Biomedical subjects

Mohammed F Saad

Publications and source records attributed to Mohammed F Saad.

At least 37 records · Page 2Linked to original sources

PubMed2004

Insulin sensitivity, body fat distribution, and family diabetes history: the IRAS Family Study.

OBJECTIVE: Markers of insulin resistance are often apparent in nondiabetic relatives of subjects with type 2 diabetes. Whether diabetes family history (FH) also predicts visceral fat accumulation and, if so, whether the increased insulin resistance in relatives of diabetic subjects occurs independently of visceral fat accumulation are not known. RESEARCH METHODS AND PROCEDURES: To examine this issue, we studied the relationship of diabetes FH with insulin sensitivity and fat measures, measured by minimal model analysis and computed tomography, respectively, in families participating in the Insulin Resistance Atherosclerosis (IRAS) Family Study. FH scores were based on the diabetes status of the participants' parents and older siblings. RESULTS: FH scores were significantly correlated with reduced insulin sensitivity (p < 0.05) and increased subcutaneous (p < 0.05) and visceral (p < 0.05, San Antonio only) fat in families from San Antonio and Los Angeles but not in the leaner Hispanic families from San Luis Valley. There was no evidence for a stronger association of FH score with visceral fat accumulation than with subcutaneous fat or insulin resistance. DISCUSSION: The absence of an association between FH score and insulin resistance/fat accumulation in San Luis Valley is consistent with the idea that the expression of transmitted diabetes genes may be suppressed in leaner, more physically active populations.

Adipose Tissue↗

PubMed2004

Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.

BACKGROUND: Although the role of vitamin D in type 2 diabetes is well recognized, its relation to glucose metabolism is not well studied. OBJECTIVE: We investigated the relation of 25-hydroxyvitamin D [25(OH)D] concentrations to insulin sensitivity and beta cell function. DESIGN: We enrolled 126 healthy, glucose-tolerant subjects living in California. Insulin sensitivity index (ISI) and first- and second-phase insulin responses (1stIR and 2ndIR) were assessed by using a hyperglycemic clamp. RESULTS: Univariate regression analyses showed that 25(OH)D concentration was positively correlated with ISI (P < 0.0001) and negatively correlated with 1stIR (P = 0.0045) and 2ndIR (P < 0.0001). Multiple regression analyses confirmed an independent correlation between 25(OH)D concentration and ISI (P = 0.0007). No independent correlation was observed between 25(OH)D concentration and 1stIR or 2ndIR. However, an independent negative relation of 25(OH)D concentration with plasma glucose concentration was observed at fasting (P = 0.0258), 60 min (P = 0.0011), 90 min (P = 0.0011), and 120 min (P = 0.0007) during the oral-glucose-tolerance test. Subjects with hypovitaminosis D (<20 ng/mL) had a greater prevalence of components of metabolic syndrome than did subjects without hypovitaminosis D (30% compared with 11%; P = 0.0076). CONCLUSIONS: The data show a positive correlation of 25(OH)D concentration with insulin sensitivity and a negative effect of hypovitaminosis D on beta cell function. Subjects with hypovitaminosis D are at higher risk of insulin resistance and the metabolic syndrome. Further studies are required to explore the underlying mechanisms.

Adult↗

PubMed2004

Association analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism in Hispanics and African Americans: the IRAS family study.

