Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty‐one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA‐IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([ΔI5/ΔG5]/HOMA‐IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol², P < 0.001). One month following BPD, in both groups BW was reduced (by ～11%), but all subjects were still severely obese; HOMA‐IR and leptin decreased significanlty, while high‐molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non‐diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.     

β‐Cell Function and Insulin Sensitivity in Adolescents From an OGTT

Given the increase in the incidence of insulin resistance, obesity, and type 2 diabetes in children and adolescents, it would be of paramount importance to assess quantitative indices of insulin secretion and action during a physiological perturbation, such as a meal or an oral glucose‐tolerance test (OGTT). A minimal model method is proposed to measure quantitative indices of insulin secretion and action in adolescents from an oral test. A 7 h, 21‐sample OGTT was performed in 11 adolescents. The C‐peptide minimal model was identified on C‐peptide and glucose data to quantify indices of β‐cell function: static φ_s and dynamic φ_d responsivity to glucose from which total responsivity φ was also measured. The glucose minimal model was identified on glucose and insulin data to estimate insulin sensitivity, S_I, which was compared to a reference measure, S_I^ref, provided by a tracer method. Disposition indices, which adjust insulin secretion for insulin action, were then calculated. Indices of β‐cell function were φ_s = 51.35 ± 8.89 × 10^?9min^?1, φ_d = 1,392 ± 258 × 10^?9, and φ = 82.09 ± 17.70 × 10^?9min^?1. Insulin sensitivity was S_I = 14.19 ± 2.73 × 10^?4, not significantly different from S_I^ref = 14.96 ± 3.04 × 10^?4 dl/kg·min per µU/ml, and well correlated: r = 0.98, P < 0.0001, thus indicating that S_I can be accurately measured from an oral test. Disposition indices were DI_s = 1,040 ± 201 × 10^?14 dl/kg/min² per pmol/l, DI_d = 33,178 ± 10,720 × 10^?14 dl/kg/min per pmol/l, DI = 1,844 ± 522 × 10^?14 dl/kg/min² per pmol/l. Virtually the same minimal model assessment was obtained with a reduced 3 h, 9‐sample protocol. OGTT interpreted with C‐peptide and glucose minimal model has the potential to provide novel insight regarding the regulation of glucose metabolism in adolescents, and to evaluate the effect of obesity and interventions such as diet and exercise.     

Changes in the serum composition of free-fatty acids during an intravenous glucose tolerance test

Recent studies suggest that measuring the free-fatty acids (FFA) during an intravenous glucose tolerance test (IVGTT) may provide information about the metabolic associations between serum FFA and carbohydrate and insulin metabolism. We evaluated the FFA profile during an IVGTT and determined whether this test changes the composition and concentration of FFA. An IVGTT was given to 38 severely obese persons before and 7 months after undergoing bariatric surgery and also to 12 healthy, nonobese persons. The concentration and composition of the FFA were studied at different times during the test. The concentration of FFA fell significantly faster during the IVGTT in the controls and in the severely obese persons with normal-fasting glucose (NFG) than in the severely obese persons with impaired-fasting glucose (IFG) or type 2 diabetes mellitus (T2DM) (P < 0.05). Significant differences were found in the time to minimum serum concentrations of FFA (control = NFG < IFG < T2DM) (P < 0.001). These variables improved after bariatric surgery in the three groups. The percentage of monounsaturated and n-6 polyunsaturated FFA in the control subjects and in the obese persons, both before and after surgery, decreased significantly during the IVGTT. In conclusion, during an IVGTT, severely obese persons with IFG or T2DM experienced a lower fall in the FFA than the severely obese persons with NFG and the controls, becoming normal after bariatric surgery.     

ADRB2 Haplotype Is Associated With Glucose Tolerance and Insulin Sensitivity in Obese Postmenopausal Women

