Impact of breastfeeding duration on coagulation in women with and without history of gestational diabetes mellitus.

OBJECTIVE: Breastfeeding is associated with a reduced maternal risk for cardiovascular diseases. Since the underlying mechanisms are still poorly understood, we here examined the impact of breastfeeding on the plasmatic coagulation system in women with and without history of gestational diabetes mellitus (GDM). METHODS: 76 participants of the German Gestational Diabetes Study (PREG; NCT04270578) were examined 14 [interquartile range: 12-26] months after delivery with a 5-point oral glucose tolerance test. Global coagulation tests, prothrombotic coagulation proteins (FII/FVII/FVIII/FIX), antithrombotic proteins (antithrombin, protein C/S) and endothelial markers (von-Willebrand-factor and PAI-1) were determined. The Framingham Risk Score was used to estimate the 10-year cardiovascular risk. The impact of breastfeeding duration on coagulation was analyzed using multivariable linear models. RESULTS: The mean duration of breastfeeding was 11 [7-14] months. Overall, longer duration of breastfeeding was associated with lower cardiovascular risk (Framingham Risk Score, p=0.05) and was negatively associated with FIX (p=0.018). We detected an interaction between previous GDM and breastfeeding duration for FIX (pInteraction=0.017): only in women with GDM history was the duration of breastfeeding negatively associated with FIX activity (p=0.016). This association persisted in statistical models adjusted for age, body-mass index, insulin sensitivity, and C-reactive protein. The duration of breastfeeding was not associated with anticoagulant proteins and endothelial markers. CONCLUSION: Longer duration of breastfeeding is associated with lower cardiovascular risk and an improved coagulation profile. Women with GDM history appear to benefit particularly from prolonged breastfeeding.

Identification of MicroRNAs Associated with Prediabetic Status in Obese Women.

MicroRNAs (miRNAs) recently emerged as means of communication between insulin-sensitive tissues to mediate diabetes development and progression, and as such they present a valuable proxy for epigenetic alterations associated with type 2 diabetes. In order to identify miRNA markers for the precursor of diabetes called prediabetes, we applied a translational approach encompassing analysis of human plasma samples, mouse tissues and an in vitro validation system. MiR-652-3p, miR-877-5p, miR-93-5p, miR-130a-3p, miR-152-3p and let-7i-5p were increased in plasma of women with impaired fasting glucose levels (IFG) compared to those with normal fasting glucose and normal glucose tolerance (NGT). Among these, let-7i-5p and miR-93-5p correlated with fasting blood glucose levels. Human data were then compared to miRNome data obtained from islets of Langerhans and adipose tissue of 10-week-old female New Zealand Obese mice, which differ in their degree of hyperglycemia and liver fat content. Similar to human plasma, let-7i-5p was increased in adipose tissue and islets of Langerhans of diabetes-prone mice. As predicted by the in silico analysis, overexpression of let-7i-5p in the rat ß-cell line INS-1 832/12 resulted in downregulation of insulin signaling pathway components (Insr, Rictor, Prkcb, Clock, Sos1 and Kcnma1). Taken together, our integrated approach highlighted let-7i-5p as a potential regulator of whole-body insulin sensitivity and a novel marker of prediabetes in women.

Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase.

Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution1,2. In particular, brain insulin action increases whole-body insulin sensitivity, but these studies were mainly performed in lean men3,4. Here we investigate metabolic and hypothalamic effects of brain insulin action in women with a focus on the impact of menstrual cycle ( ClinicalTrials.gov registration: NCT03929419 ).Eleven women underwent four hyperinsulinemic-euglycemic clamps, two in the follicular phase and two in the luteal phase. Brain insulin action was introduced using nasal insulin spray5-7 and compared to placebo spray in a fourfold crossover design with change in glucose infusion rate as the primary endpoint. Here we show that during the follicular phase, more glucose has to be infused after administration of nasal insulin than after administration of placebo. This remains significant after adjustment for blood glucose and insulin. During the luteal phase, no significant influence of brain insulin action on glucose infusion rate is detected after adjustment for blood glucose and insulin (secondary endpoint). In 15 other women, hypothalamic insulin sensitivity was assessed in a within-subject design by functional magnetic resonance imaging with intranasal insulin administration8. Hypothalamus responsivity is influenced by insulin in the follicular phase but not the luteal phase.Our study therefore highlights that brain insulin action improves peripheral insulin sensitivity also in women but only during the follicular phase. Thus, brain insulin resistance could contribute to whole-body insulin resistance in the luteal phase of the menstrual cycle.

Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS).

BACKGROUND: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. METHODS: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. FINDINGS: Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. INTERPRETATION: By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. FUNDING: German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.

Ex vivo instability of lipids in whole blood: preanalytical recommendations for clinical lipidomics studies.

Reliability, robustness, and interlaboratory comparability of quantitative measurements is critical for clinical lipidomics studies. Lipids' different ex vivo stability in blood bears the risk of misinterpretation of data. Clear recommendations for the process of blood sample collection are required. We studied by UHPLC-high resolution mass spectrometry, as part of the "Preanalytics interest group" of the International Lipidomics Society, the stability of 417 lipid species in EDTA whole blood after exposure to either 4°C, 21°C, or 30°C at six different time points (0.5 h-24 h) to cover common daily routine conditions in clinical settings. In total, >800 samples were analyzed. 325 and 288 robust lipid species resisted 24 h exposure of EDTA whole blood to 21°C or 30°C, respectively. Most significant instabilities were detected for FA, LPE, and LPC. Based on our data, we recommend cooling whole blood at once and permanent. Plasma should be separated within 4 h, unless the focus is solely on robust lipids. Lists are provided to check the ex vivo (in)stability of distinct lipids and potential biomarkers of interest in whole blood. To conclude, our results contribute to the international efforts towards reliable and comparable clinical lipidomics data paving the way to the proper diagnostic application of distinct lipid patterns or lipid profiles in the future.

Acute and long-term exercise adaptation of adipose tissue and skeletal muscle in humans: a matched transcriptomics approach after 8-week training-intervention.

BACKGROUND: Exercise exerts many health benefits by directly inducing molecular alterations in physically utilized skeletal muscle. Molecular adaptations of subcutaneous adipose tissue (SCAT) might also contribute to the prevention of metabolic diseases. AIM: To characterize the response of human SCAT based on changes in transcripts and mitochondrial respiration to acute and repeated bouts of exercise in comparison to skeletal muscle. METHODS: Sedentary participants (27 ± 4 yrs) with overweight or obesity underwent 8-week supervised endurance exercise 3×1h/week at 80% VO2peak. Before, 60 min after the first and last exercise bout and 5 days post intervention, biopsies were taken for transcriptomic analyses and high-resolution respirometry (n = 14, 8 female/6 male). RESULTS: In SCAT, we found 37 acutely regulated transcripts (FC > 1.2, FDR < 10%) after the first exercise bout compared to 394, respectively, in skeletal muscle. Regulation of only 5 transcripts overlapped between tissues highlighting their differential response. Upstream and enrichment analyses revealed reduced transcripts of lipid uptake, storage and lipogenesis directly after exercise in SCAT and point to ß-adrenergic regulation as potential major driver. The data also suggest an exercise-induced modulation of the circadian clock in SCAT. Neither term was associated with transcriptomic changes in skeletal muscle. No evidence for beigeing/browning was found in SCAT along with unchanged respiration. CONCLUSIONS: Adipose tissue responds completely distinct from adaptations of skeletal muscle to exercise. The acute and repeated reduction in transcripts of lipid storage and lipogenesis, interconnected with a modulated circadian rhythm, can counteract metabolic syndrome progression toward diabetes.

Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. We assigned 1,045 participants from the Prediabetes Lifestyle Intervention Study (PLIS) to six recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time points during a 1-year intervention. We also analyzed the change of glycemia, insulin sensitivity, and liver fat. All prediabetes high-risk clusters (cluster 3, 5, and 6) had improved glycemic traits during the lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (P < 0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (Pinteraction < 0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes.

The Acute Cytokine Response to 30-Minute Exercise Bouts Before and After 8-Week Endurance Training in Individuals With Obesity.

