Andreas L Birkenfeld

Universitätsklinikum Tübingen · Department of Diabetology Endocrinology and Nephrology

Background Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. Methods We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomiz...

Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on th...

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes¹. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MR...

Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respirat...

The COVID-19 pandemic has stretched healthcare resources and caused severe knock-on effects on patients with metabolic diseases worldwide. We encourage clinicians and patient-interest groups in the field of diabetes and metabolism to raise their voices to ensure adequate care and admission of patients.

Fat accumulation in the liver, pancreas, skeletal muscle, and visceral bed relates to type-2 diabetes (T2D). However, the distribution of fat among these compartments is heterogenous and it is unclear whether specific distribution patterns indicate high T2D risk. We therefore investigated fat-distribution patterns and their link to future T2D. From...

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 wom...

Experimental nephrotic syndrome leads to activation of the epithelial sodium channel (ENaC) by proteolysis and promotes renal sodium retention. The membrane-anchored serine protease prostasin (CAP1/PRSS8) is expressed in the distal nephron and participates in proteolytic ENaC regulation by serving as a scaffold for other serine proteases. However,...

Risk for complications and mortality among patients with type 2 diabetes (T2D) is heterogenous. Different trajectories can be identified in the prediabetic state, which comprises heterogenous metabolic clusters. It is not known whether such pathophysiologic clusters of prediabetes and diabetes affect survival in at-risk persons being evaluated for...

Introduction: Pancreatic fat accumulation is a potential pathogenic factor in type 2 diabetes. Evidence from hypocaloric diet indicates that reduction of pancreatic fat could contribute to an improvement in ß-cell function. There is no established pharmacological approach to reduce pancreatic steatosis. We now tested the ability of empagliflozin to...

Background and Aims: People with different glucose response patterns during the 2-h oral glucose tolerance test (OGTT) have substantially different clinical characteristics and risk for long-term outcomes in the general population. We aimed to identify comparable glucose response patterns in pregnancy and their association with maternal and fetal o...

Introduction: Finerenone reduced the risk of cardiovascular (CV) and kidney outcomes, without affecting HbA1c, in CKD and T2D patients in the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies. Here, we evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, and diabetes duration. Methods: Patients with...

Background: Recent data proposed a role of the citrate transporter INDY (I’m Not Dead Yet) in the development of obesity, insulin resistance and NAFLD suggesting its potential as a therapeutic target for metabolic-related disorders. The aim of our study is to determine if mammalian INDY (mINDY) inhibitors can be introduced as a new therapeutic opti...

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 autonomic nervous system (ANS) function in fetuses in utero, which can be assessed with heart rate variability (HRV) . We have now exami...

Objective: Fat accumulation in liver, pancreas, skeletal muscle, and visceral bed relates to type 2 diabetes (T2D) . However, distribution of fat in these compartments is heterogenous and it is unclear if specific distribution patterns indicate high T2D risk. We therefore investigated fat distribution patterns and their link to future T2D. Methods:...

The Prediabetes Lifestyle Intervention Study (PLIS) - a multicenter study conducted by the German Center for Diabetes Research - showed that intensified compared to conventional lifestyle intervention led to higher probability to normalize glucose regulation. Here, we examined clinical traits determining remission of prediabetes in PLIS participant...

Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosi...

Background and aims With prediabetes and diabetes increasingly recognized as heterogenous 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 OGTT- and fasting-measurements in comparison with gold standard me...

Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify k...

Background For a given body-mass index (BMI), both, impaired metabolic health (MH) and reduced cardiorespiratory fitness (CRF), associate with an increased risk of cardiovascular disease (CVD). It is still unknown whether both risk phenotypes relate to CVD independently of each other, and whether these relationships differ in normal weight, overwei...

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 in pregnant women with and without gestational diabetes. Design We analyzed data from...

Proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases is thought to contribute to renal sodium retention in nephrotic syndrome. However, the identity of the responsible proteases remains elusive. This study evaluated factor VII activating protease (FSAP) as a candidate in this context. We analyzed FS...

Introduction Even well-treated gestational diabetes mellitus (GDM) might still have impact on long-term health of the mother and her offspring, although this relationship has not yet been conclusively studied. Using in-depth phenotyping of the mother and her offspring, we aim to elucidate the relationship of maternal hyperglycaemia during pregnancy...

Background: Quantification of pancreatic fat (PF) and intrahepatic lipids (IHL) is of increasing interest in subjects at risk for metabolic diseases. There is limited data available on short- and medium-term variability of PF/IHL and on their dependence on nutritional status. Purpose: To assess short-term intraday variations of PF/IHL after a hi...

We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differenti...

Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key...

Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the...

Aims/hypothesis Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in in...

Background Balancing immunosuppressive regimen to prevent rejection yet avoiding severe infectious complications remains a key challenge following renal transplantation, especially in patients sensitized after exposure to human leukocyte antigens. We herein report a late onset infection with nocardia in a sensitized renal transplant recipient. Cas...