OBJECTIVE: Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-beta1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits. METHODS AND RESULTS: The Insulin Resistance and Atherosclerosis (IRAS) Family Study genotyped 287 African American (18 pedigrees) and 811 Hispanic American (45 pedigrees) individuals for the 4G/5G PAI-1 and two TGF-beta1 polymorphisms (R25P, C-509T). Individuals were recruited from three clinical centers located in San Antonio (urban Hispanic), San Luis Valley (rural Hispanic) and Los Angeles (African American). The presence of the 4G PAI-1 allele was positively associated with PAI-1 protein level (combined sample p < 0.0001). Hispanic Americans average 65% higher PAI-1 protein levels than African Americans (p < 0.0001). Consistently across ethnic groups, increased PAI-1 protein levels were associated with increased insulin resistance and overall and central obesity (p value < 0.0001, combined sample). Adjusting for PAI-1 protein levels, there was evidence of an association of PAI-1 genotype (4G) with insulin sensitivity (p < 0.002) and subcutaneous fat (p < 0.01). These associations were not influenced by TGF-beta1 genotypes. CONCLUSIONS: PAI-1 protein is a strong correlate of insulin resistance (IR) and obesity in Hispanics and African Americans. However, PAI-1 4G/5G polymorphism appears to influence insulin resistance and obesity beyond its direct influence on serum PAI-1 protein levels.

Black or African American↗

PubMed2004

Association of leptin receptor polymorphism with insulin resistance.

OBJECTIVE: Although the role of the leptin receptor (LEPR) in obesity is well recognized, its role in insulin sensitivity remains unknown. DESIGN: This was a cross-sectional study to investigate the impact of the Q223R polymorphism of the LEPR gene on insulin sensitivity. METHODS: Sixty-seven glucose-tolerant Caucasians were enrolled. The insulin sensitivity index and glucose clearance were measured using a hyperglycemic clamp. Genomic DNA was extracted for genotyping. RESULTS: We identified 20 QQ, 31 QR, and 16 RR subjects. The three genotypic groups were similar in age, gender distribution, body mass index, waist-hip ratio, and blood pressure, but differed in the insulin sensitivity index (P=0.0180) and in glucose clearance (P=0.0220). Multivariate analyses showed that the Q223R polymorphism was independently associated with the insulin sensitivity index (P=0.0317) and glucose clearance (P=0.0436). A trend of increasing low density lipoprotein cholesterol concentration was also observed (P=0.0447). CONCLUSION: We have reported the first association of the Q223R polymorphism of the LEPR gene with insulin resistance.

Adult↗

PubMed2004

Evaluation of insulin sensitivity and beta-cell function indexes obtained from minimal model analysis of a meal tolerance test.

Modeling analysis of glucose, insulin, and C-peptide following a meal has been proposed as a means to estimate insulin sensitivity (S(i)) and beta-cell function from a single test. We compared the model-derived meal indexes with analogous indexes obtained from an intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp (HGC) in 17 nondiabetic subjects (14 men, 3 women, aged 50 +/- 2 years [mean +/- SE], BMI 25.0 +/- 0.7 kg/m(2)). S(i) estimated from the meal was correlated with S(i) estimated from the IVGTT and the HGC (r = 0.59 and 0.76, respectively; P < 0.01 for both) but was approximately 2.3 and 1.4 times higher (P < 0.05 for both). The meal-derived estimate of the beta-cell's response to a steady-state change in glucose (static secretion index) was correlated with the HGC second-phase insulin response (r = 0.69; P = 0.002), but the estimated rate-of-change component (dynamic secretion index) was not correlated with first-phase insulin release from either the HGC or IVGTT. Indexes of beta-cell function obtained from the meal were significantly higher than those obtained from the HGC. In conclusion, insulin sensitivity and beta-cell indexes derived from a meal are not analogous to those from the clamp or IVGTT. Further work is needed before these indexes can be routinely used in clinical and epidemiological studies.

Blood Glucose↗

PubMed2004

Differences in insulin resistance in nondiabetic subjects with isolated impaired glucose tolerance or isolated impaired fasting glucose.