CONTEXT: One acute bout of exercise leads to a rapid increase in the systemic cytokine concentration. Regular exercise might alter the cytokine response, in particular in beforehand untrained and obese individuals. OBJECTIVE: Using a proximity extension assay, we studied the effects of acute exercise as well as endurance training on a panel of 92 cytokines related to inflammation. METHODS: A total of 22 individuals (30 ± 9 years; peak oxygen uptake [VO2peak] 25.2 ± 4.2 mL/[kg × min]; body mass index [BMI] 31.7 ± 4.4) participated in an 8-week endurance exercise intervention. Blood samples were collected before and immediately after 30 minutes' ergometer exercise at 80% VO2peak. RESULTS: Before and after the training intervention, 40 and 37 cytokines, respectively, were acutely increased more than 1.2-fold (Benjamini-Hochberg [BH]-adjusted P < .05). The exercise intervention did not change the acute increase in cytokines nor the resting cytokine levels, whereas fitness was improved and adiposity reduced. The increase in fitness led to a slight increase in power output when exercising at the same heart rate, which might explain the comparable increase in cytokines before and after the intervention. The largest acute increase was found for OSM, TGFA, CXCL1 and 5, and TNFSF14 (≥ 1.9-fold, BH-adjusted P < .001). The transcript levels of these proteins in whole blood were also elevated, particularly in the trained state. Only the acute increase in IL6 (1.3-fold) was related to the increase in lactate, confirming the lactate-driven secretion of IL6. CONCLUSION: Our comprehensive proteomics approach detected several underexplored serum exerkines with up to now less understood function in the adaptation to exercise.

Maternal Weight Gain during Pregnancy and the Developing Autonomic Nervous System-Possible Impact of GDM.

OBJECTIVE: The intrauterine environment is known to affect the offspring's long-term risk for obesity and diabetes. Previous data show that maternal metabolism and gestational weight gain (GWG) are associated with fetal autonomic nervous system (ANS) function, which can be assessed with heart rate variability (HRV). We investigated whether this association is also present in 2-year-old children and addressed the impact of gestational diabetes (GDM). RESEARCH DESIGN AND METHODS: We examined the 2-year-old offspring of mothers who had undergone a 5-point, 75 g oral glucose tolerance test during pregnancy. To assess HRV, a 10-minute ECG was recorded, and time domain and frequency domain parameters were analyzed. Body composition was assessed using bioelectrical impedance testing. RESULTS: We examined 67 children (33 girls, 34 boys), 30 of whom were born to mothers with treated GDM and normoglycemic pregnancies (NGT), respectively. No differences were found between the groups with regard to birth weight, weight at the age of 2 years, and body fat content. We observed that GWG was associated with heart rate and HRV, indicating that children of mothers with low GWG had a lower parasympathetic tone. This association was detected in NGT-exposed-but not in GDM-exposed-children. HR and HRV correlated with body fat and fat-free mass in children from normoglycemic pregnancies only. CONCLUSION: We found that the impact of maternal GWG on offspring ANS function was missing in the presence of treated GDM. The balance of the ANS was related to offspring body composition in children from NGT pregnancies only. Our results suggest that maternal weight gain during pregnancy has a critical impact on the developing ANS, which might be disturbed in the presence of GDM.

Diabetes and the Prostate: Elevated Fasting Glucose, Insulin Resistance and Higher Levels of Adrenal Steroids in Prostate Cancer.

Although epidemiological studies suggest a lower prostate cancer incidence rate in patients with type 2 diabetes, cancer survival is markedly reduced. Underlying mechanisms that connect the two diseases are still unclear. Potential links between type 2 diabetes and prostate cancer are hallmarks of the metabolic syndrome, such as hyperglycemia and dyslipidemia. Therefore, we explored the systemic metabolism of 103 prostate cancer patients with newly diagnosed and yet untreated prostate cancer compared to 107 healthy controls, who were carefully matched for age and BMI. Here, we report that patients with prostate cancer display higher fasting blood glucose levels and insulin resistance, without changes in insulin secretion. With respect to lipid metabolism, serum triglyceride levels were lower in patients with prostate cancer. In addition, we report increased adrenal steroid biosynthesis in these patients. Our results indicate that higher fasting glucose levels in patients with prostate cancer may be explained at least in part by insulin resistance, due to the enhanced synthesis of adrenal steroids.

Interscapular fat is associated with impaired glucose tolerance and insulin resistance independent of visceral fat mass.

