Otto Tschritter

The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: A magnetoencephalographic study

Animal studies have shown that the brain is an insulin-responsive organ and that central nervous insulin resistance induces obesity and disturbances in glucose metabolism. In humans, insulin effects in the brain are poorly characterized. We used a magnetoencephalography approach during a two-step hyperinsulinemic euglycemic clamp to (i) assess cerebrocortical insulin effects in humans, (ii) compare these effects between 10 lean and 15 obese subjects, and (iii) test whether the insulin receptor substrate (IRS)-1 Gly972Arg polymorphism in the insulin-signaling cascade modifies these effects. Both spontaneous and stimulated (mismatch negativity) cortical activity were assessed. In lean humans, stimulated cortical activity (P = 0.046) and the beta and theta band of spontaneous cortical activity (P = 0.01 and 0.04) increased with insulin infusion relative to saline. In obese humans, these effects were suppressed. Moreover, the insulin effect on spontaneous cortical activity correlated negatively with body mass index and percent body fat (all r < −0.4; all P < 0.05) and positively with insulin sensitivity of glucose disposal (theta band, r = 0.48, P = 0.017). Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P = 0.01). We conclude that, in lean humans, insulin modulates cerebrocortical activity, and that these effects are diminished in obese individuals. Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene.

Polymorphisms within novel risk loci for type 2 diabetes determine β-cell function.

Background Type 2 diabetes arises when insulin resistance-induced compensatory insulin secretion exhausts. Insulin resistance and/or β-cell dysfunction result from the interaction of environmental factors (high-caloric diet and reduced physical activity) with a predisposing polygenic background. Very recently, genetic variations within four novel genetic loci (SLC30A8, HHEX, EXT2, and LOC387761) were reported to be more frequent in subjects with type 2 diabetes than in healthy controls. However, associations of these variations with insulin resistance and/or β-cell dysfunction were not assessed. Methodology/Principal Findings By genotyping of 921 metabolically characterized German subjects for the reported candidate single nucleotide polymorphisms (SNPs), we show that the major alleles of the SLC30A8 SNP rs13266634 and the HHEX SNP rs7923837 associate with reduced insulin secretion stimulated by orally or intravenously administered glucose, but not with insulin resistance. In contrast, the other reported type 2 diabetes candidate SNPs within the EXT2 and LOC387761 loci did not associate with insulin resistance or β-cell dysfunction, respectively. Conclusions/Significance The HHEX and SLC30A8 genes encode for proteins that were shown to be required for organogenesis of the ventral pancreas and for insulin maturation/storage, respectively. Therefore, the major alleles of type 2 diabetes candidate SNPs within these genetic loci represent crucial alleles for β-cell dysfunction and, thus, might confer increased susceptibility of β-cells towards adverse environmental factors.

Variation in the FTO gene influences food intake but not energy expenditure.

Polymorphisms in the FTO (fat mass- and obesity-associated) gene are associated with obesity. The mechanisms how genetic variation in this gene influences body weight are unknown. Body weight is determined by energy intake/storage and energy expenditure. In this study, we investigated whether genetic variation in FTO influences energy expenditure or food intake in carefully phenotyped subjects. In 380 German subjects, insulin sensitivity was measured by a hyperinsulinemic euglycemic clamp. Lean body mass and body fat were quantified using the bioimpedance method. Indirect calorimetry was used to estimate the metabolic rate. Food intake was assessed using food diaries (mean 11+/-1 d) in 151 subjects participating in a lifestyle intervention program to prevent diabetes. All subjects were genotyped for the FTO single nucleotide polymorphism (SNP) rs8050136. The risk allele of SNP rs8050136 was associated with higher body fat-related parameters (all p< or =0.04, additive inheritance model). Energy expenditure was not affected by the SNP. However, the risk allele of rs8050136 was significantly associated with higher energy intake (p=0.01, dominant inheritance model) during dietary restriction. Our data suggest that the increased body weight in carriers of the risk allele of FTO SNP rs8050136 is a consequence of increased food intake, but not of impaired energy expenditure.

Insulin Modulates Food-Related Activity in the Central Nervous System

CONTEXT Previous data suggest a key role of central nervous insulin action in regulating energy homeostasis. OBJECTIVE We therefore investigated whether insulin modulates brain responses to food and nonfood pictures in a functional magnetic resonance imaging study. DESIGN AND PATIENTS Nine healthy, normal-weight subjects underwent two functional magnetic resonance imaging measurements to compare the effects of insulin and placebo administration during a visual recognition task with food and nonfood pictures. Insulin was administered intranasally to raise insulin concentrations in the cerebrospinal fluid without altering systemic effects in the periphery. Metabolic parameters were continuously determined during the experiments. MAIN OUTCOME MEASURE We measured the changes in brain activity after intranasal insulin administration. RESULTS Food pictures were detected faster when compared to nonfood pictures in all conditions without any effect of placebo or insulin. After insulin application, functional magnetic resonance imaging measurements showed a significantly reduced activity in the presence of food pictures compared to placebo in the right and left fusiform gyrus, the right hippocampus, the right temporal superior cortex, and the right frontal middle cortex. The brain activation induced by nonfood pictures remained unaffected by insulin. CONCLUSION We demonstrate that intranasal insulin led to a reduction of activity in brain areas related to object processing and memory and may have an effect on brain activation with regard to the processing of food pictures. This effect might be part of a mechanism that terminates food intake in the postprandial state.

