Genetic Evidence for a Causal Link between Intra-Pancreatic Fat Deposition and Pancreatitis: a Mendelian Randomization Study.

Introduction: Recent associative studies have linked intra-pancreatic fat deposition (IPFD) with risk of pancreatitis, but the causal relationship remains unclear. Methods: Utilizing Mendelian randomization, we evaluated the causal association between genetically predicted IPFD and pancreatitis. This approach utilized genetic variants from genome-wide association studies of IPFD (n=25,617), acute pancreatitis (n=6,787 cases/361,641 controls), and chronic pancreatitis (n=3,875 cases/361,641 controls). Results: Genetically predicted IPFD was significantly associated with acute pancreatitis (OR per 1-SD increase: 1.40[95%CI:1.12-1.76], p=0.0032) and chronic pancreatitis (OR:1.64[95%CI:1.13-2.39], p=0.0097). Discussion: Our findings support a causal role of IPFD in pancreatitis, suggesting that reducing IPFD could lower the risk of pancreatitis.

Network-targeted transcranial direct current stimulation of the hypothalamus appetite-control network: a feasibility study.

The hypothalamus is the key regulator for energy homeostasis and is functionally connected to striatal and cortical regions vital for the inhibitory control of appetite. Hence, the ability to non-invasively modulate the hypothalamus network could open new ways for the treatment of metabolic diseases. Here, we tested a novel method for network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in the control of appetite. Based on the resting-state functional connectivity map of the hypothalamus, a 12-channel net-tDCS protocol was generated (Neuroelectrics Starstim system), which included anodal, cathodal and sham stimulation. Ten participants with overweight or obesity were enrolled in a sham-controlled, crossover study. During stimulation or sham control, participants completed a stop-signal task to measure inhibitory control. Overall, stimulation was well tolerated. Anodal net-tDCS resulted in faster stop signal reaction time (SSRT) compared to sham (p = 0.039) and cathodal net-tDCS (p = 0.042). Baseline functional connectivity of the target network correlated with SSRT after anodal compared to sham stimulation (p = 0.016). These preliminary data indicate that modulating hypothalamus functional network connectivity via net-tDCS may result in improved inhibitory control. Further studies need to evaluate the effects on eating behavior and metabolism.

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.

The insulin resistant brain: impact on whole-body metabolism and body fat distribution.

Insulin exerts its actions not only on peripheral organs but is also transported into the brain where it performs distinct functions in various brain regions. This review highlights recent advancements in our understanding of insulin's actions within the brain, with a specific emphasis on investigations in humans. It summarises current knowledge on the transport of insulin into the brain. Subsequently, it showcases robust evidence demonstrating the existence and physiological consequences of brain insulin action, while also introducing the presence of brain insulin resistance in humans. This pathophysiological condition goes along with an impaired acute modulation of peripheral metabolism in response to brain insulin action, particularly in the postprandial state. Furthermore, brain insulin resistance has been associated with long-term adiposity and an unfavourable adipose tissue distribution, thus implicating it in the pathogenesis of subgroups of obesity and (pre)diabetes that are characterised by distinct patterns of body fat distribution. Encouragingly, emerging evidence suggests that brain insulin resistance could represent a treatable entity, thereby opening up novel therapeutic avenues to improve systemic metabolism and enhance brain functions, including cognition. The review closes with an outlook towards prospective research directions aimed at further elucidating the clinical implications of brain insulin resistance. It emphasises the critical need to establish feasible diagnostic measures and effective therapeutic interventions.

Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study.

Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N = 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60-7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p < 5 × 10-8) from a genome-wide association study in the UK Biobank (N = 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1-standard deviation [SD] increase in IPFD: 2.46, 95% CI: 1.38-4.40) in the Pancreatic Cancer Cohort Consortium I, II, III (PanScan I-III)/Pancreatic Cancer Case-Control Consortium (PanC4) dataset (8,275 PDAC cases and 6,723 non-cases). This study provides evidence for a potential causal role of IPFD in the pathogenesis of PDAC. Thus, reducing IPFD may lower PDAC risk.

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.

Area deprivation and demographic factors associated with diabetes technology use in adults with type 1 diabetes in Germany.