Both impaired glucose tolerance (IGT) (as defined by the 1985 World Health Organization criteria) and impaired fasting glucose (IFG) (as defined by the 1997 American Diabetes Association criteria) represent intermediate metabolic states between normal and diabetic glucose homeostasis. Cardiovascular disease may be related to postglucose load rather than fasting glycemia, i.e., IGT rather than IFG. We hypothesized that subjects with IGT may be more insulin resistant and have higher levels of common cardiovascular risk factors than those with isolated IFG. In the Insulin Resistance Atherosclerosis Study (IRAS), we studied S(i) and first-phase insulin secretion (acute insulin response [AIR]), as derived from a frequently sampled intravenous glucose tolerance test, as well as common cardiovascular risk factors in four different glucose tolerance categories (NFG/NGT [n = 654], NFG/IGT [n = 255], IFG/NGT [n = 59], and IFG/IGT [n = 102]) among nondiabetic subjects. Subjects with isolated postchallenge hyperglycemia (NFG/IGT) had lower S(i) (means +/- SE: 2.10 +/- 0.04 vs. 2.59 +/- 0.13 x 10(-4) min(-1). microU(-1). ml(-1); P = 0.005), lower proinsulin levels (34.4 +/- 1.8 vs. 42.0 +/- 4.5 pmol/l; P = 0.03), higher AIR (273.1 +/- 18.1 vs. 215.9 +/- 30.0 pmol/l; P = 0.04), higher C-reactive protein (2.49 +/- 0.3 vs. 1.49 +/- 0.5 mg/l; P = 0.0015), and higher triglyceride levels (137.7 +/- 5.5 vs. 108.4 +/- 8.9 mg/dl; P = 0.0025) than subjects with isolated fasting hyperglycemia (IFG/NGT). The relation of insulin resistance to glucose tolerance category was consistently seen in women and men and across the three ethnic groups of the IRAS (non-Hispanic whites, African Americans, and Hispanics). Nondiabetic individuals with isolated postchallenge hyperglycemia (IGT) are more insulin resistant than individuals with isolated fasting hyperglycemia (IFG). The risk factor pattern (including increased insulin resistance) seen in isolated IGT identifies a subgroup of nondiabetic individuals who are likely to benefit from early intervention.

Adult↗

PubMed2004

Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity.

Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of the metabolic syndrome. The majority of previous factor analyses, however, have used only surrogate measures of insulin sensitivity; very few have included nontraditional cardiovascular disease (CVD) risk factors such as plasminogen activator inhibitor (PAI)-1, fibrinogen, and C-reactive protein (CRP); and only a limited number have assessed the ability of factors to predict type 2 diabetes. The objective of this study was to investigate, using factor analysis, the clustering of metabolic and inflammation variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS) and to determine the association of these clusters with risk of type 2 diabetes at follow-up. This study includes information on directly measured insulin sensitivity (S(i)) from the frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years. Principal factor analysis of data from nondiabetic subjects at baseline (1992-1994) identified three factors, which explained 28.4, 7.4, and 6% of the total variance in the dataset, respectively. Based on factor loadings of >or= 0.40, these factors were interpreted as 1) a "metabolic" factor, with positive loadings of BMI, waist circumference, 2-h glucose, log triglyceride, and log PAI-1 and inverse loadings of log S(i) + 1 and HDL; 2) an "inflammation" factor, with positive loadings of BMI, waist circumference, fibrinogen, and log CRP and an inverse loading of log S(i) + 1; and 3) a "blood pressure" factor, with positive loadings of systolic and diastolic blood pressure. The results were similar within strata of ethnicity, and there were only subtle differences in sex-specific analyses. In a prospective analysis, each of the factors was a significant predictor of diabetes after a median follow-up period of 5.2 years, and each factor remained significant in a multivariate model that included all three factors, although this three-factor model was not significantly more predictive than models using either impaired glucose tolerance or conventional CVD risk factors. Factor analysis identified three underlying factors among a group of inflammation and metabolic syndrome variables, with insulin sensitivity loading on both the metabolic and inflammation variable clusters. Each factor significantly predicted diabetes in multivariate analysis. The findings support the emerging hypothesis that chronic subclinical inflammation is associated with insulin resistance and comprises a component of the metabolic syndrome.

Adult↗

PubMed2004

Identification of quantitative trait loci for glucose homeostasis: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study.

