Elevated Fasting Insulin Concentrations Research Articles

Insulin and BMI as predictors of adult type 2 diabetes mellitus.

Fasting insulin concentrations are increasingly being used as a surrogate for insulin resistance and risk for type 2 diabetes (T2DM), although associations with adult outcomes are unclear. Our objective was to determine whether fasting insulin concentrations in childhood associate with later T2DM. Fasting insulin values were available from 2478 participants in the longitudinal Cardiovascular Risk in Young Finns Study at baseline age 3 to 18 years, along with data on adult T2DM (N = 84, mean age = 39.6 years). Among 3- to 6-year-olds, a 1-SD increase in fasting insulin was associated with a relative risk (RR) of 2.04 (95% confidence interval [CI], 1.54-2.70) for later T2DM, which remained significant after we adjusted for BMI and parental history of T2DM. For those aged 9 to 18 years, a 1-SD increase in insulin was associated with an RR of 1.32 (95% CI, 1.06-1.65) for T2DM, but this became nonsignificant after we adjusted for BMI and parental history of T2DM. In the latter age group, a 1-SD increase in BMI was associated with an RR of 1.45 (95% CI, 1.21-1.73) for T2DM, with adjustment for insulin and parental history of T2DM not improving this association. BMI in younger children was not associated with later T2DM. In life course analyses, those with T2DM had higher fasting insulin levels in early childhood and later adulthood but not in peripubertal years. Elevated fasting insulin concentrations in early childhood, but not adolescence, are independently associated with an elevated risk of T2DM in adulthood.

Abstract B76: Evidence of a causal association between fasting insulin concentrations and endometrial cancer: A Mendelian randomization analysis

Abstract Introduction: Epidemiological studies have consistently demonstrated an association between type 2 diabetes (T2D) and increased endometrial cancer risk. Compensatory hyperinsulinemia, resulting from insulin resistance in T2D, is a leading hypothesis for this association. This study utilized genetic risk scores for T2D and fasting insulin concentrations (FI) to determine whether a genetic predisposition to T2D or elevated FI is associated with an increased risk of endometrial cancer. Methods: Genetic variants associated with T2D or FI at genome-wide significance thresholds (5 × 10−8) from genome-wide association study (GWAS) meta-analyses were included as risk score variants. Forty-nine T2D and eighteen FI variants were tested for their association with endometrial cancer in 1,287 cases and 8,273 controls from the United Kingdom and Australia. A weighted risk score method was implemented to determine the risk of endometrial cancer per genetically predicted increase in the risk of T2D or FI. An unweighted per-allele method was also used to determine the risk of endometrial cancer per T2D risk or FI increasing allele. Risk score variants associated with body mass index (BMI) at Bonferroni-corrected significance thresholds in GWAS meta-analyses were removed in sensitivity analyses, as BMI is a potential confounding factor. Results: The T2D risk score was not significantly associated with endometrial cancer using either the weighted (odds ratio [OR]=0.99, 95% confidence interval [CI], 0.98-1.01; P=0.278) or per-allele (OR=1.00; 95% CI, 0.99-1.02; P=0.567) methods. However, the weighted FI risk score demonstrated a significantly increased risk of endometrial cancer (OR, 1.16; 95% CI, 1.01-1.34; P=0.035) per genetically predicted 0.1 unit elevation in log FI. Additionally, in the unweighted method a borderline statistically significant association per FI risk score allele was observed (OR, 1.02; 95% CI, 1.00-1.04; P=0.058). Removal of variants associated with BMI did not appreciably attenuate the magnitude of the observed effect in either the weighted (OR=1.15) or unweighted per-allele (OR=1.02) methods for the FI risk score analysis. Conclusion: This is the first study to examine the effect of FI on endometrial cancer risk using a Mendelian randomization approach and provides evidence to support a causal relationship between elevated FI and increased endometrial cancer risk that has not been previously shown. Citation Format: Kevin T. Nead, Robert A. Scott, Stephen A. Sharp, Adam S. Butterworth, Deborah J. Thompson, Toby Johnson, Amanda B. Spurdle, Paul D. Pharoah, Claudia Langenberg, Douglas F. Easton, Nick J. Wareham. Evidence of a causal association between fasting insulin concentrations and endometrial cancer: A Mendelian randomization analysis. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B76.

