Insulin resistance in myotonic dystrophy.

The aim of the present study was to obtain a comprehensive picture of the rate of insulin secretion and of tissue sensitivity to the endogenous hormone in myotonic dystrophy patients (MyD). The minimal model approach was utilized for the analysis of frequently sampled intravenous glucose tolerance test data (FSIGT). This method provided the characteristic parameters: SI, insulin sensitivity index; SG fractional glucose disappearance independent of dynamic insulin; n, fractional insulin clearance; phi 1 and phi 2 first and second phase insulin delivery sensitivities to glucose stimulation. In MyD patients SI was reduced (p less than 0.01) by 71% to 1.4 +/- 0.3 x 10(-4) min-1/(microU/ml), whereas in controls it was 4.85 +/- 0.77; SG was within the normal range: 0.044 +/- 0.012 min-1 in MyD patients and 0.036 +/- 0.017 min-1 in controls; phi 1 increased in MyD patients (7.4 +/- 1.3 min (microU/ml)/(mg/dl) versus 4.1 +/- 1.2 in controls); phi 2 increased in MyD patients (126 +/- 47 x 10(4) min-2/(microU/ml)/(mg/dl) versus 17 +/- 6 in controls; p less than 0.05). MyD patients showed a normal tolerance with the glucose disappearance constant, KG within the normal range: 2.75 versus 2.62% min-1 in controls. In MyD patients insulin resistance was associated with a higher than normal insulin delivery for both secretory phases, although the second phase was responsible for releasing a greater amount of hormone. In conclusion MyD patients try to compensate for overall insulin resistance by a more marked pancreatic response.     

Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians.

Susceptibility to non-insulin-dependent diabetes mellitus (NIDDM) is largely genetically determined. In Pima Indians, obesity, insulin resistance, and a low acute insulin response (AIR) to an intravenous glucose infusion are each predictors of the disease. To ascertain whether these phenotypes are genetically determined, we estimated their familiality in nondiabetic Pima Indians with a maximum-likelihood method. Percentage body fat (PFAT) was highly familial (h2 =.76), whereas waist/ thigh circumference ratio (W/T ratio) was not significantly familial after controlling for PFAT (h2 = .16). AIR was also highly familial (h2 = .80 at 10 min), even after controlling for PFAT and insulin action (h2 = .70). Insulin action at physiologic plasma insulin concentrations was familial (h2 = .61) but less so after controlling for PFAT and W/T ratio (h2 = .38). At maximally stimulating insulin concentrations, insulin action was familial (h2 = .45) and was less influenced by controlling for PFAT and W/T ratio (h2 = .49). We conclude that in Pima Indians (1) PFAT and AIR are highly familial traits, (2) central distribution of fat is not a familial trait when controlled for PFAT, (3) 38%-49% of the variance in insulin action, independent of the effect of obesity, is familial, and (4) PFAT, AIR, and insulin action are useful traits to study genetic susceptibility to NIDDM. Because genetic parameter estimates are applicable only to the populations from which they were estimated, it is important to determine whether these estimates of familialities in Pima Indians can be confirmed in other populations before the utility of these traits in searching for NIDDM susceptibility genes in those populations can be fully advocated.     

Elevated plasma proinsulin/insulin ratio is a marker of reduced insulin secretory capacity in healthy young men.

AIM: To examine whether reduced insulin secretory capacity or increased insulin secretory demand is associated with elevated ratio of plasma proinsulin to immunoreactive insulin (PI/IRI ratio) in non-diabetic subjects. SUBJECTS AND METHODS: We measured various indices of insulin secretory function and insulin sensitivity by frequently sampled intravenous glucose tolerance test (FSIGT) and hyerglycemic glucose clamp in 21 healthy young men. We then examined the relationships between these indices and PI, IRI, or PI/IRI ratio in the fasting state. RESULTS: Insulin sensitivity index (SI) measured by FSIGT correlated inversely with basal IRI (r=-0.53, P < 0.01) and PI levels (r=-0.57, P < 0.01), but there was no significant correlation between SI and PI/IRI ratio (r=0.26, NS). On the other hand, PI/IRI ratio correlated inversely with insulin secretory indices, such as acute insulin responses during FSIGT (r =-0.46, P < 0.01) and hyperglycemic glucose clamp (r=-0.54, P < 0.01) and submaximum insulin response during hyperglycemic glucose clamp (r=-0.59, P < 0.01). CONCLUSIONS: These results indicate that elevated PI/IRI ratio may serve as a marker of reduced insulin secretory function in non-diabetic subjects.     