OBJECTIVE: Dysregulated body fat distribution is a major determinant of various diseases. In particular, increased visceral fat mass and ectopic lipids in the liver are linked to metabolic disorders such as insulin resistance and type 2 diabetes. Furthermore, interscapular fat is considered to be a metabolically active fat compartment. METHODS: This study measured interscapular fat mass and investigated its relationship with glucose metabolism in 822 individuals with a wide range of BMI values and different glucose tolerance statuses. Magnetic resonance imaging was used to quantify body fat depots, and an oral glucose tolerance test was performed to determine glucose metabolism. RESULTS: Elevated interscapular fat mass was positively associated with age, BMI, and total body, visceral, and subcutaneous adipose tissue mass. High interscapular fat mass associated with elevated fasting glucose levels, glucose levels at 2 hours during the oral glucose tolerance test, glycated hemoglobin, and insulin resistance, independent of sex, age, and total body and visceral fat mass. CONCLUSIONS: In conclusion, interscapular fat might be a highly specific fat compartment with a potential impact on glucose metabolism and the pathogenesis of diabetes mellitus.

Comprehensive validation of fasting-based and oral glucose tolerance test-based indices of insulin secretion against gold standard measures.

INTRODUCTION: With pre-diabetes and diabetes increasingly recognized as heterogeneous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on oral glucose tolerance test (OGTT) and fasting measurements in comparison with gold standard methods. RESEARCH DESIGN AND METHODS: The hyperglycemic clamp extended with glucagon-like peptide 1 (GLP-1) infusion and intravenous glucose tolerance test (IVGTT), as well as OGTT, was performed in two well-phenotyped cohorts. The gold standard-derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearson's and Spearman's correlation coefficients. The insulin-based and C-peptide-based indices were analyzed separately in different groups of glucose tolerance and the entire cohorts. RESULTS: The highest correlation coefficients were found for area under curve (AUC) (I0-30)/AUC (G0-30), I30/G30, first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycemic clamp. AUC (I0-120)/AUC (G0-120), BIGTT-AIR0-60-120, I30/G30, first-phase Stumvoll and AUC (I0-30)/AUC (G0-30) demonstrated the strongest association with incretin-stimulated insulin response. CONCLUSIONS: We have identified glucose-stimulated and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold standard measures and could be potentially used in future researches and clinical practice.

Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese.

BACKGROUNDInsulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior.METHODSIn this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21-59 years; BMI range 27.5-45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention.RESULTSThe exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger.CONCLUSIONOur study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.TRIAL REGISTRATIONClinicalTrials.gov (NCT03151590).FUNDINGBMBF/DZD 01GI0925.

Diagnostic Performance of Sex-Specific Modified Metabolite Patterns in Urine for Screening of Prediabetes.

Aims/Hypothesis: Large-scale prediabetes screening is still a challenge since fasting blood glucose and HbA1c as the long-standing, recommended analytes have only moderate diagnostic sensitivity, and the practicability of the oral glucose tolerance test for population-based strategies is limited. To tackle this issue and to identify reliable diagnostic patterns, we developed an innovative metabolomics-based strategy deviating from common concepts by employing urine instead of blood samples, searching for sex-specific biomarkers, and focusing on modified metabolites. Methods: Non-targeted, modification group-assisted metabolomics by liquid chromatography-mass spectrometry (LC-MS) was applied to second morning urine samples of 340 individuals from a prediabetes cohort. Normal (n = 208) and impaired glucose-tolerant (IGT; n = 132) individuals, matched for age and BMI, were randomly divided in discovery and validation cohorts. ReliefF, a feature selection algorithm, was used to extract sex-specific diagnostic patterns of modified metabolites for the detection of IGT. The diagnostic performance was compared with conventional screening parameters fasting plasma glucose (FPG), HbA1c, and fasting insulin. Results: Female- and male-specific diagnostic patterns were identified in urine. Only three biomarkers were identical in both. The patterns showed better AUC and diagnostic sensitivity for prediabetes screening of IGT than FPG, HbA1c, insulin, or a combination of FPG and HbA1c. The AUC of the male-specific pattern in the validation cohort was 0.889 with a diagnostic sensitivity of 92.6% and increased to an AUC of 0.977 in combination with HbA1c. In comparison, the AUCs of FPG, HbA1c, and insulin alone reached 0.573, 0.668, and 0.571, respectively. Validation of the diagnostic pattern of female subjects showed an AUC of 0.722, which still exceeded the AUCs of FPG, HbA1c, and insulin (0.595, 0.604, and 0.634, respectively). Modified metabolites in the urinary patterns include advanced glycation end products (pentosidine-glucuronide and glutamyl-lysine-sulfate) and microbiota-associated compounds (indoxyl sulfate and dihydroxyphenyl-gamma-valerolactone-glucuronide). Conclusions/Interpretation: Our results demonstrate that the sex-specific search for diagnostic metabolite biomarkers can be superior to common metabolomics strategies. The diagnostic performance for IGT detection was significantly better than routinely applied blood parameters. Together with recently developed fully automatic LC-MS systems, this opens up future perspectives for the application of sex-specific diagnostic patterns for prediabetes screening in urine.