Genetic and environmental determinants play critical roles in insulin resistance and beta-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity (S(I)), glucose disposition (S(G)), acute insulin response to glucose (AIR(G)), and disposition index (DI). Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes and atherosclerotic cardiovascular disease. A genome scan for glucose homeostasis phenotypes in nondiabetic subjects has been carried out in African-American (n = 21) and Hispanic (n = 45) extended families as part of the IRAS Family Study. In African-American families, there was significant evidence for linkage of DI between D11S2371 and D11S2002 (logarithm of odds [LOD] = 3.21) at 81 cM, and in the combined sample of African-American and Hispanic families, there was evidence at GATA117D01 (140 cM) on chromosome 11 (LOD = 2.21). Evidence of linkage was also observed for S(I) in Hispanic (LOD = 2.28, between D15S822 and GTTTT001) and AIR(G) in African-American families (LOD = 2.73, between D4S1625 and D4S1629; and LOD = 2.56 at PAH (phenylalanine hydroxylase) on chromosome 12). These results provide impetus for future positional cloning of quantitative trait loci (QTLs). Identifying genes in these regions should provide insight into the nature of the metabolic syndrome and diabetes, and facilitate the development of more effective therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.

Adult↗

PubMed2004

Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study.

OBJECTIVE: The aim of this study was to evaluate whether low insulin sensitivity (Si) measured using a modified frequently sampled intravenous glucose tolerance test with minimal model analysis is associated with coronary artery disease (CAD) independent of other cardiovascular risk factors. RESEARCH DESIGN AND METHODS: We studied 1,482 women and men, age 40-69 years old, African American (28%), Hispanic (34%), or non-Hispanic white (38%), with normal (45%), impaired (23%), or diabetic (32%) glucose tolerance. CAD defined as confirmed past myocardial infarction, coronary artery bypass graft, coronary angioplasty, or presence of a major Q-wave was found in 91 participants. RESULTS: The odds ratio (OR) for CAD was greatest among individuals in the two lowest quintiles of Si (2.4, 95% CI 1.0-5.6 and 4.7, 2.1-10.7) compared with the highest Si quintile. After adjusting for demographic and cardiovascular risk factors, a decrement from the 75th to 25th percentile in Si was associated with a 56% increase in CAD (P=0.028). Similar increments in fasting or 2-h insulin levels were associated with, respectively, only 15 (NS) and 3% (NS) increases in CAD. The association between Si and CAD was partially mediated by insulin, HDL cholesterol and triglyceride levels, hypertension, diabetes, and obesity, but not LDL cholesterol or cigarette smoking. CONCLUSIONS: Low Si is associated with CAD independently of and stronger than plasma insulin levels. Part of the association is accounted for by dyslipidemia, hypertension, diabetes, and obesity.

Adult↗

PubMed2004

Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm.

OBJECTIVE: Ragaglitazar is a novel insulin sensitizer with dual peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha stimulating activities that improve plasma glucose and lipid profiles. The aim of the present dose-ranging study was to assess the efficacy and safety of ragaglitazar in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This study included 177 hypertriglyceridemic type 2 diabetic subjects who participated in a 12-week, double-blind, parallel, randomized, placebo-controlled dose-ranging study (open pioglitazone arm). Subjects received ragaglitazar (0.1, 1, 4, or 10 mg), placebo, or pioglitazone (45 mg). Efficacy parameters included fasting plasma levels of triglycerides and glucose (FPG) along with other lipid levels, A1C, and insulin. RESULTS: Ragaglitazar in doses of 1, 4, and 10 mg resulted in a significant decrease from baseline as compared with placebo in FPG (-48, -74, -77 mg/dl) and triglycerides (-40, -62, -51%), free fatty acids (-36, -54, -62%), apolipoprotein B (-13, -29, -25%), LDL cholesterol (-14 and -19% for 4- and 10-mg groups), and total cholesterol (-16 and -15% for 4 and 10 mg) and a significant increase in HDL cholesterol (20 and 31% for 1- and 4-mg groups, respectively). Changes in triglycerides and FPG for pioglitazone treatment were similar to 1 mg ragaglitazar. Mean A1C values of the 1-, 4-, and 10-mg ragaglitazar and pioglitazone groups were significantly reduced compared with placebo (-0.5, -1.3, -1.1, and -0.3%, respectively). Common adverse events were edema, weight increase, leukopenia, and anemia. CONCLUSIONS: Ragaglitazar provided glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided significant improvement in the lipid profile.