The β₂‐adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly‐Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45–75 years) women (n = 123) underwent genotyping, dual‐energy X‐ray absorptiometry, and computed tomography scans, exercise testing (VO_2max), 2‐h oral glucose tolerance tests (OGTTs), and hyperinsulinemic‐euglycemic clamps (80 mU/m²/min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO_2max as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO_2max, insulin sensitivity (M/ΔInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16–Gln27 haplotype had the highest % body fat (52.7 ± 1.9%), high abdominal fat, low M/ΔInsulin (0.49 ± 0.08 mg/kg/min/pmol/l/10²), and impaired glucose tolerance (IGT) during an OGTT (G₁₂₀ = 10.2 ± 0.9 mmol/l). Women homozygous for Gly16–Glu27 haplotype also had low M/ΔInsulin (0.51 ± 0.05 mg/kg/min/pmol/l/10²) and IGT (G₁₂₀ = 8.2 ± 0.7 mmol/l). Subjects with Arg16–Gln27/Gly16–Gln27 haplotype combination had the highest VO_2max (1.84 ± 0.07 l/min) and M/ΔInsulin (0.7 ± 0.04 mg/kg/min/pmol/l/10²), and normal glucose tolerance (G₁₂₀ = 6.4 ± 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly‐Gln27Glu haplotype with VO_2max and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women.     

Low 25‐Hydroxyvitamin D Does Not Affect Insulin Sensitivity in Obesity after Bariatric Surgery

Objective: A positive correlation between levels of 25‐hydroxyvitamin D [25(OH)D] and insulin sensitivity has been shown in healthy subjects. We aimed to test the hypothesis that concentration of 25(OH)D influences insulin sensitivity in obesity before and after weight loss. Research Methods and Procedures: We investigated the relation between serum 25(OH)D and insulin sensitivity (estimated by euglycemic‐hyperinsulinemic clamp) in 116 obese women (BMI ≥ 40 kg/m²) evaluated before and 5 and 10 years after biliopancreatic diversion (BPD). Body composition was estimated by the isotope dilution method. Results: Prevalence of hypovitaminosis D was 76% in the obese status and 91% and 89% at 5 and 10 years after BPD, respectively, despite ergocalciferol supplementation. 25(OH)D concentration decreased from 39.2 ± 22.3 in obesity (p = 0.0001) to 27.4 ± 16.4 and 25.1 ± 13.9 nM 5 and 10 years after BPD, respectively. Whole‐body glucose uptake increased from 24.27 ± 4.44 at the baseline to 57.29 ± 11.56 and 57.71 ± 8.41 μmol/kg_{fat free mass} per minute 5 and 10 years after BPD, respectively (p = 0.0001). Predictor of 25(OH)D was fat mass (R² = 0.26, p = 0.0001 in obesity; R² = 0.20, p = 0.02 after BPD). Parathormone correlated with fat mass (R² = 0.19; p = 0.0001) and BMI (R² = 0.053; p = 0.01) and inversely with M value (R² = 0.16; p = 0.0001), but only in obese subjects. Discussion: A high prevalence of hypovitaminosis D was observed in morbid obesity both before and after BPD. Low 25(OH)D did not necessarily imply increased insulin resistance after BPD, a condition where, probably, more powerful determinants of insulin sensitivity overcome the low circulating 25(OH)D levels. However, the present data cannot exclude some kind of influence of vitamin D status on glucose and insulin metabolism.     

Growth hormone and ghrelin secretion in severely obese women before and after bariatric surgery

Objective: The objective was to evaluate ghrelin and growth hormone (GH) interactions and responses to a growth hormone‐releasing hormone (GHRH)/arginine test in severe obesity before and after surgically‐induced weight loss. Research Methods and Procedures: Our study population included 11 severely obese women 39 ± 12 years of age, with a mean BMI of 48.6 ± 2.4 kg/m², re‐studied in a phase of stabilized body weight, with a BMI of 33.4 ± 1.2 kg/m², 18 months after having successfully undergone biliopancreatic diversion (BPD). A GHRH/arginine test was performed before and 18 months after BPD to evaluate ghrelin and GH interactions. Active ghrelin, measured by radioimmunoassay (RIA), and GH, measured by chemiluminescence assay, were assayed before and after the GHRH/arginine test. Results: Fasting serum GH levels and GH area under the curve (AUC) significantly increased from 0.2 ± 0.05 ng/mL to 1 ± 0.3 ng/mL (p < 0.05) and from 514.76 ± 98.7 ng/mL for 120 minutes to 1957.3 ± 665.1 ng/mL for 120 minutes after bariatric surgery (p < 0.05), respectively. Although no significant change in fasting ghrelin levels was observed (573 ± 77.9 before BPD vs. 574.1 ± 32.7 after BPD), ghrelin AUC significantly increased from ?3253.9 ± 2180.9 pg/mL for 120 minutes to 1142.3 ± 916.4 pg/mL for 120 minutes after BPD (p < 0.05). Fasting serum insulin‐like growth factor (IGF)‐1 concentration did not change significantly (133.6 ± 9.9 ng/mL before vs. 153.3 ± 25.2 ng/mL after BPD). Discussion: Our study demonstrates that the mechanisms involved in ghrelin and GH secretion after the secretagogue stimulus (GHRH/arginine) are consistent with patterns observed in other populations.     

