Genetic determination of body fat distribution and the attributive influence on metabolism.

OBJECTIVE: Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with estimates of body fat distribution. Using predefined risk allele scores, the correlation of these scores with precisely quantified body fat distribution assessed by magnetic resonance (MR) imaging techniques and with metabolic traits was investigated. METHODS: Data from 4,944 MR scans from 915 subjects of European ancestry were analyzed. Body fat distribution was determined by MR imaging and liver fat content by 1 H-MR spectroscopy. All subjects underwent a five-point 75-g oral glucose tolerance test. A total of 65 SNPs with reported genome-wide significant associations regarding estimates of body fat distribution were genotyped. Four genetic risk scores were created by summation of risk alleles. RESULTS: A higher allelic load of waist-to-hip ratio SNPs was associated with lower insulin sensitivity, higher postchallenge glucose levels, and more visceral and less subcutaneous fat mass. CONCLUSIONS: GWAS-derived polymorphisms estimating body fat distribution are associated with distinct patterns of body fat distribution exactly measured by MR. Only the risk score associated with the waist-to-hip ratio in GWAS showed an unhealthy pattern of metabolism and body fat distribution. This score might be useful for predicting diseases associated with genetically determined, unhealthy obesity.

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

AIMS/HYPOTHESIS: Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. METHODS: Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. RESULTS: Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03). CONCLUSIONS/INTERPRETATION: Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.

Variation in the obesity risk gene FTO determines the postprandial cerebral processing of food stimuli in the prefrontal cortex.

Variation in FTO is the strongest genetic determinant of body weight and has recently been linked with impaired neural processing of food stimuli. However, whether this brain-expressed gene affects neuronal processing of food-related stimuli after ingestion is still poorly understood. In this study, twenty-four participants were examined before, 30 and 120 min after ingesting 75 g of glucose solution or water on two separate days. Functional magnetic resonance imaging (fMRI) during visual food presentation was performed. All participants were genotyped for FTO SNP rs8050136. We detected significant differences between FTO genotypes in the prefrontal cortex 30 min post-glucose load in BOLD-response to food pictures (p=0.0017), while no differences were detected in response to water ingestion or 120 min post-glucose load. Since the prefrontal cortex plays a major role in the inhibitory control of eating, we propose that reduced postprandial activity in FTO risk allele carriers contributes to overeating and obesity.

Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action.

OBJECTIVE: The cannabinoid-receptor system is involved in the regulation of food intake. Here, we test whether single nucleotide polymorphisms (SNPs) in CNR2, encoding the cannabinoid-receptor 2, are associated with weight in a cross-sectional cohort. Furthermore, we wanted to investigate if the identified hits influence weight loss during lifestyle intervention; and study a potential involvement of cerebral insulin action. METHODS: 2006 subjects at increased risk for type 2 diabetes mellitus were genotyped for 5 tagging SNPs in the CNR2 locus. All subjects underwent a 75-g OGTT. 345 subjects participated in a lifestyle intervention (TUebingen Lifestyle Intervention Programme). Cerebrocortical insulin sensitivity was measured by magnetoencephalography after intranasal insulin application in 43 subjects. RESULTS: In the cross-sectional cohort, the minor allele of rs3123554 was associated with lower BMI (Padd = 0.01, Prec = 0.004), and this was attributable to its effect in women only. Interestingly, during lifestyle intervention, carriers of the same allele lost less body weight (Padd = 0.03, Prec = 0.008). Moreover, carriers of this minor allele showed lower cerebral insulin sensitivity (Prec = 0.0402). CONCLUSIONS: The minor allele of rs3123554 is associated cross-sectionally with lower body weight, whereas during intervention the same allele led to less reduction of body weight. Reduced cerebral insulin sensitivity in carriers of this allele might contribute to these disadvantageous effects during lifestyle intervention.

Differential effect of glucose ingestion on the neural processing of food stimuli in lean and overweight adults.