Impact of Variation in the FTO Gene on Whole Body Fat Distribution, Ectopic Fat, and Weight Loss

Polymorphisms in the fat mass‐ and obesity‐associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome‐wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single‐nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two‐hundred and four subjects participated in a lifestyle intervention program and were examined after a follow‐up of 9 months. In the cross‐sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P < 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat (P ≤ 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P ≤ 0.1). However, the single‐nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P > 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.

Tissue selectivity of insulin detemir action in vivo

Aims/hypothesisRecombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo.MethodsC57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection.ResultsThe time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir.Conclusions/interpretationTaken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.

Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans

regulation. Based on this, we investigated the relationship between the FTO variant rs8050136 and BMI using data obtained from the Tubingen Family (TUF) Study [5]. BMI was higher in carriers of the risk allele than in wild-type individuals (AA [n=463] 27.2±0.3 kg/m 2 ,A C [n=732] 29.0±0.3kg/m 2 ,C C [n=267] 29.5±0.5 kg/m 2 ,m eans±SEM, p<0.001) as a result of increased body weight (AA 79.8± 0.9 kg, AC 84.7±1.0 kg, CC 84.8±1.5 kg, p<0.001). This finding replicates the previously reported weight difference in our population [1–4]. However, the mechanism by which FTO polymorphisms affect body weight in humans is still unclear. In mice, FTO is expressed in multiple tissues, including the brain. It is located on a region on chromosome 8 that is deleted by the Fused toes mutation [6]. The fused toes mutation causes a complex phenotype that features partial syndactyly of forelimbs and defects in brain morpho

Cerebrocortical Beta Activity in Overweight Humans Responds to Insulin Detemir

Background Insulin stimulates cerebrocortical beta and theta activity in lean humans. This effect is reduced in obese individuals indicating cerebrocortical insulin resistance. In the present study we tested whether insulin detemir is a suitable tool to restore the cerebral insulin response in overweight humans. This approach is based on studies in mice where we could recently demonstrate increased brain tissue concentrations of insulin and increased insulin signaling in the hypothalamus and cerebral cortex following peripheral injection of insulin detemir. Methodology/Principal Findings We studied activity of the cerebral cortex using magnetoencephalography in 12 lean and 34 overweight non-diabetic humans during a 2-step hyperinsulinemic euglycemic clamp (each step 90 min) with human insulin (HI) and saline infusion (S). In 10 overweight subjects we additionally performed the euglycemic clamp with insulin detemir (D). While human insulin administration did not change cerebrocortical activity relative to saline (p = 0.90) in overweight subjects, beta activity increased during D administration (basal 59±3 fT, 1st step 62±3 fT, 2nd step 66±5, p = 0.001, D vs. HI). As under this condition glucose infusion rates were lower with D than with HI (p = 0.003), it can be excluded that the cerebral effect is the consequence of a systemic effect. The total effect of insulin detemir on beta activity was not different from the human insulin effect in lean subjects (p = 0.78). Conclusions/Significance Despite cerebrocortical resistance to human insulin, insulin detemir increased beta activity in overweight human subjects similarly as human insulin in lean subjects. These data suggest that the decreased cerebral beta activity response in overweight subjects can be restored by insulin detemir.

Interaction effect between common polymorphisms in PPARγ2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity

Abstract. The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) γ2 gene is associated with a reduced risk of type 2 diabetes. A beneficial effect on insulin sensitivity is reported in some but not all populations. It is possible that this genetic variant produces a characteristic phenotype only against a certain genetic background. We therefore tested the hypothesis that carriers of the Ala allele of PPARγ2 exhibit a different phenotype against the background of the Gly972Arg polymorphism in the insulin receptor substrate (IRS) 1. We determined insulin sensitivity in the four combinations defined by the absence or presence of the polymorphic allele (healthy, glucose tolerant subjects), by the oral glucose tolerance test (OGTT; using a validated index, n=318) and hyperinsulinemic clamp (n=201). Insulin sensitivity was not or was only marginally different between Pro/Pro and X/Ala in the overall population. Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARγ2) + X/Arg (IRS-1) than in Pro/Pro (PPARγ2) + X/Arg (IRS-1). On the other hand, insulin sensitivity was similar in the X/Ala (PPARγ2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARγ2) + Gly/Gly (IRS-1). The results were practically identical using insulin sensitivity from the clamp. In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARγ) which was not present in the whole population or against the Gly972 (IRS-1) background. This suggests that the Ala allele of PPARγ2 becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism. Allowing for gene-gene interaction effects may reveal novel information regarding metabolic effects of genetic variants.

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.