Associations of Free Fatty Acids With Insulin Secretion and Action Among African‐American and European‐American Girls and Women

Ethnic differences in insulin secretion and action between African Americans (AAs) and European Americans (EAs) may influence mobilization of free fatty acids (FFAs). We tested the hypotheses that FFA concentrations would be associated with measures of insulin secretion and action before and during a glucose challenge test. Subjects were 48 prepubertal girls, 60 premenopausal women, and 46 postmenopausal women. Fasting insulin (insulin₀), the acute insulin response to glucose (AIR_g), the insulin sensitivity index (S_I), basal and nadir FFA (FFA₀, FFA_nadir), and nadir time (TIME_nadir) were determined during an intravenous glucose tolerance test (IVGTT). Stepwise multiple linear regression (MLR) analysis was conducted to identify associations of FFA₀, FFA_nadir, and TIME_nadir with ethnicity, age group, insulin measures, indexes of body composition from dual‐energy X‐ray absorptiometry, and measures of fat distribution from computed tomography scan. In this population, insulin₀ and AIR_g were higher among AAs vs. EAs, whereas S_I was lower, independent of age group. MLR analyses indicated that FFA₀ was best predicted by lean tissue mass (LTM), leg fat mass, ethnicity (lower in AAs), S_I, and insulin₀. FFA_nadir was best predicted by FFA₀, age group, and intra‐abdominal adipose tissue (IAAT). TIME_nadir was best predicted by leg fat mass, AIR_g, and S_I. In conclusion, indexes of insulin secretion and action were associated with FFA dynamics in healthy girls and women. Lower FFA₀ among AAs was independent of insulin₀ and S_I. Whether lower FFA₀ is associated with substrate oxidation or risk for obesity remains to be determined.     

Adiposity and β‐Cell Function: Relationships Differ With Ethnicity and Age

The prevalence of type 2 diabetes is higher among African Americans (AA) vs. European Americans (EA), is highest at middle age, and is related to obesity. This study was conducted to test the hypothesis that the association of adiposity (percent body fat (%fat)) with indexes of insulin sensitivity (S_I) and β‐cell function would differ with ethnicity and age. Subjects were 168 healthy, normoglycemic AA and EA girls and women aged 7–12 years, 18–32 years, and 40–70 years. An intravenous glucose tolerance test (IVGTT) was used to assess indexes of insulin secretion and action: S_I, acute C‐peptide secretion (X0); basal, first‐phase, second‐phase, and total β‐cell responsivity to glucose (PhiB, Phi1, Phi2, and Phi_TOT, respectively); and the disposition index (DI = S_I × Phi_TOT). %Fat was assessed with dual energy X‐ray absorptiometrys. Adiposity was significantly associated with S_I among EA (?0.57, P < 0.001) but not AA (?0.20, P = 0.09). Adiposity appeared stimulatory to β‐cell function in the two groups of younger subjects and in EA, but inhibitory in postmenopausal women, particularly AA postmenopausal women. Among AA postmenopausal women, %fat was inversely associated with Phi1 (r = ?0.57, P < 0.05) and Phi_TOT (r = ?0.68, P < 0.01). These results suggest that the impact of adiposity on insulin secretion and action differs with age and ethnicity.     

Retinol‐binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients

Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m²) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m²) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m²). Adipose RBP4, glucose transport protein‐4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese‐T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.     

Increasing preweaning milk replacer supply affects postweaning energy metabolism of Holstein male calves