Background Incretins are crucial stimulators of insulin secretion after food intake. We investigated the incretin response during an oral glucose tolerance test in pregnant women with and without gestational diabetes. Methods Subjects underwent a 5-point OGTT with 75 g glucose. We assessed insulin secretion and levels of total GLP-1, GIP, glicentin...

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, ther...

The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) dur...

Background It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations...

Objective: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment fo...

Aims: Insulin sensitivity and insulin secretion can be estimated by multiple indices from fasting blood samples or blood samples obtained during oral glucose tolerance tests. The test-retest reliability of these indices in repeated measurements within the same individuals can strongly vary. Methods: We analyzed data of persons without diabetes w...

Fat accumulation outside subcutaneous adipose tissue often has unfavourable effects on systemic metabolism. In addition to non-alcoholic fatty liver disease, which has received considerable attention, pancreatic fat has become an important area of research throughout the past 10 years. While a number of diagnostic approaches are available to quanti...

BACKGROUND Sodium–glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS In this double-blind trial, we randomly assigned 5988 patients with class...

Parasympathetic nervous system innervates peripheral organs including pancreas, hepatic portal system, and gastrointestinal tract. It thereby contributes to the regulation of whole-body glucose metabolism especially in the postprandial state when it promotes secretion of insulin and enhances its action in major target organs. We now aimed to evalua...

Background The reasons why patients are treated or not with PCSK9 inhibitors (PCSK9i) are incompletely understood. In Germany, access to PCSK9i is limited by local regulations and many high-risk cardiovascular patients do not receive these therapies. The PERI-DYS study aims to describe and compare two groups of dyslipidaemia patients at very high C...

Introduction Since the introduction of the new International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for gestational diabetes mellitus (GDM) in 2012, diagnosis and treatment of GDM has improved. But even well-treated GDM might still have impact on long-term health of the mother and her offspring, though, this relati...

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developin...

Purpose Recent trials demonstrated remission of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) following formula diet-induced weight loss. To improve the outreach for populations in need, many mobile health apps targeting weight loss have been developed with limited scientific evaluation of these apps. The present feasibility study i...

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developin...

Objective Liver mitochondria adapt to high calorie intake. We investigated how exercise alters the early compensatory response of mitochondria and thus prevents fatty liver disease as a long-term consequence of overnutrition. Methods We compared the effects of a steatogenic high-energy diet (HED, for 6 weeks) on mitochondrial metabolism of sedenta...

HypothesisObesity is one of the main drivers of type 2 diabetes (T2D), but not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown features of body...

Background: 30-80% of patients being treated in intensive care units in the perioperative period develop hyperglycemia. This stress hyperglycemia is induced and maintained by inflammatoryendocrine and iatrogenic stimuli and generally requires treatment. There is uncertainty regarding the optimal blood glucose targets for patients with diabetes mel...

Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested if prediabetic individuals with low risk benefit from conventional LI and individuals with high risk benefit from an intensification of LI in a multi-center randomized controlled intervention over 12 months with 2 years foll...

Anemia is a common complication of chronic kidney disease, affecting the quality of life of patients. Among various factors, such as iron and erythropoietin deficiency, reduced red blood cell (RBC) lifespan has been implicated in the pathogenesis of anemia. However, mechanistic data on in vivo RBC dysfunction in kidney disease are lacking. Herein,...

Background: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unc...

Background Sodium–glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. Methods In this double-blind trial, we randomly assigned 5988 patients with class...

Proteolytic activation of the renal epithelial sodium channel ENaC involves cleavage events in its α- and γ-subunits and is thought to mediate sodium retention in nephrotic syndrome (NS). However, detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to rel...

Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria in mice, is related to the single-nucleotide polymorphism (SNP) C6418T of the Prkdc gene encoding for the DNA-repair enzyme DNA-PKcs. In addition, plasminogen (Plg) has been reported to play a role in glomerular damage. Here, we investigated the...

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calori...

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of ess...

Aims As the first long-term RCT on insoluble cereal fibre, the optimal fibre trial demonstrated glycometabolic benefits, confirming cohort studies. The combined study intervention of lifestyle recommendations and supplementation with insoluble oat hulls fibre allows to clarify, which amount of fibre is required for a beneficial effect. Methods One...

Background: In patients with obesity and end-stage kidney disease, implantation of the peritoneal dialysis (PD) catheter may be complicated by increased abdominal circumference or skin folds. Relocation of the implantation site to the upper abdomen could solve this problem. However, this would require an extended catheter. Methods: We developed...

Posttransplantation diabetes mellitus (PTDM) is a relevant complication following liver transplantation with profound impact on morbidity and mortality. To date, little is known about the evolution and dynamics of glucose metabolism and the impact of prediabetes in long-term follow-up. To address this issue, all consecutive adult liver transplant r...