Association of the -514C-->T polymorphism in the hepatic lipase gene (LIPC) promoter with elevated fasting insulin concentrations, but not insulin resistance, in non-diabetic Germans.

Hepatic lipase hydrolyses triglycerides and phospholipids in all major classes of lipoproteins. The -514C-->T genetic variation in the hepatic lipase gene promoter was found to be associated with diminished lipase activity, dyslipidemia, and atherosclerosis. We investigated whether this polymorphism associates with hyperinsulinemia and insulin resistance in 535 normal glucose-tolerant Germans. Only in homozygous individuals (22 subjects), the T allele (frequency: 18.1 %) was significantly associated with elevated glucose concentrations after 120 min of oral glucose tolerance test (p = 0.05) and with elevated fasting concentrations of insulin (p = 0.03), triglycerides (p < 0.01), total and HDL-cholesterol (p = 0.02), as determined by multivariate linear regression analysis. In a recessive model (C/C+C/T vs. T/T), T/T was associated with decreased insulin sensitivity index (p = 0.03) as calculated from oral glucose tolerance test data (n = 535), but not with the glucose infusion rate during hyperinsulinemic euglycemic clamp (n = 218). In conclusion, we have provided evidence that, among the metabolic parameters tested, the hepatic lipase -514C-->T gene polymorphism correlates with elevated fasting insulin concentrations in a German population. Since no corresponding difference in insulin sensitivity was seen in the clamp-subgroup, an effect of this polymorphism on insulin clearance has to be considered.

Genotype Gly/Gly of the Arg16Gly polymorphism of the β 2-adrenergic receptor is associated with elevated fasting serum insulin concentrations, but not with acute insulin response to glucose, in type 2 diabetic patients

The beta(2)-adrenergic receptor (B2AR) is expressed in pancreatic beta-cells and modulates insulin secretion. The purpose of the present study was to evaluate the influence of the Arg16Gly variant allele of B2AR on insulin secretion in patients with type 2 diabetes. We used minimal model analysis of the frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) and polymerase chain reaction (PCR)-restriction fragment length polymorphism to examine differences of insulin secretion and insulin resistance among three genotypes. There were no significant differences in baseline clinical characteristics, HbA1c, uric acid, CRP or lipid profiles among the three groups. The Gly/Gly group had significantly higher levels of fasting insulin (38.2+/-4.7 pmol/l versus 23.6+/-3.5 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (1.90+/-0.19 versus 1.32+/-0.24), compared with the Arg/Arg group, but there were no significant differences in acute insulin response to glucose (AIRg) bolus, insulin sensitivity (Si), or glucose effectiveness (Sg) among the three genotypes. Several reports have speculated that the Gly16 allele of B2AR exhibits agonist-promoted downregulation, but our findings, elevated fasting insulin concentrations, and previous clinical studies of blood pressure and lypolysis are controversial. The direct mechanism by which the Gly16 allele of B2AR may influence insulin secretion of pancreatic beta-cells is unknown. Further studies of the expression of the allelic receptor in islet cells may help to resolve the role of B2AR in insulin secretion. However, increased sensitivity to catecholamine-induced lipolysis of the Gly allele promotes higher free fatty acids concentrations in the portal system, which could enhance the higher levels of fasting insulin.

Elevated fasting insulin concentrations associate with impaired insulin signaling in skeletal muscle of healthy subjects independent of obesity.