Adult↗

PubMed2003

Peroxisomal proliferator-activated receptor alpha deficiency diminishes insulin-responsiveness of gluconeogenic/glycolytic/pentose gene expression and substrate cycle flux.

Our previous work led to the hypothesis that peroxisomal proliferator-activated receptor alpha (PPAR alpha) modulates insulin action in a compensatory fashion for hepatic glucose balance vs. peripheral glucose disposal. Therefore, we have examined the expression of insulin-dependent gluconeogenic/glycolytic/pentose cycle enzymes and compared these to insulin responsiveness for peripheral vs. hepatic substrate flux and futile cycling in the PPAR alpha knockout mouse. Hepatic gluconeogenic flux, glucose absorption, clearance and recycling, as well as in vivo glucose disposal were evaluated using new mass isotopomer methods. Insulin-dependent gluconeogenic/glycolytic/pentose cycle enzyme expression and glucose futile cycling were diminished; however, glucose disappearance was increased. This supports the hypothesis of hepatic insulin resistance and increased peripheral glucose uptake as compensatory events secondary to the decrease in fatty acid oxidation characteristic of the PPAR alpha knockout. We conclude that 1) the loss of PPAR alpha results in lower expression levels and diminished response to meal regulation for gluconeogenic/glycolytic enzyme expression; and 2) consequently, substrate/futile cycling of glucose is decreased when PPAR alpha is absent despite increased gluconeogenesis. The compensatory changes in liver and peripheral tissue substrate flux and the resultant adaptation for enzyme expression in the liver to have a diminished insulin dependence reflect the loosely linked correlation between phenotype and genotype in hepatic glucose metabolism.

Animals↗

PubMed2003

Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods.

PURPOSE: Insulin resistance and visceral adiposity are associated with increased risk of type 2 diabetes. In this report, we describe the methods of the IRAS Family Study, which was designed to identify the genetic and environmental risk factors for insulin resistance and visceral adiposity. METHODS: Families from two ethnic groups (African American and Hispanic) have been recruited from three clinical sites. Blood samples for DNA as well as other standard measures were collected. A CT scan (visceral adiposity) and a frequently sampled glucose tolerance test (insulin resistance) were performed. Preliminary estimates of heritability for indirect measures related to insulin resistance and visceral adiposity were obtained using a variance components approach in the first 93 families (approximately 1000 individuals). RESULTS: Estimates of heritability ranged from low (0.08) for fasting insulin and HOMA, to moderate (0.28) for fasting glucose, to high (0.54) for BMI. After adjustment for age, gender and ethnicity, all heritability estimates were significantly greater than zero (p < 0.05). CONCLUSIONS: These results are consistent with the expectation that intermediate measures of insulin resistance and visceral adiposity are heritable, and that the IRAS Family Study has statistical power to detect these intermediate phenotypes of type 2 diabetes and atherosclerosis.

Adipose Tissue↗

PubMed2003

Modeling beta-cell insulin secretion--implications for closed-loop glucose homeostasis.