Introduction: Diabetes technology improves glycemic control and quality of life for many people with type 1 diabetes (T1D). However, inequalities in access to diabetes technology exist in many countries. In Germany, disparities in technology use have been described in pediatric T1D, but no data for adults are available so far. We therefore aimed to analyze whether demographic factors and area deprivation are associated with technology use in a representative population of adults with T1D. Materials and methods: In adults with T1D from the German prospective diabetes follow-up registry (DPV), we analyzed the use of continuous subcutaneous insulin infusion (CSII), continuous glucose monitoring (CGM), and sensor augmented pump therapy (SAP, with and without automated insulin delivery) in 2019-2021 by age group, gender, migration background, and area deprivation using multiple adjusted regression models. Area deprivation, defined as a relative lack of area-based resources, was measured by quintiles of the German index of Multiple Deprivation (GIMD 2015, from Q1, least deprived, to Q5, most deprived districts). Results: Among 13,351 adults with T1D, the use of technology decreased significantly with older age: CSII use fell from 56.1% in the 18-<25-year age group to 3.1% in the ≥80-year age group, CGM use from 75.3% to 28.2%, and SAP use from 45.1% to 1.5% (all p for trend <0.001). The use of technology was also significantly higher in women than in men (CSII: 39.2% vs. 27.6%; CGM: 61.9% vs. 58.0%; SAP: 28.7% vs. 19.6%, all p <0.001), and in individuals without migration background than in those with migration background (CSII: 38.8% vs. 27.6%; CGM: 71.1% vs. 61.4%; SAP: 30.5% vs. 21.3%, all p <0.001). Associations with area deprivation were not linear: the use of each technology decreased only from Q2 to Q4. Discussion: Our real-world data provide evidence that higher age, male gender, and migration background are currently associated with lower use of diabetes technology in adults with T1D in Germany. Associations with area deprivation are more complex, probably due to correlations with other factors, like the higher proportion of migrants in less deprived areas or the federal structure of the German health care system.

Clusters of prediabetes and type 2 diabetes stratify all-cause mortality in a cohort of participants undergoing invasive coronary diagnostics.

BACKGROUND: Heterogeneous metabolic clusters have been identified in diabetic and prediabetic states. It is not known whether such pathophysiologic clusters impact survival in at-risk persons being evaluated for coronary heart disease. METHODS: The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56-70) with a follow-up of 16.1 (IQR 9.6, 17.7) years. Clustering of 1269 subjects without diabetes was performed with oGTT-derived glucose and insulin; fasting triglyceride, high-density lipoprotein, BMI, waist and hip circumference. Patients with T2D (n = 794) were clustered using age, BMI, glycemia, homeostasis model assessment, and islet autoantibodies. Associations of clusters with mortality were analysed using Cox regression. RESULTS: Individuals without diabetes were classified into six subphenotypes, with 884 assigned to subjects at low-risk (cluster 1,2,4) and 385 at high-risk (cluster 3,5,6) for diabetes. We found significantly increased mortality in clusters 3 (hazard ratio (HR)1.42), 5 (HR 1.43), and 6 (HR 1.46) after adjusting for age, BMI, HbA1c and sex. In the T2D group, 508 were assigned to mild age-related diabetes (MARD), 183 to severe insulin-resistant diabetes (SIRD), 84 to mild obesity-related diabetes (MOD), 19 to severe insulin-deficient diabetes (SIDD). Compared to the low-risk non-diabetes group, crude mortality was not different in MOD. Increased mortality was found for MARD (HR 2.2), SIRD (HR 2.2), and SIDD (HR 2.5). CONCLUSIONS: Metabolic clustering successfully stratifies survival even among persons undergoing invasive coronary diagnostics. Novel clustering approaches based on glucose metabolism can identify persons who require special attention as they are at risk of increased mortality.

Acylated- and unacylated ghrelin during an oral glucose tolerance test in humans at risk for type 2 diabetes mellitus.

BACKGROUND/OBJECTIVES: The orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity. SUBJECTS/METHODS: In this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²-76.25 kg/m²). RESULTS: Fasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90-120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m². CONCLUSION: Our data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels.

Extracellular Matrix Expression in Human Pancreatic Fat Cells of Patients with Normal Glucose Regulation, Prediabetes and Type 2 Diabetes.

Previously, we found that human pancreatic preadipocytes (PPAs) and islets influence each other and that the crosstalk with the fatty liver via the hepatokine fetuin-A/palmitate induces inflammatory responses. Here, we examined whether the mRNA-expression of pancreatic extracellular matrix (ECM)-forming and -degrading components differ in PPAs from individuals with normal glucose regulation (PPAs-NGR), prediabetes (PPAs-PD), and type 2 diabetes (PPAs-T2D), and whether fetuin-A/palmitate impacts ECM-formation/degradation and associated monocyte invasion. Human pancreatic resections were analyzed (immuno)histologically. PPAs were studied for mRNA expression by real-time PCR and protein secretion by Luminex analysis. Furthermore, co-cultures with human islets and monocyte migration assays in Transwell plates were conducted. We found that in comparison with NGR-PPAs, TIMP-2 mRNA levels were lower in PPAs-PD, and TGF-ß1 mRNA levels were higher in PPAs-T2D. Fetuin-A/palmitate reduced fibronectin, decorin, TIMP-1/-2 and TGF-ß1 mRNA levels. Only fibronectin was strongly downregulated by fetuin-A/palmitate independently of the glycemic status. Co-culturing of PPAs with islets increased TIMP-1 mRNA expression in islets. Fetuin-A/palmitate increased MMP-1, usherin and dermatopontin mRNA-levels in co-cultured islets. A transmigration assay showed increased monocyte migration towards PPAs, which was enhanced by fetuin-A/palmitate. This was more pronounced in PPAs-T2D. The expression of distinct ECM components differs in PPAs-PD and PPAs-T2D compared to PPAs-NGR, suggesting that ECM alterations can occur even in mild hyperglycemia. Fetuin-A/palmitate impacts on ECM formation/degradation in PPAs and co-cultured islets. Fetuin-A/palmitate also enhances monocyte migration, a process which might impact on matrix turnover.