Improved beta-cell function after standardized weight reduction in severely obese subjects

Islet function was examined in 13 severely obese women [body mass index 46.4 +/- 5.5 (SD) kg/m(2)] before and after standardized 15 and 25% weight reduction (WR) instituted by bariatric surgery. The insulin response to arginine at fasting (AIR(1)), at 14 mmol/l, and at >25 mmol/l glucose was reduced by 37-50% after 15 and 25% WR (P 相似文献   

The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. II. An autosomal genome scan for diabetes-related quantitative-trait loci

Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.     

Beta-cell function and islet morphology in normal, obese, and obese beta-cell mass-reduced Göttingen minipigs

Herein, we bridge beta-cell function and morphology in minipigs. We hypothesized that different aspects of beta-cell dysfunction are present in obesity and obesity with reduced beta-cell mass by using pulsatile insulin secretion as an early marker. Measures for beta-cell function (glucose and arginine stimulation plus baseline and glucose-entrained pulsatile insulin secretion) and islet morphology were studied in long-term (19-20 mo) obese (n = 5) and obese beta-cell-reduced [nicotinamide + streptozotocin (STZ), n = 5] minipigs and normal controls, representing different stages in the development toward type 2 diabetes. Acute insulin response (AIR) to glucose and arginine were, surprisingly, normal in obese (0.3 g/kg glucose: AIR = 246 +/- 119 vs. 255 +/- 61 pM in control; 67 mg/kg arginine: AIR = 230 +/- 124 vs. 214 +/- 85 pM in control) but reduced in obese-STZ animals (0.3 g/kg glucose: AIR = 22 +/- 36, P < 0.01; arginine: AIR = 87 +/- 92 pM, P < 0.05 vs. control). Baseline pulsatile insulin secretion was reduced in obese (59 +/- 16 vs. 76 +/- 16% in control, P < 0.05) and more so in obese-STZ animals (43 +/- 13%, P < 0.01), whereas regularity during entrainment was increased in obese animals (approximate entropy: 0.85 +/- 0.14 vs. 1.13 +/- 0.13 in control, P < 0.01). Beta-cell mass (mg/kg body wt) was normal in obese and reduced in obese-STZ animals, with pancreatic fat infiltration in both groups. In conclusion, obesity and insulin resistance are not linked with a general reduction of beta-cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of beta-cell dysfunction, with the three groups representing stages in the progression from normal physiology to diabetes, and assessment of pulsatility as the single most sensitive marker of beta-cell dysfunction.     

Insulin-stimulated glucose uptake and fasting blood glucose.

Changes in insulin-stimulated glucose metabolism were studied in young and aged subjects, subjects with impaired glucose tolerance, and patients with NIDDM by means of the glucose clamp technique. The diabetic group includes obese and non-obese patients treated without insulin and non-obese patients treated with insulin. The glucose disposal rate (GDR) was decreased in aged subjects (5.8 +/- 0.4 mg/kg/min) compared with young controls (7.4 +/- 0.3 mg/kg/min). In patients with IGT, it was further decreased to 3.6 +/- 0.5 mg/kg/min, which was comparable to the rate in NIDDM without insulin treatment (3.3 +/- 0.4 mg/kg/min). There were no differences in the GDR between obese (3.0 +/- 0.3 mg/kg/min) and non-obese (3.4 +/- 0.6 mg/kg/min) diabetic patients. In insulin-treated diabetic patients, GDR ranged widely, but the mean value was partially normalized (5.2 +/- 0.9 mg/kg/min). In the diabetic group, no correlation was observed between fasting blood glucose and GDR. These results suggest that in the course of developing NIDDM, a decrease in insulin-stimulated glucose uptake precedes a rise in fasting blood glucose. Thus, as previously reported for Caucasian NIDDM patients, resistance to insulin-stimulated glucose uptake may be one of the basic defects in Japanese patients with NIDDM. The degree of glycemia, however, is not directly related to the magnitude of the defect in insulin action.     

Acute effects of valsartan on insulin sensitivity in obese, non-hypertensive subjects with and without type 2 diabetes.