Male Holstein calves commonly receive minimal quantities of milk replacer (MR) to speed up weaning and reduce costs. Studies with Holstein female calves show that early life feed restriction affects energy metabolism later in life. Aiming to test this hypothesis, 120 Holstein bull calves (48.4 ± 2.2 kg of BW and 20 ± 3.2 d of age) housed in 24 pens were blocked and randomized to two treatments: A low calf MR allowance (LP) (two daily doses of 2 l each, 582 g/d of DM), or a high MR allowance (HP) (two daily meals of 4 l each, 1 164 g/d of DM). Calves were weaned at day 49 of the study and slaughtered at 32.8 ± 0.5 weeks of age. Throughout the study, animals had ad libitum access to a common compound feed, straw, and water. Twenty-four animals were randomly selected for an intravenous glucose tolerance test (IVGTT). The IVGTT was performed at week 6 and 12 of the study and consisted of an intravenous glucose infusion and sequential blood sampling up to 90 min after glucose infusions. Calves were heavier for HP until week 12, after which the difference disappeared. By design, the MR intake was higher in the HP group resulting in a higher energy intake and a higher average daily gain in the preweaning phase. Blood glucose curves were not different at week 6, but at week 12, 5 min after the infusion, glucose was higher in HP calves. Insulin curves were not different at week 6. Nevertheless, in week 12, a higher insulin concentration was observed for HP 5, 10, 15, 20, 30, 35, and 45 min’ postinfusion, indicating a higher requirement of insulin to control glycemia. Differences between HP and LP calves were also observed for the quantitative insulin sensitivity check index, maximum insulin concentration, and insulin delta at week 12. Blood glucose reached maximum concentration within 5–10 min of the IVGTT test, and the concentration was, on average, 8.58 and 10.80 mmol/l at weeks 6 and 12, respectively. Insulin reached maximum concentration within 10–15 min of the IVGTT, and concentrations were, on average, 33.32 and 32.61 μUI/ml at weeks 6 and 12, respectively. Doubling MR supply improved animal growth up to weaning, but these differences disappeared by the end of the feeding period. Despite similar responses to glucose infusions preweaning, higher milk supply seemed to decrease insulin sensitivity after weaning.     

Differential Effect of Weight Loss on Adipocyte Size Subfractions in Patients With Type 2 Diabetes

The size of adipocytes influences their function suggesting a differential responsiveness to intervention. We hypothesized that weight loss in patients with type 2 diabetes mellitus (T2DM) predominantly decreases the size of large and very‐large adipocyte subfractions in parallel with beneficial changes in serum adipokines and improved insulin sensitivity. A total of 44 volunteers from the Look Action for Health in Diabetes trial, who lost weight after 1‐year of intense lifestyle intervention, were included. Insulin sensitivity (hyperinsulinemic–euglycemic clamp), size of subcutaneous abdominal adipocytes (osmium fixation), and selected serum adipokines were measured. A 13% weight loss was accompanied by 46% improvement in insulin sensitivity (increased glucose disposal rate from 5.9 ± 2.2 to 8.6 ± 2.7 mg/min/kg fat‐free mass, P < 0.05) in parallel with a 36% increase in plasma adiponectin concentration (6.1 ± 3.1 to 8.3 ± 3.9 µg/ml, P < 0.05], but no changes in the proinflammatory cytokines interleukin‐6 and tumor necrosis factor‐α. Change in adiponectin correlated with changes in glucose disposal rate (r = 0.34, P < 0.05). Mean adipocyte size decreased (0.84 ± 0.25 to 0.64 ± 0.23 µl, P < 0.05), mainly due to changes in the large adipocyte subfraction (size 0.75–0.44 µl, relative number 19–26%; P < 0.05). Our data suggest that change in the large adipocyte subfraction may contribute to the improvement in insulin sensitivity via an increase in serum adiponectin. Such a relationship, which does not imply cause and effect, could not be obtained by measuring only mean adipocyte size. These data provide support for the measures of adipocyte size distribution in concert with in vitro adipokine secretion and lipolysis in future studies.     

