Katarzyna Linder

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on whole-body insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.

Resting‐state functional connectivity of the human hypothalamus

The hypothalamus is of enormous importance for multiple bodily functions such as energy homeostasis. Especially, rodent studies have greatly contributed to our understanding how specific hypothalamic subregions integrate peripheral and central signals into the brain to control food intake. In humans, however, the neural circuitry of the hypothalamus, with its different subregions, has not been delineated. Hence, the aim of this study was to map the hypothalamus network using resting‐state functional connectivity (FC) analyses from the medial hypothalamus (MH) and lateral hypothalamus (LH) in healthy normal‐weight adults (n = 49). Furthermore, in a separate sample, we examined differences within the LH and MH networks between healthy normal‐weight (n = 25) versus overweight/obese adults (n = 23). FC patterns from the LH and MH revealed significant connections to the striatum, thalamus, brainstem, orbitofrontal cortex, middle and posterior cingulum and temporal brain regions. However, our analysis revealed subtler distinctions within hypothalamic subregions. The LH was functionally stronger connected to the dorsal striatum, anterior cingulum, and frontal operculum, while the MH showed stronger functional connections to the nucleus accumbens and medial orbitofrontal cortex. Furthermore, overweight/obese participants revealed heightened FC in the orbitofrontal cortex and nucleus accumbens within the MH network. Our results indicate that the MH and LH network are tapped into different parts of the dopaminergic circuitry of the brain, potentially modulating food reward based on the functional connections to the ventral and dorsal striatum, respectively. In obese adults, FC changes were observed in the MH network. Hum Brain Mapp 35:6088–6096, 2014.

Relationships of body composition and liver fat content with insulin resistance in obesity-matched adolescents and adults

While in adults not total body‐ or visceral fat mass, but liver fat content was found to independently determine insulin resistance, it is unclear whether these relationships are already present in obese adolescents.

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.

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/m2 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.

Gestational Diabetes Impairs Human Fetal Postprandial Brain Activity

CONTEXT Gestational diabetes (GDM) influences the fetal phenotype. OBJECTIVE In the present study, our aim was to determine the effect of GDM specifically on fetal brain activity. DESIGN Pregnant participants underwent an oral glucose tolerance test (OGTT, 75 g). At 0, 60, and 120 minutes, maternal metabolism was determined, and fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device. SETTING All measurements were performed at the fMEG Center in Tübingen. PARTICIPANTS Twelve women with GDM and 28 normal glucose-tolerant (NGT) pregnant women participated on a voluntary basis. INTERVENTIONS OGTT (75 g, 120 minutes) was used in this study. MAIN OUTCOMES AND MEASURES Fetal auditory evoked response latencies were determined for this study. RESULTS In the fetuses of NGT women, latencies decreased between 0 and 60 minutes from 260 ± 90 to 206 ± 74 ms (P = .008) and remained stable until 120 minutes (206 ± 74 vs 230 ± 79, P =.129). In fetuses of women with GDM, there was no change in response latencies during OGTT (P = .11). Sixty minutes after glucose ingestion, fetal latencies in the GDM group were longer than in the NGT group (296 ± 82 vs 206 ± 74 ms, P = .001). Linear regression revealed a significant effect of maternal glucose, insulin levels, and insulin sensitivity on response latencies after 60 minutes. CONCLUSIONS Fetal postprandial brain responses were slower in the offspring of women with GDM. This might indicate that gestational diabetes directly affects fetal brain development and may lead to central nervous insulin resistance in the fetus.

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

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.

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.

Dopamine Depletion Reduces Food-Related Reward Activity Independent of BMI

Reward sensitivity and possible alterations in the dopaminergic-reward system are associated with obesity. We therefore aimed to investigate the influence of dopamine depletion on food-reward processing. We investigated 34 female subjects in a randomized placebo-controlled, within-subject design (body mass index (BMI)=27.0 kg/m2 ±4.79 SD; age=28 years ±4.97 SD) using an acute phenylalanine/tyrosine depletion drink representing dopamine depletion and a balanced amino acid drink as the control condition. Brain activity was measured with functional magnetic resonance imaging during a ‘wanting’ and ‘liking’ rating of food items. Eating behavior-related traits and states were assessed on the basis of questionnaires. Dopamine depletion resulted in reduced activation in the striatum and higher activation in the superior frontal gyrus independent of BMI. Brain activity during the wanting task activated a more distributed network than during the liking task. This network included gustatory, memory, visual, reward, and frontal regions. An interaction effect of dopamine depletion and the wanting/liking task was observed in the hippocampus. The interaction with the covariate BMI was significant in motor and control regions but not in the striatum. Our results support the notion of altered brain activity in the reward and prefrontal network with blunted dopaminergic action during food-reward processing. This effect is, however, independent of BMI, which contradicts the reward-deficiency hypothesis. This hints to the hypothesis suggesting a different or more complex mechanism underlying the dopaminergic reward function in obesity.

Olive oil aroma extract modulates cerebral blood flow in gustatory brain areas in humans

BACKGROUND Low- and high-fat meals affect homeostatic and gustatory brain areas differentially. In a previous study, we showed that a high-fat meal decreased cerebral blood flow (CBF) in homeostatic brain areas (hypothalamus), whereas a low-fat meal increased CBF in gustatory regions (anterior insula). OBJECTIVE The aim of this study was to investigate the long-lasting effect of fat-free flavor-active compounds of olive oil on the brain and whether those aroma components can trigger fat-associated brain responses in homeostatic and gustatory regions. DESIGN Eleven healthy male subjects participated in a functional magnetic resonance imaging study. On 2 measurement days, subjects consumed single-blinded a plain low-fat yogurt or low-fat yogurt mixed with a fat-free aroma extract of olive oil. Resting CBF was measured before and 30 and 120 min after yogurt intake. Hunger was rated before each measurement. Blood samples were collected at 6 time points. RESULTS The extract-containing yogurt elicited higher CBF in the frontal operculum 30 and 120 min after a meal. Furthermore, the activity change in the anterior insula after 30 min correlated positively with the glucose change in the extract condition only. No effects were observed in the hypothalamus. CONCLUSIONS The anterior insula and the frontal operculum are regarded as the primary taste cortex. Modulation of the frontal operculum by the yogurt containing the olive oil extract suggests that it might be possible to simulate fat-triggered sensations in the brain on the gustatory level, possibly by ingredients the body implicitly associates with fat. This trial was registered at clinicaltrials.gov as NCT01716286.