Eating behavior is crucial in the development of obesity and Type 2 diabetes. To further investigate its regulation, we studied the effects of glucose versus water ingestion on the neural processing of visual high and low caloric food cues in 12 lean and 12 overweight subjects by functional magnetic resonance imaging. We found body weight to substantially impact the brain's response to visual food cues after glucose versus water ingestion. Specifically, there was a significant interaction between body weight, condition (water versus glucose), and caloric content of food cues. Although overweight subjects showed a generalized reduced response to food objects in the fusiform gyrus and precuneus, the lean group showed a differential pattern to high versus low caloric foods depending on glucose versus water ingestion. Furthermore, we observed plasma insulin and glucose associated effects. The hypothalamic response to high caloric food cues negatively correlated with changes in blood glucose 30 min after glucose ingestion, while especially brain regions in the prefrontal cortex showed a significant negative relationship with increases in plasma insulin 120 min after glucose ingestion. We conclude that the postprandial neural processing of food cues is highly influenced by body weight especially in visual areas, potentially altering visual attention to food. Furthermore, our results underline that insulin markedly influences prefrontal activity to high caloric food cues after a meal, indicating that postprandial hormones may be potential players in modulating executive control.

Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans.

CONTEXT: Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models. OBJECTIVE: To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content. DESIGN: We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%). OUTCOME MEASURES: Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed. RESULTS: SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected. CONCLUSIONS: We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.

Functional network connectivity underlying food processing: disturbed salience and visual processing in overweight and obese adults.

In order to adequately explore the neurobiological basis of eating behavior of humans and their changes with body weight, interactions between brain areas or networks need to be investigated. In the current functional magnetic resonance imaging study, we examined the modulating effects of stimulus category (food vs. nonfood), caloric content of food, and body weight on the time course and functional connectivity of 5 brain networks by means of independent component analysis in healthy lean and overweight/obese adults. These functional networks included motor sensory, default-mode, extrastriate visual, temporal visual association, and salience networks. We found an extensive modulation elicited by food stimuli in the 2 visual and salience networks, with a dissociable pattern in the time course and functional connectivity between lean and overweight/obese subjects. Specifically, only in lean subjects, the temporal visual association network was modulated by the stimulus category and the salience network by caloric content, whereas overweight and obese subjects showed a generalized augmented response in the salience network. Furthermore, overweight/obese subjects showed changes in functional connectivity in networks important for object recognition, motivational salience, and executive control. These alterations could potentially lead to top-down deficiencies driving the overconsumption of food in the obese population.

Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women.

AIM: There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. METHODS: We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. RESULTS: Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. CONCLUSION: This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy.

Polymorphism rs11085226 in the gene encoding polypyrimidine tract-binding protein 1 negatively affects glucose-stimulated insulin secretion.

OBJECTIVE: Polypyrimidine tract-binding protein 1 (PTBP1) promotes stability and translation of mRNAs coding for insulin secretion granule proteins and thereby plays a role in ß-cells function. We studied whether common genetic variations within the PTBP1 locus influence insulin secretion, and/or proinsulin conversion. METHODS: We genotyped 1,502 healthy German subjects for four tagging single nucleotide polymorphisms (SNPs) within the PTBP1 locus (rs351974, rs11085226, rs736926, and rs123698) covering 100% of genetic variation with an r(2)≥0.8. The subjects were metabolically characterized by an oral glucose tolerance test with insulin, proinsulin, and C-peptide measurements. A subgroup of 320 subjects also underwent an IVGTT. RESULTS: PTBP1 SNP rs11085226 was nominally associated with lower insulinogenic index and lower cleared insulin response in the OGTT (p≤0.04). The other tested SNPs did not show any association with the analyzed OGTT-derived secretion parameters. In the IVGTT subgroup, SNP rs11085226 was accordingly associated with lower insulin levels within the first ten minutes following glucose injection (p = 0.0103). Furthermore, SNP rs351974 was associated with insulin levels in the IVGTT (p = 0.0108). Upon interrogation of MAGIC HOMA-B data, our rs11085226 result was replicated (MAGIC p = 0.018), but the rs351974 was not. CONCLUSIONS: We conclude that common genetic variation in PTBP1 influences glucose-stimulated insulin secretion. This underlines the importance of PTBP1 for beta cell function in vivo.

Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans.

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tübingen Family (TÜF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC-Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and ß-cell dysfunction, possibly via this gene's role in inflammatory signalling. This variation's impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI.

Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals.

INTRODUCTION: Single nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies. It is not known whether a similar genetic impact on the risk of prediabetes (impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) exists. METHODS: In our cohort of 1442 non-diabetic subjects of European origin (normal glucose tolerance [NGT] n = 1046, isolated IFG n = 142, isolated IGT n = 140, IFG+IGT n = 114), an impact on glucose homeostasis has been shown for 9 SNPs in previous studies in this specific cohort. We analyzed these SNPs (within or in the vicinity of the genes TCF7L2, KCNJ11, HHEX, SLC30A8, WFS1, KCNQ1, MTNR1B, FTO, PPARG) for association with prediabetes. RESULTS: The genetic risk load was significantly associated with the risk for IGT (p = 0.0006) in a model including gender, age, BMI and insulin sensitivity. To further evaluate potential confounding effects, we stratified the population on gender, BMI and insulin sensitivity. The association of the risk score with IGT was present in female participants (p = 0.008), but not in male participants. The risk score was significantly associated with IGT (p = 0.008) in subjects with a body mass index higher than 30 kg/m(2) but not in non-obese individuals. Furthermore, only in insulin resistant subjects a significant association between the genetic load and the risk for IGT (p = 0.01) was found. DISCUSSION: We found that T2D genetic risk alleles cause an increased risk for IGT. This effect was not present in male, lean and insulin sensitive subjects, suggesting a protective role of beneficial environmental factors on the genetic risk.

Fat intake modulates cerebral blood flow in homeostatic and gustatory brain areas in humans.

BACKGROUND: The hypothalamus is the central homeostatic control region of the brain and, therefore, highly influenced by nutrients such as glucose and fat. Immediate and prolonged homeostatic effects of glucose ingestion have been well characterized. However, studies that used stimulation with fat have mainly investigated immediate perceptional processes. Besides homeostatic processes, the gustatory cortex, including parts of the insular cortex, is crucial for the processing of food items. OBJECTIVE: The aim of this study was to investigate the effect of high- compared with low-fat meals on the hypothalamus and the insular cortex. DESIGN: Eleven healthy men participated in a single-blinded, functional MRI study of high- and low-fat meals on 2 measurement days. Cerebral blood flow (CBF) was measured before and 30 and 120 min after intake of high- and low-fat yogurts. Hunger was rated and blood samples were taken before each CBF measurement. RESULTS: High-fat yogurt induced a pronounced decrease in CBF in the hypothalamus, and the corresponding CBF change correlated positively with the insulin change. Furthermore, insular activity increased after 120 min in the low-fat condition only. The CBF change in both regions correlated positively in the high-fat condition. CONCLUSIONS: The decrease in hypothalamic activity and the interaction with the insular cortex elicited by fat may contribute to an efficient energy homeostasis. Therefore, fat might be a modulator of homeostatic and gustatory brain regions and their interaction. This trial was registered at clinicaltrials.gov as NCT01516021.

Monounsaturated fatty acids prevent the aversive effects of obesity on locomotion, brain activity, and sleep behavior.

