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Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Most of the literature related to high altitude medicine is devoted to the short-term effects of high-altitude exposure on human physiology. However, long-term effects of living at high altitudes may be more important in relation to human disease because more than 400 million people worldwide reside above 1500 m. Interestingly, individuals living at higher altitudes have a lower fasting glycemia and better glucose tolerance compared with those who live near sea level. There is also emerging evidence of the lower prevalence of both obesity and diabetes at higher altitudes. The mechanisms underlying improved glucose control at higher altitudes remain unclear. In this review, we present the most current evidence about glucose homeostasis in residents living above 1500 m and discuss possible mechanisms that could explain the lower fasting glycemia and lower prevalence of obesity and diabetes in this population. Understanding the mechanisms that regulate and maintain the lower fasting glycemia in individuals who live at higher altitudes could lead to new therapeutics for impaired glucose homeostasis.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

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, glucose effectiveness, acute insulin response to glucose, 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. There is increasing evidence that variation in glucose homeostasis reflects genetic control better than that of commonly used surrogate measures (fasting glucose or fasting insulin). Further, recent linkage scans have identified regions in the human genome that may contain loci that contribute to variation in glucose homeostasis phenotypes. Thus, the prospects are encouraging for positional cloning of genes contributing to glucose homeostasis and providing insight into the nature of the metabolic syndrome and diabetes. Ultimately, knowledge of the genetic basis of glucose homeostasis will facilitate the development of more directed therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.

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.

Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMAIR] and of β-cell function [HOMAB]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [SI] and acute insulin response [AIRg]) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMAB-AIRg: ρG = 0.28-0.73; HOMAIR-SI: ρG = -0.73 to -0.83) with increased heritability for the dynamic measure AIRg Significant association of variants with dynamic measures (P < 8.77 × 10(-4)) was observed. A pattern of superior performance of AIRg was observed for well-established loci including MTNR1B (P = 9.46 × 10(-12)), KCNQ1 (P = 1.35 × 10(-4)), and TCF7L2 (P = 5.10 × 10(-4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIRg (P < 1.38 × 10(-9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically "closer" to causal pathways and provide insight into the discrete mechanisms of action.

Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure. [ABSTRACT FROM AUTHOR]

Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness (Sg), insulin sensitivity (Si), and the disposition index (DI), only Si can be reliably measured in conscious mice. To determine the importance of the other parameters in murine glucose homeostasis in lean and obese states, we developed the frequently sampled intravenous glucose tolerance test (FSIVGTT) for use in unhandled mice. We validated the conscious FSIVGTT against the euglycemic clamp for measuring Si in lean and obese mice. Insulin-resistant mice had increased first-phase insulin secretion, decreased Sg, and a reduced DI, qualitatively similar to humans. Intriguingly, although insulin secretion explained most of the variation in glucose disposal in lean mice, Sg and the DI more strongly predicted glucose disposal in obese mice. DI curves identified individual diet-induced obese (DIO) mice as having compensated or decompensated insulin secretion. Conscious FSIVGTT opens the door to apply mouse genetics to the determinants of in vivo insulin secretion, Sg, and DI, and further validates the mouse as a model of metabolic disease. [ABSTRACT FROM AUTHOR]

Recent studies in animal and human models have revealed that free tatty acid (FFA) release from adipose tissue is oscillatory. We have shown in our laboratory that these oscillations are controlled by the sympathetic nervous system (SNS). Although FFAs have been shown to directly stimulate glucose production [endogenous glucose production (EGP)] by the liver and to reduce peripheral glucose utilization, whether the specific pattern of FFA release affects glucose metabolism is unknown. The aim of this study was to examine the effects of pulsatile vs. constant infusion of FFA on glucose homeostasis in the canine model. Euglycemic clamps with basal insulin replacement (0.1 mU·kg-1·min-1 insulin) were performed in dogs (n = 8) during infusion of saline (SAL) or the medium-chain fatty acid octanoate, which was given by either pulsatile infusion (PUL: 10 mmol over 2 rain every 10 min) or continuous infusion (C-INF: 1 mmol/min) designed to achieve equivalent total FFA mass. Endogenous lipolytic pulses were suppressed with the β3-specific adrenergic receptor antagonist bupranolol. PUL infusion elicited a pulsatile pattern of FFA in circulation with average maximum pulse height of 0.82 ± 0.04 mM, whereas C-INF FFA levels reached 0.47 ± 0.03 mM (fasting levels) and were maintained throughout. Glucose uptake was not affected by PUL; however, C-INF significantly reduced glucose uptake compared with both SAL and PUL. Steady-state EGP increased by >90% from basal steady state during PUL but did not change during either SAL or C-INF. Thus, pulsatile FFA infusion led to an increase in EGP while preserving glucose disposal. These data suggest that the pattern of FFA may have a role in regulation of glucose homeostasis, which may have consequences in the obese or insulin-resistant state where the SNS is known to be altered. [ABSTRACT FROM AUTHOR]

Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and βcell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.21 at 81 cM flanked by markers D11S2371 and D11S2002 (support interval from 71 to 96 cM). In this study, genotyping and analysis of an additional 214 African-American subjects in 21 pedigrees from the IRASFS yielded independent evidence of linkage to DI. When these two datasets were combined, a DI linkage peak was observed with an LOD of 3.89 at 78 cM (support interval from 67 to 89 cM). Fine mapping with 15 additional microsatellite markers in this 11q region for the entire 42 pedigrees resulted in an LOD score of 4.80 at 80 cM near marker D11S937 (support interval from 76 to 84 cM). In these 42 pedigrees, there was also suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002). No evidence of linkage to the insulin sensitivity index (Si) was observed. Nine positional candidate genes were evaluated for association to DI and AIR. Among these candidates, single nucleotide polymorphisms (SNPs) in muscle glycogen phosphorylase showed evidence of association with DI (P < 0.011). In addition, SNPs in the pyruvate carboxylase gene showed evidence of association (P < 0.002) with AIR. Further analysis of these candidate genes, however, did not provide evidence that these SNPs accounted for the evidence of linkage to either DI or AIR. These detailed genetic analyses provide strong evidence of a DI locus on 11q in African-American pedigrees, with additional suggestive evidence of independent AIR loci in the same region. Diabetes 55:911-918, 2006 [ABSTRACT FROM AUTHOR]

The minimal model was proposed over 25 years ago. Despite (or because of) its simplicity it continues to be used today – both as a clinical tool and an approach to understanding the composite effects of insulin secretion and insulin sensitivity on glucose tolerance and risk for type 2 diabetes mellitus. The original assumptions of the model have led to an understanding of the kinetics of insulin in vivo, as well as the relative importance of β-cell compensatory failure in the pathogenesis of diabetes. The disposition index (DI), a parameter emerging from the model, represents the ability of the pancreatic islets to compensate for insulin resistance. There is evidence that a locus on chromosome 11 codes for the DI, which has a significant heritability and can predict type 2 diabetes better than any known genetic locus. Even today, the model continues to be a subject of scientific discovery and discourse. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor. The genetic contribution of PTPN1 to measures of glucose homeostasis has been assessed in 811 Hispanic subjects from the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). Thirty-five single nucleotide polymorphisms (SNPs) spanning 161 kb and containing the PTPN1 gene were genotyped and tested for association. All 20 SNPs with minor allele frequencies >0.1 in a single haplotype block covering the PTPN1 genomic sequence show significant association with the insulin sensitivity index (S(i)) (P = 0.044-0.003) and fasting glucose (P = 0.029 to <0.001). In contrast, there is no evidence for association of PTPN1 polymorphisms with acute insulin response (a measure of beta-cell function). Haplotype analysis of eight SNP haplotypes that have independently been shown to be associated with type 2 diabetes risk and protection in Caucasian type 2 diabetic subjects are associated with lower (P = 0.007) and higher (P = 0.0002) S(i) and higher (P = 0.00007) and lower (P = 0.001) fasting glucose, respectively, in the IRASFS. This comprehensive genetic analysis of PTPN1 reveals significant association with metabolic traits consistent with the proposed in vivo role for the PTP-1B protein. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Despite the well-described association between obesity and insulin resistance, the physiologic mechanisms that link these two states are poorly understood. The present study was performed to elucidate the role of visceral adipose tissue in whole-body glucose homeostasis. Dogs made abdominally obese with a moderately elevated fat diet had catheters placed into the superior mesenteric artery so that the visceral adipose bed could be insulinized discretely. Omental insulin infusion was extracted at approximately 27%, such that systemic insulin levels were lower than in control (portal vein) insulin infusions. Omental infusion did not lower systemic free fatty acid levels further than control infusion, likely because of the resistance of the omental adipose tissue to insulin suppression and the confounding lower systemic insulin levels. The arteriovenous difference technique showed that local infusion of insulin did suppress omental lipolysis, but only at extremely high insulin concentrations. The median effective dose for suppression of lipolysis was almost fourfold higher in the visceral adipose bed than for whole-body suppression of lipolysis. Thus, the omental adipose bed represents a highly insulin-resistant depot that drains directly into the portal vein. Increased free fatty acid flux to the liver may account for hepatic insulin resistance in the moderately obese state. [ABSTRACT FROM AUTHOR]

Normal glucose tolerance is maintained by a complex interrelationship between insulin secretion (AIRg) and insulin sensitivity (SI). Previously, we have hypothesized that under normal conditions the product of SI and AIRg (called Disposition Index (DI)) is constant. In this study we examined longitudinally the mechanism by which DI is maintained during the development of obesity induced insulin resistance. Male mongrel dogs (n=9) were fed a hypercaloric high fat diet (∼5400kcal/d, 53% kcal from fat) for 6 weeks. The Frequently Sampled Intravenous Glucose Tolerance (FSIGT) test was utilized to assess changes in glucose homeostasis at weeks 0 (pre-diet), 2, 4 and 6 (W:0; W:2; W:4; W:6, respectively). Body weight was significantly increased by W:2 (+2.5+/-0.33 kg, P<.001) and remained elevated throughout the entire study. There were no changes in the basal glucose, insulin concentration, or glucose tolerance (KG) over the six week period of fat feeding. Within two weeks of fat feeding, SI dramatically decreased by 45% (5.6+/-0.9 vs. 3.1+/-1.2; W:0 vs. W:2 P=.04). At W:6, SI decreased by 66% (1.9+/-1.3, P=.006). AIRg rose modestly by W:2 (14%, P=NS), increasing by 46% (P<0.02) and 59% (P<0.01) at W:4 and W:6, respectively. Insulin clearance did not change, suggesting that the increase in AIRg was solely due to enhanced β-cell function, i.e., insulin secretion and not decreased clearance. Interestingly, even in the face of extreme insulin resistance, DI was unchanged. Thus, 6 weeks of high fat feeding in the canine model exhibits total compensation of the ensuing resistance, thereby maintaining glucose tolerance. [ABSTRACT FROM AUTHOR]

Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeo-stasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal. [ABSTRACT FROM AUTHOR]