Glucose sensing and insulin delivery technology can potentially be linked to form a closed-loop insulin delivery system. Ideally, such a system would establish normal physiologic glucose profiles. To this end, a model of beta-cell secretion can potentially provide insight into the preferred structure of the insulin delivery algorithm. Two secretion models were evaluated for their ability to describe plasma insulin dynamics during hyperglycemic clamps (humans; n=7), and for their ability to establish and maintain fasting euglycemia under conditions simulated by the minimal model. The first beta-cell model (SD) characterized insulin secretion as a static component that had a delayed response to glucose, and a dynamic component that responded to the rate of increase of glucose. The second model (PID) described the response in terms of a proportional component without delay, an integral component that adjusted basal delivery in proportion to hyper/hypoglycemia, and a derivative component that responded to the rate of glucose change. Both models fit the beta-cell response during the clamp, and established fasting euglycemia under simulated closed-loop conditions; however, the SD model did not maintain euglycemia following simulated changes in insulin sensitivity or glucose appearance, whereas the PID model did. The PID model was more stable under the simulated closed-loop conditions. Both the SD and PID models described beta-cell secretion in response to a rapid increase in glucose. However, the PID model could maintain fasting euglycemia and was more stable under closed-loop conditions, and thus is more suited for such conditions.

Algorithms↗

PubMed2003

Determination of plasma glucose during rapid glucose excursions with a subcutaneous glucose sensor.

Continuous glucose monitoring has the potential to improve glucose management and reduce the risk of hypoglycemia in individuals with diabetes. Accurate sensors may also allow the development of a closed-loop insulin delivery system. The purpose of this work was to determine the delay time associated with a subcutaneous glucose sensor during rapidly changing glucose excursions. Subcutaneous glucose sensors (Medtronic MiniMed, Inc., Northridge, CA) were inserted in five healthy men. After a 2-h stabilization period, a 3-h hyperglycemic (approximately 11 mM) clamp was performed followed by a 90-min period in which plasma glucose was allowed to decline to as low as 2.8 mM. Sensors were calibrated using two points (basal and hyperglycemia), and the calibrated sensor glucose measurements were compared with those from a reference analyzer (Beckman Instruments, Fullerton, CA). Response time was estimated from a first-order kinetic model. Plasma glucose levels, determined with the subcutaneous sensor, were highly correlated with those obtained with the reference glucose analyzer (r(2) = 0.91, p < 0.001; mean absolute difference of approximately 8%). The half-time for the sensor response was estimated to be 4.0 +/- 1.0 min. The subcutaneous glucose sensor has the potential to facilitate the detection of hypoglycemia and improve overall glycemic control when used in a real-time monitor. The rapid response should be sufficient to allow a fully automated closed-loop insulin delivery system to be developed based on the subcutaneous sensing site.

Biosensing Techniques↗

PubMed2003

New insulin sensitivity adjusted beta cell indices: validation according to a genetic study.

PURPOSE: The role of hepatocyte nuclear factor-1alpha (HNF1alpha) in the maturity-onset diabetes of the young 3 (MODY3) is well established. A common polymorphism, I27L that is not linked to MODY3, has been demonstrated to affect beta cell function. To facilitate the identification of subjects with a low beta cell reserve, we developed beta cell indices and validated according to a genetic study. METHODS: Insulin sensitivity index (ISI), 1st phase insulin response (1stIR), and 2nd phase insulin response (2ndIR) were assessed in 60 glucose tolerant subjects using hyperglycemic clamps. Delta1stIR and delta2ndIR were defined as differences between 1stIR (or 2ndIR) and the ISI-adjusted 1stIR (or 2ndIR). The genotypes were determined from genomic DNA. RESULTS: Delta1stIR (P = 0.0130) and delta2ndIR (P = 0.0482) differed among the 3 genotypic groups. Multivariate analysis confirmed the independent influence of the I27L polymorphism on delta1stIR (P = 0.0130) and delta2ndIR (P = 0.0369). Within the LL group, 75% and 63% of the subjects were within the lowest quartile of delta1stIR (P = 0.0011) and delta2ndIR (P = 0.0277), respectively. CONCLUSIONS: With new beta cell indices, we demonstrated the independent impact of the I27L polymorphism on beta cell function. The new beta cell indices will facilitate the identification of glucose tolerant subjects with reduced beta cell reserve.

