24-hours post-LPS were analyzed using the minimal model. ResultsFSIGTT derived insulin sensitivity index (SI), disposition index (DI) and glucose effectiveness (SG) decreased significantly following LPS (p<0.0001) while the acute insulin response to glucose (AIRg) increased (p<0.0001). Although expected race differences were observed in glucose homeostasis parameters at baseline prior to LPS e.g., lower SI (2.5 vs. 4.1μU/L/min, p<0.0001) but higher AIRg (median 848 vs. 290μU/L/min, p<0.0001) in AA vs. EA, the changes in glucose homeostasis responses to LPS were directionally and proportionally consistent across race e.g., SI median −35% in EA and −29% in AA and AIRg median +17% in EA and +26% in AA. ConclusionBoth EA and AA samples modulated glucose and insulin homeostasis similarly during endotoxemia. ImplicationsRace differences in response to environmental inflammatory stress are unlikely to be a substantial contributor to the observed difference in diabetes incidence and complications between EA and AA.

Combination of peptide YY3-36 with GLP-1(7-36) amide causes an increase in first-phase insulin secretion after IV glucose.

Context:The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown.Objective:This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity.Setting and Design:Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility.Results:PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention.Conclusions:PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Acute Administration of Unacylated Ghrelin Has No Effect on Basal or Stimulated Insulin Secretion in Healthy Humans

Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 men and 8 women) on four occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h intravenous glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and intravenous glucose tolerance (kg) were compared for each subject during the four infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared with the saline control, AG and AG+UAG both decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon, or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared with the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or β-cell function and neither augments nor antagonizes the effects of AG.

Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome.

Are differences in metabolic dysfunction between polycystic ovary syndrome (PCOS) and control women related to differences in their fat to lean mass (F/L) ratio? Compared with controls of similar body mass index (BMI), women with PCOS demonstrate adverse body composition characterized by increased whole body fat relative to lean mass (i.e. a higher F/L ratio), which is associated with differences in metabolic dysfunction between the two groups. Previous studies examining body composition and insulin resistance (IR) in PCOS have yielded conflicting results. Excess total fat mass (i.e. fat mass index [fat BMI]) correlates with IR, whereas increased total lean mass (i.e. lean BMI) has been associated with higher insulin sensitivity. However, the role of the F/L ratio, which integrates the antagonistic effects of both fat and lean mass depots, on IR in PCOS, has not been investigated. We conducted a prospective cross-sectional study of 120 women between the ages of 22-44 years to study the relation of the F/L ratio with measures of insulin action and secretion in both steady and dynamic states. Sixty PCOS (by NIH, 1990 criteria) and 60 control (age, race and BMI-matched) women were prospectively studied for body composition (by bioelectrical impedance analysis [BIA]) and basal IR and insulin secretion by the homeostasis model assessment (HOMA-IR and HOMA-%β-cell function, respectively) in a tertiary care academic referral center. A subset of 12 PCOS and 12 matched control women also underwent a modified frequently sampled intravenous glucose tolerance test (FSIVGTT) to determine glucose uptake and insulin secretion in dynamic state. Our results indicate that women with PCOS demonstrated greater degrees of hyperandrogenism, and higher waist-to-hip ratio (WHR), %body fat, fat BMI, F/L, fasting insulin levels, and HOMA-IR and HOMA-%β-cell values, than controls. In models adjusted for WHR and free testosterone and diagnostic groups, fasting insulin levels, HOMA-IR, and HOMA-%beta cell function were positively related to the F/L ratio. A positive relationship was also found in both study groups between F/L and the FSIVGTT measures insulin sensitivity (Si) and acute insulin response to glucose (AIRg). The F/L tended to negatively correlate with glucose effectiveness or non-insulin-mediated glucose transport (Sg) only in PCOS women. Regional tissue sub-compartments, which have been shown to have potential independent associations with metabolic variables, cannot be determined by bioelectrical impedance analysis (BIA). The current results suggest that BIA could be used to assess F/L in place of dual energy X-ray absorptiometry (DXA) in research protocols, and that F/L could possibly be used as an alternative to WHR as a surrogate marker of metabolic dysfunction in clinical practice. This work was supported by grants R01-DK073632 and R01-HD29364 from the NIH and an endowment of the Helping Hand of Los Angeles, Inc. (to R.A.). The authors have no competing interests to declare. Not applicable.