Fat and physical inactivity are the most evident factors in the pathogenesis of obesity, and fat quality seems to play a crucial role for measures of glucose homeostasis. However, the impact of dietary fat quality on brain function, behavior, and sleep is basically unknown. In this study, mice were fed a diet supplemented with either monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs) and their impact on glucose homeostasis, locomotion, brain activity, and sleep behavior was evaluated. MUFAs and SFAs led to a significant increase in fat mass but only feeding of SFAs was accompanied by glucose intolerance in mice. Radiotelemetry revealed a significant decrease in cortical activity in SFA-mice whereas MUFAs even improved activity. SFAs decreased wakefulness and increased non-rapid eye movement sleep. An intracerebroventricular application of insulin promoted locomotor activity in MUFA-fed mice, whereas SFA-mice were resistant. In humans, SFA-enriched diet led to a decrease in hippocampal and cortical activity determined by functional magnetic resonance imaging techniques. Together, dietary intake of MUFAs promoted insulin action in the brain with its beneficial effects for cortical activity, locomotion, and sleep, whereas a comparable intake of SFAs acted as a negative modulator of brain activity in mice and humans.

Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.

OBJECTIVE: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. SUBJECTS/METHODS: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). RESULTS: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). CONCLUSION: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.

The obese brain: association of body mass index and insulin sensitivity with resting state network functional connectivity.

Obesity is a key risk factor for the development of insulin resistance, Type 2 diabetes and associated diseases; thus, it has become a major public health concern. In this context, a detailed understanding of brain networks regulating food intake, including hormonal modulation, is crucial. At present, little is known about potential alterations of cerebral networks regulating ingestive behavior. We used "resting state" functional magnetic resonance imaging to investigate the functional connectivity integrity of resting state networks (RSNs) related to food intake in lean and obese subjects using independent component analysis. Our results showed altered functional connectivity strength in obese compared to lean subjects in the default mode network (DMN) and temporal lobe network. In the DMN, obese subjects showed in the precuneus bilaterally increased and in the right anterior cingulate decreased functional connectivity strength. Furthermore, in the temporal lobe network, obese subjects showed decreased functional connectivity strength in the left insular cortex. The functional connectivity magnitude significantly correlated with body mass index (BMI). Two further RSNs, including brain regions associated with food and reward processing, did not show BMI, but insulin associated functional connectivity strength. Here, the left orbitofrontal cortex and right putamen functional connectivity strength was positively correlated with fasting insulin levels and negatively correlated with insulin sensitivity index. Taken together, these results complement and expand previous functional neuroimaging findings by demonstrating that obesity and insulin levels influence brain function during rest in networks supporting reward and food regulation.

Neuronal correlates of reduced memory performance in overweight subjects.

There is growing evidence that excessive body weight correlates with impaired cognitive performance like executive function, attention and memory. In our study, we applied a visual working memory task to quantify associations between body weight and executive function. In total, 34 lean (BMI 22±2.1 kg/m(2)) and 34 obese (BMI 30.4±3.2 kg/m(2)) subjects were included. Magnetic brain activity and behavioral responses were recorded during a one-back visual memory task with food and non-food pictures, which were matched for color, size and complexity. Behavioral responses (reaction time and accuracy) were reduced in obese subjects independent of the stimulus category. Neuronal activity at the source level showed a positive correlation between the right dorsolateral prefrontal cortex (DLPFC) activity and BMI only for the food category. In addition, a negative correlation between BMI and neuronal activity was observed in the occipital area for both categories. Therefore we conclude that increased body weight is associated with reduced task performance and specific neuronal changes. This altered activity is probably related to executive function as well as encoding and retrieval of information.

Insulin sensitivity of the human brain.

The brain is an insulin sensitive organ and insulin signaling is important to regulate feeding behavior, body weight, and cognitive processes. Insulin resistance in peripheral tissues is a hallmark in the development of type 2 diabetes mellitus (T2DM), yet the finding of insulin resistance in the brain is relatively novel. Studies in humans revealed that environmental factors like obesity, age, and the genetic background have an impact on central insulin sensitivity. According to the physiological effects of insulin in the brain, disturbances of this signaling chain lead to an impairment of cognitive functions and a deterioration of eating behavior with a potential role in the pathogenesis of obesity and T2DM. First attempts to treat insulin resistance not only in peripheral tissues but also in the CNS have therefore come on its way: Cerebral insulin resistance can at least partially be overcome by intranasal treatment with insulin or by commercial insulins that exhibit specific effects in the brain due to their pharmacokinetic properties. Despite the advances towards a better understanding of insulin function in the human brain in the last years, achieving a more profound knowledge of mechanisms behind central insulin function and identifying further strategies to overcome insulin resistance must be a main goal of future research.