BACKGROUND: Two studies were designed to determine whether a single dose (80 mg) of the angiotensin II receptor blocker (ARB), valsartan, alters insulin sensitivity in obese, non-hypertensive subjects with and without Type 2 diabetes. METHODS: Insulin sensitivity (S(I)), glucose effectiveness (S(G)), and acute insulin response (AIR(0-10 min)) were measured by means of a 3-hour insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) before and after a single dose of valsartan. Study 1: obese, normotensive non-diabetic male subjects (n = 12), mean (SD) age 37.2 +/- 11.2 years, BMI 32.8 +/- 6.8 kg/m (2); Study 2: obese, normotensive Type 2 diabetic patients (n = 12), mean age 55.7 +/- 6.9 years, BMI 35.0 +/- 6.8 kg/m (2)/l. Both studies were randomised, double-blind, placebo-controlled, single-dose crossover group studies involving subjects in two study days, two weeks apart. After fasting samples were taken, a 300 mg/kg iv glucose bolus was injected at 0 min, and 0.05 U/kg iv insulin was given 20 min later. Blood samples for analysis of glucose and insulin were taken throughout the 3-hour study period. RESULTS: Study 1 (non-diabetic subjects) S(I) 2.81 vs. 2.63 x 10 (-4) min (-1) per microU/ml (p = 0.54), S(G) 0.020 vs. 0.020 min (-1) (p = 0.90), AIR(0-10) min 3305 vs. 3450 microU/min/ml (p = 0.71); Study 2 (patients with type 2 diabetes) S(I) 0.59 vs. 0.85 x 10 (-4) min (-1) per microU/ml (p = 0.15), S(G) 0.013 vs. 0.014 min (-1) (p = 0.71), AIR(0-10) min 65 vs. 119 microU/min/ml (p = 0.14), placebo vs. valsartan, respectively. CONCLUSION: In obese, non-hypertensive non-diabetic and Type 2 diabetic subjects a single dose of valsartan does not alter insulin sensitivity.     

Insulin sensitivity in normotensive offspring of hypertensive parents.

OBJECTIVES: To investigate the insulin sensitivity in normotensive offspring of hypertensive parents. SUBJECTS: Fifteen young normotensive offspring of hypertensive parents were paired with 15 controls matched for age, sex and body mass index. METHODS: The insulin sensitivity was investigated by 75 g oral glucose tolerance test (OGTT) and modified insulin suppression test. A high-fat mixed meal was administered to observe the changes of TG levels. RESULTS: The plasma glucose and serum insulin responses to oral glucose challenge were comparable between both groups. High-fat mixed meal made no difference in the plasma glucose, serum triglyceride or insulin between the 2 groups. With the modified insulin suppression test, the steady-state plasma glucose levels (SSPG) were higher in the offspring of parents with essential hypertension (138+/-43 mg/dl) than in the control group (95+/-26 mg/dl). The diastolic blood pressure and heart rate of the offspring of hypertensive parents are also higher than the control group. CONCLUSIONS: Insulin resistance exists in young normotensive offspring of hypertensive parents, and the impairment of insulin-mediated glucose uptake in these subjects develop before any alteration of fasting and postprandial triglyceride.     

Hypoglycemic and hypolipidemic effects of processed Aloe vera gel in a mouse model of non-insulin-dependent diabetes mellitus

The effects of processed Aloe vera gel (PAG) on the course of established diet-induced non-insulin-dependent diabetes mellitus (NIDDM) were studied in C57BL/6J mice. NIDDM was induced in C57BL/6J mice by feeding them a high-fat diet. Mice exhibiting diet-induced obesity (DIO) with blood glucose levels above 180 mg/dl were selected to examine the antidiabetic effects of PAG. Oral administration of PAG for 8 weeks reduced circulating blood glucose concentrations to a normal level in these DIO mice. In addition, the administration of PAG significantly decreased plasma insulin. The antidiabetic effects of PAG were also confirmed by intraperitoneal glucose tolerance testing. PAG appeared to lower blood glucose levels by decreasing insulin resistance. The administration of PAG also lowered triacylglyceride levels in liver and plasma. Histological examinations of periepididymal fat pad showed that PAG reduced the average size of adipocytes. These results demonstrate that the oral administration of PAG prevents the progression of NIDDM-related symptoms in high-fat diet-fed mice, and suggest that PAG could be useful for treating NIDDM.     

Genetic dissection of "OLETF," a rat model for non-insulin-dependent diabetes mellitus: quantitative trait locus analysis of (OLETF x BN) x OLETF.

To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.     