糖尿病不同发展阶段胰岛功能的变化趋势*

目的:研究糖尿病不同发展阶段胰岛素敏感性及胰岛素分泌功能的改变,指导2型糖尿病的早期诊断。方法:57例行OGTT体检者,分为NGT、IGT、IFG+IGT、新诊断T2DM四组,并行IVGTT,采用HOMA-IR评估胰岛素敏感性,采用葡萄糖处置指数[DI1=HOMA-β/HOMA-IR,DI2=ΔI30/ΔG30/HOMA-IR,DI3=MBCI×IAI,DI4=AIR0-10/HOMA-IR]及AUCINS/HOMA-IR评估胰岛素分泌功能。结果:IGT、IFG+IGT、新诊断T2DM组HOMA-IR无统计学差异(P>0.05),均显著高于NGT组(P<0.05)。IGT、IFG+IGT、新诊断T2DM组DI1逐步降低(P<0.05);NGT、IGT组DI1无统计学差异(P>0.05)。NGT、IGT、IFG+IGT、新诊断T2DM组DI2、DI3、DI4逐步降低(P<0.05)。IFG+IGT、新诊断T2DM组OGTTAUCINS/HOMA-IR逐步降低(P<0.05),且显著低于NGT组(P<0.05);NGT、IGT组OGTTAUCINS/HOMA-IR无统计学差异(P>0.05)。结论:(1)IGT阶段胰岛素抵抗及胰岛素1相、早期相分泌功能的下降同时存在。IFG+IGT阶段胰岛素1相、早期相分泌进一步下降,并出现基础相、2相分泌的减少,胰岛素抵抗加重不明显。新诊断T2DM阶段胰岛素各相分泌进一步减少,胰岛素抵抗加重不明显。(2)在T2DM发生过程中,胰岛素分泌功能下降较胰岛素敏感性下降更为明显。(3)胰岛素抵抗及胰岛素1相、早期相分泌功能的下降是T2DM的预测因子。(4)IFG+IGT阶段应积极干预。     

Advanced glycation end products (AGEs) are cross-sectionally associated with insulin secretion in healthy subjects

It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6–31.0 kg/m²). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43; p < 0.05) and lower 2-h glucose concentrations during OGTT (r = ?0.31; p < 0.05). In addition, fasting (r = ?0.36; p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = ?0.39; p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.     

Reduction of Plasma Leptin Concentrations by Arginine but Not Lipid Infusion in Humans

Objective: We examined short-term effects of arginine infusion on plasma leptin in diabetic and healthy subjects. Research Methods and Procedures: Arginine stimulation tests were performed in C-peptide negative type 1 [DM1; hemoglobin A_1c; 7.3 ± 0.3%], hyperinsulinemic type 2 diabetic (DM2; 7.6 ± 0.7%), and nondiabetic subjects (CON; 5.4 ± 0.1%). Results: Fasting plasma leptin correlated linearly with body mass index among all groups (r = 0.61, p = 0.001). During arginine infusion, peak plasma insulin was lower in DM1 than in DM2 (p < 0.05) and CON (p < 0.01). Plasma leptin decreased within 30 minutes by ∼11% in DM1 (p < 0.001), DM2 (p < 0.01), and CON (p < 0.005), slowly returning to baseline thereafter. Plasma free fatty acids (FFAs) were higher in DM1 (0.6 ± 0.1 mM) and DM2 (0.6 ± 0.1 mM) than in CON (0.4 ± 0.1 mM, p < 0.05) and transiently declined by ∼50% (p < 0.05) at 45 minutes in all groups before rebounding toward baseline. To examine the direct effects of FFAs on plasma leptin, we infused healthy subjects with lipid/heparin and glycerol during fasting, and somatostatin-insulin (∼35 pM) -glucagon (∼90 ng/mL) clamps were performed. In both protocols, plasma leptin continuously declined by ∼25% (p < 0.05) during 540 minutes without any difference between the high and low FFA conditions. Discussion: Arginine infusion transiently decreased plasma leptin concentrations both in insulin-deficient and hyperinsulinemic diabetic patients, indicating a direct inhibitory effect of the amino acid but not of insulin or FFAs.     

Plasma Adiponectin Levels in High Risk African‐Americans with Normal Glucose Tolerance,Impaired Glucose Tolerance,and Type 2 Diabetes**

Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African‐American patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C‐peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment‐insulin resistance index (HOMA‐IR) and HOMA‐β cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA‐IR < 2.68 and insulin resistance as HOMA‐IR > 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA‐IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2‐fold greater (11.09 ± 4.98 vs. 6.42 ± 3.3811 μg/mL) in insulin‐sensitive (HOMA‐IR, 1.74 ± 0.65) than in insulin‐resistant (HOMA‐IR, 5.12 ± 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin‐resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA‐IR (r = ?0.502, p = 0.046) and with HOMA‐β cell function (r = ?0.498, p = 0.042) but not with the percentage body fat (r = ?0.368, p = 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin‐resistant, non‐diabetic first degree relatives of African‐American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African‐American relatives before development of IGT and type 2 diabetes.     