Genetic Evidence Causally Linking Pancreas Fat to Pancreatic Cancer: A Mendelian Randomization Study.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and any clues to understanding its elusive etiology could lead to breakthroughs in prevention, early detection, or treatment. Observational studies have shown a relationship between pancreas fat accumulation and PDAC, but the causality of this link is unclear. We therefore investigated whether pancreas fat is causally associated with PDAC using two-sample Mendelian randomization. Methods: We leveraged eight genetic variants associated with pancreas fat (P<5×10 -8 ) from a genome-wide association study (GWAS) in the UK Biobank (25,617 individuals), and assessed their association with PDAC in the Pancreatic Cancer Cohort Consortium I-III and the Pancreatic Cancer Case-Control Consortium dataset (8,275 PDAC cases and 6,723 non-cases). Causality was assessed using the inverse-variance weighted method. Although none of these genetic variants were associated with body mass index (BMI) at genome-wide significance, we further conducted a sensitivity analysis excluding genetic variants with a nominal BMI association in GWAS summary statistics from the UK Biobank and the Genetic Investigation of Anthropometric Traits consortium dataset (806,834 individuals). Results: Genetically determined higher levels of pancreas fat using the eight genetic variants was associated with increased risk of PDAC. For one standard deviation increase in pancreas fat levels (i.e., 7.9% increase in pancreas fat fraction), the odds ratio of PDAC was 2.46 (95%CI:1.38-4.40, P=0.002). Similar results were obtained after excluding genetic variants nominally linked to BMI (odds ratio:3.79, 95%CI:1.66-8.65, P=0.002). Conclusions: This study provides genetic evidence for a causal role of pancreas fat in the pathogenesis of PDAC. Thus, reducing pancreas fat could lower the risk of PDAC.

Brain insulin responsiveness is linked to age and peripheral insulin sensitivity.

AIMS: Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. MATERIALS AND METHODS: We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m2 , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions). RESULTS: We found significant negative associations between age and insulin action in the hippocampus (ß = -0.215; p = .017) and caudate nucleus (ß = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (ß = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (ß = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions. CONCLUSION: We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.

Inceptor correlates with markers of prostate cancer progression and modulates insulin/IGF1 signaling and cancer cell migration.

OBJECTIVE: The insulin/insulin-like growth factor 1 (IGF1) pathway is emerging as a crucial component of prostate cancer progression. Therefore, we investigated the role of the novel insulin/IGF1 signaling modulator inceptor in prostate cancer. METHODS: We analyzed the expression of inceptor in human samples of benign prostate epithelium and prostate cancer. Further, we performed signaling and functional assays using prostate cancer cell lines. RESULTS: We found that inceptor was expressed in human benign and malignant prostate tissue and its expression positively correlated with various genes of interest, including genes involved in androgen signaling. In vitro, total levels of inceptor were increased upon androgen deprivation and correlated with high levels of androgen receptor in the nucleus. Inceptor overexpression was associated with increased cell migration, altered IGF1R trafficking and higher IGF1R activation. CONCLUSIONS: Our in vitro results showed that inceptor expression was associated with androgen status, increased migration, and IGF1R signaling. In human samples, inceptor expression was significantly correlated with markers of prostate cancer progression. Taken together, these data provide a basis for investigation of inceptor in the context of prostate cancer.

Diabetes in all hospitalized cases in Germany 2015-2019 and impact of the first COVID-19 year 2020.

Objective: To analyze the proportion of diabetes among all hospitalized cases in Germany between 2015 and 2020. Methods: Using the nationwide Diagnosis-Related-Groups statistics, we identified among all inpatient cases aged ≥ 20 years all types of diabetes in the main or secondary diagnoses based on ICD-10 codes, as well all COVID-19 diagnoses for 2020. Results: From 2015 to 2019, the proportion of cases with diabetes among all hospitalizations increased from 18.3% (3.01 of 16.45 million) to 18.5% (3.07 of 16.64 million). Although the total number of hospitalizations decreased in 2020, the proportion of cases with diabetes increased to 18.8% (2.73 of 14.50 million). The proportion of COVID-19 diagnosis was higher in cases with diabetes than in those without in all sex and age subgroups. The relative risk (RR) for a COVID-19 diagnosis in cases with vs without diabetes was highest in age group 40-49 years (RR in females: 1.51; in males: 1.41). Conclusions: The prevalence of diabetes in the hospital is twice as high as the prevalence in the general population and has increased further with the COVID-19 pandemic, underscoring the increased morbidity in this high-risk patient group. This study provides essential information that should help to better estimate the need for diabetological expertise in inpatient care settings.

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.

Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.

Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.