Postprandial Dynamics of Proglucagon Cleavage Products and Their Relation to Metabolic Health.

Introduction: While oral glucose ingestion typically leads to a decrease in circulating glucagon levels, a substantial number of persons display stable or rising glucagon concentrations when assessed by radioimmunoassay (RIA). However, these assays show cross-reactivity to other proglucagon cleavage products. Recently, more specific assays became available, therefore we systematically assessed glucagon and other proglucagon cleavage products and their relation to metabolic health. Research Design and Methods: We used samples from 52 oral glucose tolerance tests (OGTT) that were randomly selected from persons with different categories of glucose tolerance in an extensively phenotyped study cohort. Results: Glucagon concentrations quantified with RIA were non-suppressed at 2 hours of the OGTT in 36% of the samples. Non-suppressors showed lower fasting glucagon levels compared to suppressors (p=0.011). Similar to RIA measurements, ELISA-derived fasting glucagon was lower in non-suppressors (p<0.001). Glucagon 1-61 as well as glicentin and GLP-1 kinetics were significantly different between suppressors and non-suppressors (p=0.004, p=0.002, p=0.008 respectively) with higher concentrations of all three hormones in non-suppressors. Levels of insulin, C-peptide, and free fatty acids were comparable between groups. Non-suppressors were leaner and had lower plasma glucose concentrations (p=0.03 and p=0.047, respectively). Despite comparable liver fat content and insulin sensitivity (p≥0.3), they had lower 2-hour post-challenge glucose (p=0.01). Conclusions: Glucagon 1-61, glicentin and GLP-1 partially account for RIA-derived glucagon measurements due to cross-reactivity of the assay. However, this contribution is small, since the investigated proglucagon cleavage products contribute less than 10% to the variation in RIA measured glucagon. Altered glucagon levels and higher post-challenge incretins are associated with a healthier metabolic phenotype.

Sex differences in central insulin action: Effect of intranasal insulin on neural food cue reactivity in adults with normal weight and overweight.

BACKGROUND/OBJECTIVES: Central insulin action influences cognitive processes, peripheral metabolism, and eating behavior. However, the contribution of obesity and sex on central insulin-mediated neural food cue processing still remains unclear. SUBJECTS/METHODS: In a randomized within-participant design, including two visits, 60 participants (30 women, BMI 18-32 kg/m2, age 21-69 years) underwent a functional MRI task measuring blood oxygen level-dependent (BOLD) signal in response to visual food cues after intranasal insulin or placebo spray administration. Central insulin action was defined as the neural BOLD response to food cues after insulin compared to placebo administration. Afterwards, participants were asked to rate the food cues for desire to eat (i.e., wanting rating). For statistical analyses, participants were grouped according to BMI and sex. RESULTS: Food cue reactivity in the amygdala showed higher BOLD activation in response to central insulin compared to placebo. Furthermore, women with overweight and obesity and men of normal weight showed higher BOLD neural food cue responsivity to central insulin compared to placebo. Higher central insulin action in the insular cortex was associated with better peripheral insulin sensitivity and higher cognitive control. Moreover, central insulin action in the dorsolateral prefrontal cortex (DLPFC) revealed significant sex differences. In response to central insulin compared to placebo, men showed lower DLPFC BOLD activity, whereas women showed higher DLPFC activity in response to highly desired food cues. On behavioral level, central insulin action significantly reduced hunger, whereas the desire to eat, especially for low caloric food cues was significantly higher with central insulin than with placebo. CONCLUSIONS: Obesity and sex influenced the central insulin-mediated neural BOLD activity to visual food cues in brain regions implicated in reward and cognitive control. These findings show that central insulin action regulates food response differentially in men and women, which may have consequences for metabolism and eating behavior.

A novel smartphone app to change risk behaviors of women after gestational diabetes: A randomized controlled trial.