Adult↗

PubMed2003

Insulin sensitivity, insulin secretion, and abdominal fat: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study.

The relationship between insulin sensitivity and overall obesity is well established. However, there remains debate as to which of the fat depots, visceral abdominal tissue (VAT) or subcutaneous abdominal tissue (SAT), is of greater importance. Also, the relationship between fat distribution and insulin secretion is largely unknown. We studied SI, acute insulin response (AIR), and disposition index (DI), as obtained by minimal model analysis, in 999 Hispanic and 458 African-American men and women as part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. VAT and SAT were measured from computed tomography scans performed at the L4/L5 vertebral region. A mixed-model approach was used to determine the relationship between each of the glucose homeostasis measures (SI, AIR, and DI) versus abdominal fat measures. Mean values were as follows: age, 41 years; SI, 1.98 10(-4).min(-1).microU(-1).ml(-1); AIR, 840 pmol.ml(-1).min(-1); BMI, 28.5 kg/m2; VAT, 100 cm2; and SAT, 333 cm2. SAT, VAT, and their joint interaction were each inversely and significantly associated with SI, adjusting for age, sex, ethnicity, and BMI. SAT, but not VAT, was positively associated with AIR, except when additionally adjusting for SI, in which case VAT was inversely associated with AIR. VAT and the joint interaction of VAT and SAT were inversely associated with DI. The fat measures explained 27% of the model R2 for SI, 16% for AIR, and 16% for DI. Thus, fat distribution is an important determinant of both insulin resistance and insulin secretion.

Abdomen↗

PubMed2003

Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin.

Insulin resistance is an important risk factor for development of type 2 diabetes as well as other chronic conditions, including hypertension, cardiovascular disease, and colon cancer. To find genes for insulin resistance it is necessary to assess insulin action in large populations. We have previously measured insulin action in a large cohort of subjects (Insulin Resistance and Atherosclerosis Study [IRAS] Family Study) using the minimal model approach. In this study, we compare sensitivity from the minimal model (insulin sensitivity index [S(I)]) with the measure of insulin resistance emanating from the homeostasis model assessment (HOMA) approach. The former measure emerges from the glycemic response to endogenous and exogenous insulin; the latter is based solely on fasting measures of glucose and insulin. A total of 112 pedigrees were represented, including 1,362 individuals with full phenotypic assessment. Heritability of S(I) was significantly greater than that for HOMA (0.310 vs. 0.163) and for fasting insulin (0.171), adjusted for age, sex, ethnicity, and BMI. In addition, correlation between S(I) and either HOMA or fasting insulin was only approximately 50% accounted for by genetic factors, with the remainder accounted for by environment. Thus S(I), a direct measure of insulin sensitivity, is determined more by genetic factors rather than measures such as HOMA, which reflect fasting insulin.

Adult↗

PubMed2003

Low insulin sensitivity (S(i) = 0) in diabetic and nondiabetic subjects in the insulin resistance atherosclerosis study: is it associated with components of the metabolic syndrome and nontraditional risk factors?

OBJECTIVE: To determine the meaning of S(i) = 0 derived from the frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODS: The issue of assessing insulin resistance in large studies is important because the most definitive method ("gold standard"), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose S(i) is zero. The interpretation of an S(i) equaling zero is unknown. RESULTS: -To address this issue, we examined 1482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of S(i). The proportion of insulin-resistant subjects (S(i) < 1.61 x 10(-4) [min(-1). microU(-1) x ml(-1)] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with S(i) = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with S(i) = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In type 2 diabetes, subjects with S(i) = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In addition, diabetic subjects with S(i) = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with S(i) > 0. CONCLUSIONS: We found very few subjects with S(i) = 0 among subjects with NGT and few subjects with S(i) = 0 among subjects with IGT. In contrast, S(i) = 0 was common in subjects with diabetes. Subjects with S(i) = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with S(i) > 0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with S(i) = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.

Arteriosclerosis↗