Insulin signaling is impaired in the skeletal muscle of obese subjects but whether defects in skeletal muscle insulin signaling also characterize insulin resistance of non-obese individuals is unknown. The detection of insulin signaling defects in muscle biopsies is hampered by the variation of the contaminating non-muscle elements such as blood, connective tissue, fat, and blood vessel structures. Freeze-drying and macroscopic purification of the muscle fibers prior to the analysis might offer a possibility to minimize the analytical variation due to these contaminants. In the present study we first determined whether insulin signaling could be reliably assessed in freeze-dried muscle specimens, which are free of non-muscle contaminants, and then applied this method to the study of insulin signaling in weight-matched insulin-sensitive and insulin-resistant non-diabetic men. In rat muscle, increases in tyrosine phosphorylation of insulin receptor (IR) and activity of the insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity by insulin were similar or higher in freeze-dried and purified muscle than wet muscle. Prior to freeze-drying and purification, biopsies of human vastus lateralis muscle contained between 1% and 40% non-muscle contaminants (11+/-3%, mean+/-SEM, n=19). In freeze-dried biopsies of human vastus lateralis muscle taken before and after 30 min of hyperinsulinemia (serum free insulin 61+/-1 mU/l) in 13 non-diabetic men, insulin increased IR tyrosine phosphorylation 1.4-fold (p<0.05) and IRS-1-associated PI 3-kinase activity 1.7-fold (p<0.005). Insulin-stimulated PI 3-kinase activity was significantly inversely correlated with the fasting serum insulin concentration (r=-0.57, p<0.05). When divided according to the median fasting serum insulin concentration, the men with high fasting insulin [HI, n=7, age 44+/-3 years, body mass index (BMI) 25+/-1 kg/m(2)] as compared to the men with low fasting insulin [LI, n=6, age 45+/-3 years (NS), BMI 24+/-1 kg/m(2) (NS)] had lower rates of whole-body glucose uptake (3.4+/-0.4 vs 5.5+/-0.3 mg/kg min, p<0.005), higher fasting plasma glucose concentrations (5.9+/-0.2 vs 5.2+/-0.1 mmol/l, p<0.05), higher fasting serum triglycerides (1.4+/-0.2 vs 0.9+/-0.1 mmol/l, p<0.05) and lower high-density lipoprotein (HDL) cholesterol concentrations (1.3+/-0.1 vs 1.7+/-0.1 mmol/l, p<0.05). Insulin-stimulated IR tyrosine phosphorylation (p<0.05) and IRS-1-associated PI 3-kinase activity (p<0.05) were significantly lower in the HI than the LI group. Taken together these data demonstrate that early insulin signaling events can be reliably assessed in freeze-dried human skeletal muscle, and that in vivo insulin resistance and its accompanying features are associated with defects in early insulin signaling events in human skeletal muscle independent of body weight.

Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study

Apolipoprotein (apo) CIII participates in the regulation of the metabolism of triglyceride-rich lipoproteins and it is a major component of chylomicrons and VLDL. The APOC3 gene is on chromosome 11q23 and is highly polymorphic. The less common allele (S2) of the SstI polymorphism on the 3' untranslated region of the APOC3 gene has been previously associated with increased triglycerides, total cholesterol (TC), and apoCIII levels and cardiovascular risk on several, but not all, studies. The aim of this study was to examine the association of this polymorphism with plasma lipid levels, lipoprotein subfractions and coronary heart disease (CHD) risk in a population-based study: The Framingham Offspring Study. The frequency of the S2 allele was 0.086, consistent with previous reports in Caucasian populations. In men, the S2 allele was associated with lower concentrations of high-density lipoprotein cholesterol (HDL-C; P<0.04) and HDL2-C (P<0.02) and a significant increase in apoCIII non-HDL (P<0.05). TG levels were higher in men carriers of the S2 allele, but this association did not reach statistical significance (P=0.30). Conversely, in women, the S2 allele was associated with increased TC (P<0.03), low-density lipoprotein cholesterol (LDL-C; P<0.03), and ApoB levels (P<0.04). Lipoproteins subfractions were also examined using nuclear magnetic resonance (NMR) spectroscopy. S2 male carriers had significantly lower concentrations of large LDL and a significant reduction in LDL particle size (P<0.04). In women, there was a significant increase in intermediate LDL particles (P<0.05) with no significant effect on lipoprotein diameters. We also examined the associations between the S2 allele and biochemical markers of glucose metabolism. In men, the S2 allele was associated with elevated fasting insulin concentrations (P<0.04), whereas no significant associations were observed in women. Despite the described associations with lipid and glucose metabolism related risk factors, we did not find any significant increase in CHD risk associated with the S2 allele in this population.