An Obesity Risk SNP (rs17782313) near the MC4R Gene Is Associated with Cerebrocortical Insulin Resistance in Humans.

Activation of melanocortin-4 receptor (MC4R) by insulin sensitive neurons is a central mechanism in body weight regulation, and genetic variants in the MC4R gene (e.g., rs17782313) are associated with obesity. By using magnetoencephalography, we addressed whether rs17782313 affects the cerebrocortical insulin response. We measured the cerebrocortical insulin response by using magnetoencephalography in a hyperinsulinemic euglycemic clamp (versus placebo) in 51 nondiabetic humans (26 f/25 m, age 35 ± 3 years, BMI 28 ± 1 kg/m(2)). The C-allele of rs17782313 was minor allele (frequency 23%), and the genotype distribution (TT 30, TC 19, CC 2) was in Hardy-Weinberg-Equilibrium. Insulin-stimulated cerebrocortical theta activity was decreased in the presence of the C-allele (TT 33 ± 16 fT; TC/CC -27 ± 20 fT; P = .023), and this effect remained significant after adjusting for BMI and peripheral insulin sensitivity (P = .047). Cerebrocortical theta activity was impaired in carriers of the obesity risk allele. Therefore, cerebral insulin resistance may contribute to the obesity effect of rs17782313.

Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes.

The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic ß-cell dysfunction. We genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency ≥0.05) within the TRPM5 locus (D' = 1.0; r² ≥ 0.8). Rs800344, rs800345, and rs2301699 were significantly associated with area under the curve (AUC) glucose during the OGTT in the additive and dominant models after adjustment for sex, age, and body mass index (all Ps ≤ .0025). Furthermore, rs800344 was significantly associated with 2-hour glucose in the dominant model (P = .0009). After stratification for sex, rs2301699 was significantly associated with the ratio of AUC insulin 0 to 30 minutes to AUC glucose 0 to 30 minutes in women (P = .0097), but not in men (P = .3), in the dominant model. Female minor allele carriers of rs2301699 showed significantly lower glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P = .0124), whereas in male subjects, no significant differences were found (P = .3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes; and this may in turn contribute to the development of type 2 diabetes mellitus.

Genetic variation within the NR1H2 gene encoding liver X receptor ß associates with insulin secretion in subjects at increased risk for type 2 diabetes.

The liver X receptors (LXRs)-α and -ß play a crucial role in control of insulin production and secretion in pancreatic ß-cells. We hypothesized that common variants in the NR1H2 and NR1H3 genes, encoding LXR-ß and -α, respectively, may alter pancreatic ß-cell function. One thousand five hundred seventy-four subjects of European ancestry with elevated risk for type 2 diabetes were genotyped for the two NR1H2 single nucleotide polymorphisms (SNPs) rs2248949 and rs1405655 and for the four NR1H3 SNPs rs11039149, rs3758673, rs12221497 and rs2279238, and association studies with metabolic traits were performed. Metabolic characterization comprised an oral glucose tolerance test (OGTT) in all participants and, in addition, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test (IVGTT) in subsets. One hundred per cent of common genetic variation (minor allele frequency ≥1%) within the NR1H2 and NR1H3 loci (D' = 1.0; r² ≥ 0.8) were covered by the six chosen tagging SNPs. NR1H2 rs2248949 was nominally associated with OGTT-derived first-phase insulin secretion and proinsulin conversion to insulin and significantly associated with the AUC of insulin levels during the IVGTT (p = 0.007) after adjustment for age, gender, BMI and insulin sensitivity in the dominant model, with the minor allele conferring reduced pancreatic ß-cell function to the carriers. In subjects of European ancestry at increased risk for type 2 diabetes, common variation within the NR1H2 gene impaired insulin secretion, which may facilitate the development of type 2 diabetes.