Acute hyperglycemia alters the ability of the normal beta-cell to sense and respond to glucose

Impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) are associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose. The aim of this study was to establish whether acute hyperglycemia per se plays a role in inducing this defect in beta-cell response. Seven healthy volunteers with no family history of NIDDM were studied on two occasions during a 12-h oscillatory glucose infusion with a periodicity of 144 min. Once, low-dose glucose was infused at a mean rate of 6 mg x kg(-1) x min(-1) and amplitude 33% above and below the mean rate, and, once, high-dose glucose was infused at 12 mg x kg(-1) x min(-1) and amplitude 16% above and below the mean rate. Mean glucose levels were significantly higher during the high-dose compared with the low-dose glucose infusion [9.5 +/- 0.8 vs. 6.8 +/- 0.2 mM (P < 0.01)], resulting in increased mean insulin secretion rates [ISRs; 469.1 +/- 43.8 vs. 268.4 +/- 29 pmol/min (P < 0.001)] and mean insulin levels [213.6 +/- 46 vs. 67.9 +/- 10.9 pmol/l (P < 0.008)]. Spectral analysis evaluates the regularity of oscillations in glucose, insulin secretion, and insulin at a predetermined frequency. Spectral power for glucose, ISR, and insulin was reduced during the high-dose glucose infusion [11.8 +/- 1.4 to 7.0 +/- 1.6 (P < 0.02), 7.6 +/- 1.5 to 3.2 +/- 0.5 (P < 0.04), and 10.5 +/- 1.6 to 4.6 +/- 0.7 (P < 0.01), respectively]. In conclusion, short-term infusion of high-dose glucose to obtain glucose levels similar to those previously seen in IGT subjects results in reduced spectral power for glucose, ISR, and insulin. The reduction in spectral power previously observed for ISR in IGT or NIDDM subjects may be due partly to hyperglycemia.     

Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes

Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Visceral fat resection in humans: Effect on insulin sensitivity,beta‐cell function,adipokines, and inflammatory markers

Objective: The visceral fat is linked to insulin resistance, the metabolic syndrome, type 2 diabetes and an increased cardiovascular risk, but it is not clear whether it has a causative role. Design and Methods: Surgical resection of this fat depot is a research model to address this issue. Twenty premenopausal women with metabolic syndrome and grade III obesity were randomized to undergo Roux‐en‐Y gastric bypass (RYGBP) either alone or combined with omentectomy. Insulin sensitivity (IS; euglycemic‐hyperinsulinemic clamp), acute insulin response to glucose (AIR; intravenous glucose tolerance test), disposition index (DI = AIR × IS measured by clamp), lipid profile, adipokine profile (leptin, adiponectin, resistin, visfatin, interleukin‐6, TNF‐α, MCP‐1), ultra‐sensitive C‐reactive protein (CRP), body composition, and abdominal fat echography were assessed prior to surgery and 1, 6, and 12 months post‐surgery. Results: Omentectomy was associated with greater weight loss at all time points. IS improved similarly in both groups. Omentectomy was associated to lower CRP after 12 months, but it did not influence adipokines and other metabolic parameters. Among non‐diabetic subjects, omentectomy was associated with a preservation of baseline AIR after 12 months (as opposed to deterioration in the control group) and a greater DI after 6 and 12 months. Conclusion: Although omentectomy did not enhance the effect of RYGBP on insulin sensitivity and adipokines, it was associated with a preservation of insulin secretion, a greater weight loss, and lower CRP.     

Effects of parity and periconceptional metabolic state of Holstein–Friesian dams on the glucose metabolism and conformation in their newborn calves

The metabolic state of pregnant mammals influences the offspring’s development and risk of metabolic disease in postnatal life. The metabolic state in a lactating dairy cow differs immensely from that in a non-lactating heifer around the time of conception, but consequences for their calves are poorly understood. The hypothesis of this study was that differences in metabolic state between non-lactating heifers and lactating cows during early pregnancy would affect insulin-dependent glucose metabolism and development in their neonatal calves. Using a mixed linear model, concentrations of glucose, IGF-I and non-esterified fatty acids (NEFAs) were compared between 13 non-lactating heifers and 16 high-yielding dairy cows in repeated blood samples obtained during the 1st month after successful insemination. Calves born from these dams were weighed and measured at birth, and subjected to intravenous glucose and insulin challenges between 7 and 14 days of age. Eight estimators of insulin-dependent glucose metabolism were determined: glucose and insulin peak concentration, area under the curve and elimination rate after glucose challenge, glucose reduction rate after insulin challenge, and quantitative insulin sensitivity check index. Effects of dam parity and calf sex on the metabolic and developmental traits were analysed in a two-way ANOVA. Compared with heifers, cows displayed lower glucose and IGF-I and higher NEFA concentrations during the 1st month after conception. However, these differences did not affect developmental traits and glucose homeostasis in their calves: birth weight, withers height, heart girth, and responses to glucose and insulin challenges in the calves were unaffected by their dam’s parity. In conclusion, differences in the metabolic state of heifers and cows during early gestation under field conditions could not be related to their offspring’s development and glucose homeostasis.     