AIMS: Women after gestational diabetes mellitus (GDM) are a risk group for cardiometabolic diseases but are hard to reach by conventional lifestyle programs. Therefore, we tested whether a novel, smartphone-delivered intervention, TRIANGLE, is accepted by women after GDM and alters cardiometabolic risk behaviors and outcomes. TRIANGLE targets gradual habit change of mind and emotion, physical activity, nutrition, and sleep. METHODS: We conducted a 6-month multicenter, randomized-controlled trial of TRIANGLE versus standard care with 66 women 3-18 months after GDM in Germany. The primary outcome was the proportion of women achieving ≥3 out of 5 Diabetes Prevention Program goals, i.e. physical activity ≥150 min/week (moderate to high intensity), fiber intake ≥15 g/1,000 kcal, fat intake <30% of total energy intake, saturated fat intake <10% of total energy intake, and weight reduction ≥5% if BMI ≥23 kg/m2 or weight maintenance if BMI <23 kg/m2. Intervention participants also rated the TRIANGLE app in the Mobile Application Rating Scale (uMARS). RESULTS: In the predefined, modified intention-to-treat analysis including 64 women, 6 out of 27 women in the intervention group [22%(10-40)] and 3 out of 27 women in the control group [11%(3-27)] reached the primary outcome (p = 0.47). In the predefined per-protocol intervention subgroup, the proportion was 4 out of 14 women [29%(11-55); p = 0.20 vs. control]. TRIANGLE app users were active on 42% of days and rated the app's quality and perceived impact with 4.3±0.8 out of 5 uMARS points. CONCLUSIONS: This first trial did not show the efficacy of the TRIANGLE intervention. However, the app was well accepted and considered helpful by most users. Therefore, this trial supports further development and testing of TRIANGLE and other app interventions for women after GDM. Additionally, it identifies necessary adaptations in trial design to better accommodate non-intensive lifestyle interventions for this target group. TRIAL REGISTRATION: Trial registration at drks.de (DRKS00012996).

Pre-pregnancy BMI but not mild stress directly influences Interleukin-6 levels and insulin sensitivity during late pregnancy.

BACKGROUND: This study investigates the influence of maternal stress during pregnancy on maternal insulin sensitivity and Interleukin-6 (IL-6) levels in pregnant women (N = 277) in dependence of pre-pregnancy Body-Mass-Index (BMI). METHODS: Gestational diabetes was diagnosed in 80 women. We used the Patient Health Questionnaire (PHQ-D) to investigate maternal stress during pregnancy with a higher scoring indicating higher maternal stress level. IL-6 and cortisol were measured and maternal insulin sensitivity was assessed with the non-esterified fatty acid insulin sensitivity index (NEFA-ISI). Generalized Linear Model analysis was used to analyze effects within different stress groups. RESULTS: Maternal low stress symptoms during pregnancy showed no significant association with maternal insulin sensitivity or IL-6. Higher cortisol levels during pregnancy were associated with elevated IL-6 concentrations. Pre-pregnancy BMI had the strongest positive effect on IL-6 levels and was negatively associated with insulin sensitivity during pregnancy. CONCLUSIONS: Therefore, preconceptional interventions to reduce BMI are needed to improve maternal metabolism during pregnancy.

Incretin Hypersecretion in Gestational Diabetes Mellitus.

CONTEXT: Incretins are crucial stimulators of insulin secretion following food intake. Data on incretin secretion and action during pregnancy are sparse. OBJECTIVE: The aim of the study was to investigate the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes mellitus (GDM). DESIGN: We analyzed data from the ongoing observational PREG study (NCT04270578). SETTING: The study was conducted at the University Hospital Tübingen. PARTICIPANTS: We examined 167 women (33 with GDM) during gestational week 27 ±â€…2.2. INTERVENTION: Subjects underwent 5-point OGTT with a 75-g glucose load. MAIN OUTCOME MEASURES: We assessed insulin secretion and levels of total glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), glicentin, and glucagon during OGTT. Linear regression was used to analyze the relation of GLP-1 and glucose with insulin secretion and the association of incretin levels on birth outcome. RESULTS: Insulin secretion was significantly lower in women with GDM (P < 0.001). Postload GLP-1 and GIP were ~20% higher in women with GDM (all P < 0.05) independent of age, body mass index, and gestational age. GLP-1 increase was associated with insulin secretion only in GDM, but not in normal glucose tolerance. Postprandial GLP-1 levels were negatively associated with birth weight. CONCLUSIONS: The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. Higher GLP-1 levels might be protective against fetal overgrowth.