Epidemiology of type 2 diabetes: risk factors.

A number of cross-sectional and prospective studies that compared the insulin sensitivity of various national and ethnic populations within the U.S. to the total U.S. population were analyzed to find possible risk factors for the development of type 2 diabetes. It was found that the risks for diabetes in African-Americans, Hispanics, and Native Americans are approximately 2, 2.5, and 5 times greater, respectively, than in Caucasians. Studies of the prevalence of type 2 diabetes in Mexican Americans and non-Hispanic whites in San Antonio showed that there is an inverse relationship between socioeconomic status and the prevalence of diabetes. It also appears that cultural effects lead to an increased incidence of obesity in these populations, which may lead to insulin resistance. Genetic factors may also be a contributing factor. A 5-year, prospective study of insulin resistance in Pima Indians showed a relationship between impaired glucose tolerance and subsequent development of type 2 diabetes. In a 7-year study in Mexican Americans, those subjects who had both high insulin secretion and impaired insulin sensitivity had a 14-fold increased risk of developing type 2 diabetes. Regardless of cultural and ethnic factors, the San Antonio Heart Study, which compared Mexican Americans and non-Hispanic whites, showed that in both groups, the strongest predictors of developing type 2 diabetes are elevated fasting insulin concentrations and low insulin secretion.

Insulin sensitivity and intake of vitamins E and C in African American, Hispanic, and non-Hispanic white men and women: the Insulin Resistance and Atherosclerosis Study (IRAS)

Elevated fasting insulin concentrations and insulin resistance have been associated with non-insulin-dependent diabetes mellitus (NIDDM), obesity, atherosclerosis, and hypertension. Vitamin E supplementation in persons with and without NIDDM may be related to greater insulin sensitivity (SI). The cross-sectional associations of the intake of vitamins E and C with SI and insulin concentrations were evaluated among African American, Hispanic, and non-Hispanic white men and women with a wide spectrum of glucose tolerance included in the Insulin Resistance and Atherosclerosis Study (IRAS) (n = 1151). Insulin sensitivity was measured by minimal model analysis of a 12-sample, insulin-modified, frequently sampled intravenous glucose tolerance test. Nutrient intake (including vitamin supplement use) was assessed with a food-frequency questionnaire modified to include foods consumed by the three ethnic groups. Linear-regression models were used, including rank of SI and the log of fasting insulin as the outcome variables. Pearson correlation coefficients for vitamins E and C in relation to rank SI were r = 0.07 (P = 0.01) and r = 0.07 (P = 0.02), respectively. After adjustment for total energy and BMI these associations were no longer statistically significant and did not differ between ethnic groups. Results were similar when vitamins E and C were combined in categories of low and high antioxidant intake. Models replicated with log of fasting insulin as the outcome variable also did not produce significant associations with vitamins E or C. Thus, these cross-sectional analyses do not support the hypothesis of improved SI with increased intake of vitamins E and C.

Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

Insulin resistance in patients with myotonic dystrophy.

Evaluation of insulin sensitivity in 12 patients with myotonic dystrophy gave results different from those found in other insulin-resistant conditions. Nine of our subjects were insensitive to exogenous insulin, but only three had elevated fasting insulin concentrations. Eight had an excessive insulin response to a glucose challenge. Monocyte insulin receptor affinity was decreased (myotonics, 1.21 +/- 0.74 X 10(9) liters per mole; controls, 2.62 +/- 1.28 X 10(9)), and this parameter correlated best with the insulin resistance. No circulating receptor antibody or insulin binding inhibitor was found. Our studies suggest that the insulin resistance seen in patients with myotonic dystrophy is related to decreased insulin receptor affinity.