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。     

Strategies for mapping heterogeneous recessive traits by allele-sharing methods.

We investigate strategies for detecting linkage of recessive and partially recessive traits, using sibling pairs and inbred individuals. We assume that a genomewide search is being conducted and that locus heterogeneity of the trait is likely. For sibling pairs, we evaluate the efficiency of different statistics under the assumption that one does not know the true degree of recessiveness of the trait. We recommend a sibling-pair statistic that is a linear compromise between two previously suggested statistics. We also compare the power of sibling pairs to that of more distant relatives, such as cousins. For inbred individuals, we evaluate the power of offspring of different types of matings and compare them to sibling pairs. Over a broad range of trait etiologies, sibling pairs are more powerful than inbred individuals, but for traits caused by very rare alleles, particularly in the case of heterogeneity, inbred individuals can be much more powerful. The models we develop can also be used to examine specific situations other than those we look at. We present this analysis in the idealized context of a dense set of highly polymorphic markers. In general, incorporation of real-world complexities makes inbred individuals, particularly offspring of distant relatives, look slightly less useful than our results imply.     

INSIG2 SNPs Associated With Obesity and Glucose Homeostasis Traits in Hispanics: The IRAS Family Study

The genome‐wide association study by Herbert et al. identified the INSIG2 single‐nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify the matter, by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 1,425 IRASFS Hispanics. SNPs were tested for association with six adiposity measures: BMI, waist circumference (WAIST), waist‐to‐hip ratio (WHR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and VAT to SAT ratio (VSR). SNPs were also tested for association with fasting glucose (GFAST), fasting insulin (FINS), and three measures obtained from the frequently sampled intravenous glucose tolerance test: insulin sensitivity (S_I), acute insulin response (AIR), and disposition index (DI). Most prominent association was observed with direct computed tomography (CT)‐measured adiposity phenotypes, including VAT, SAT, and VSR (P values range from 0.007 to 0.044 for rs17586756, rs17047718, rs17047731, rs9308762, rs12623648, and rs11673900). Multiple SNP associations were observed with all glucose homeostasis traits (P values range from 0.001 to 0.031 for rs17047718, rs17047731, rs2161829, rs10490625, rs889904, and rs12623648). Using BMI as a covariate in evaluation of glucose homeostasis traits slightly reduced their association. However, association with adiposity and glucose homeostasis phenotypes is not significant following multiple comparisons adjustment. Trending association after multiple comparisons adjustment remains suggestive of a role for genetic variation of INSIG2 in obesity, but these results require validation.     

Enhancement of beta-cell sensitivity to glucose by oral fat load.

Recent studies have demonstrated that 6 h infusions of lipid emulsion enhance insulin release, whereas 24 h infusions inhibit insulin secretion. How insulin release is modulated after oral fat loading has not yet been elucidated. 17 healthy fasting volunteers were subjected to 3 experiments in random order: test 1 was a frequently sampled i. v. glucose tolerance test (FSIVGTT, 0.3 g/kg glucose), test 2 began with the ingestion of 50 % sunflower oil (1.5 g/kg) followed by FSIVGTT 4 h later. Test 3 was identical to test 2 with i. v. addition of 100 U/kg heparin prior to FSIVGTT. Glucose and insulin data were analyzed by minimal model assumptions - glucose sensitivity of the beta-cells (Theta1), acute insulin response (AIR) (10 min), 3 h insulin release (Theta2), glucose threshold of insulin secretion (h), insulin degradation rate (n), peripheral insulin sensitivity (S(I)), and glucose-dependent glucose disposal (S(G)). After drinking the fat emulsion, FFAs increased to 0.8 +/- 0.3 mmol/l (test 2) and to 3.0 +/- 0.3 mmol/l (test 3). Moderately increased FFA concentrations were associated with elevation of Theta1 (test 1, control 335 +/- 157 vs. test 2: 859 +/- 612 pM x min x mM(-1), p = 0.030). At high plasma FFA levels and in the presence of heparin (test 3), Theta1 was reduced compared to test 2 and unchanged compared to test 1. Theta2 and h were elevated in both tests 2 and 3 compared to test 1. No changes of n, S(I) and S(G) were found. In conclusion, the ingestion of sunflower oil triglyceride emulsion resulted in a 60 % increase in plasma free fatty acids and enhanced the capacity of beta-cells to secrete insulin. Heparin-induced high levels of FFA further augmented the total insulin release and inhibited parameters of glucose responsiveness.