Prostacyclin does not affect insulin secretion in humans

The effects of Prostacyclin (PGI₂) infusion on insulin secretion and glucose tolerance were investigated in 7 healthy subjects. PGI₂ infusion caused no statistically significant changes of either glucose or insulin concentration, over the range 2.5–20 ng/Kg/min. A constant PGI₂ infusion (10 ng/Kg/min) did not inhibit acute insulin responses to a glucose (20 g i.v.) pulse (response before PGI₂ = 612±307%; during PGI₂ = 515±468%, mean ± SD, mean change 3–5 min insulin, % basal; P=NS). Glucose disappearance rates were similar after the first and second glucose pulse.Thus, in contrast to PGE₂, PGI₂ does not affect insulin secretion nor glucose disposal at doses producing platelet and vascular changes. It is hypothesized that an altered PGI₂/PGE₂ balance in diabetes may represent a link between vascular, platelet and metabolic changes.     

Weight Loss and Leptin Changes in Individuals with Type 2 Diabetes

WILLIAMS, KATHERINE V., MONICA MULLEN, WE1 LANG, ROBERT V. CONSIDINE, AND RENA R. WING. Weight loss and leptin changes in individuals with type 2 diabetes. Obes Res. Objective To identify variables associated with leptin change in subjects with type 2 diabetes after 3 weeks and 20 weeks of weight loss. Research Methods and Procedures Subjects with type 2 diabetes treated with diet or sulfonylureas (n = 54) were enrolled in a 20-week behavioral weight control program. Sulfonylureas were stopped ≥2 weeks before study entry. Seven subjects who restarted sulfonylureas after week 3 had their data analyzed separately after this point. Results Leptin, fasting plasma glucose, and insulin levels were measured at baseline and at 3, 10, and 20 weeks. After 3 weeks, subjects lost 2.7±2.0 kg (p<0.001), and had significant decreases in leptin (5.2±7.0 ng/mL, p<0.001), fasting plasma glucose (1.8±1.8 mmol/L, p<0.001), and insulin (23±60 pmol/L, p<0.03). Between week 3 and week 20, subjects lost an additional 6.3±4.4 kg (P<0.001), but had no further changes in leptin. The primary determinants of leptin change at all time-points were weight loss and initial leptin level. Changes in insulin were not related to changes in leptin after controlling for the effects of weight loss. At week 20, more recent weight loss (week 10 to week 20) was as strong a predictor of overall change in leptin as overall weight loss (baseline to 20 week). Subjects who restarted sulfonylureas had an increase in both leptin levels (+1.9±9.0 ng/mL, p<0.05) and insulin levels (+23±65 pmol/L, p<0.05), despite significant overall weight loss (-7.4±4.0 kg, p<0.01). Initial changes in leptin (0 weeks to 3 weeks) did not affect subsequent ability to lose weight. Discussion Both short- and long-term changes in weight had an effect on leptin changes in individuals with type 2 diabetes. Although physiological insulin changes did not independently influence changes in leptin concentration with weight loss, increases in insulin levels with sulfonyl-urea therapy were associated with increases in leptin levels despite weight loss.     

Protein Tyrosine Phosphatase 1B Variant Associated with Fat Distribution and Insulin Metabolism

Protein tyrosine phosphatase 1B (PTPN1) affects the regulation of insulin signaling and energy metabolism. We studied whether polymorphisms in the PTPN1 gene impact body fat distribution in the HERITAGE Family Study cohort in 502 white and 276 black subjects. Insulin sensitivity index, glucose disappearance index, acute insulin response to glucose (AIR_glucose), and the disposition index (DI) were obtained from the frequently sampled intravenous glucose tolerance test. White subjects with the G82G at the PTPN1 IVS6+G82A polymorphism had higher body fat levels (p = 0.031) and sum of eight skinfolds (p = 0.003) and highest subcutaneous fat on the limbs (p = 0.002). G82A subjects had the lowest AIR_glucose (p = 0.005) and disposition index (p = 0.040). Interaction effects between PTPN1 and leptin receptor gene variants influenced insulin sensitivity index and AIR_glucose (p from 0.006 to 0.010). The variant PTPN1 Pro387Leu was associated with lower fasting insulin level (p = 0.035) and glucose disappearance index (p = 0.038). In summary, PTPN1 IVS6+G82G homozygotes showed higher levels of all measures of adiposity. G82 allele heterozygotes are potentially at higher risk for type 2 diabetes. Gene‐gene interactions between the PTPN1 and leptin receptor genes contributed to the phenotypic variability of insulin sensitivity. The PTPN1 Pro387Leu variant was associated with lower glucose tolerance.     

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

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