German Diabetes Center

In our study, we developed a pipeline to integrate single-molecule real-time sequencing (SMRT-seq) with comprehensive metabolic phenotyping to examine reduced mitochondrial respiration in the skeletal muscle of individuals with type 2 diabetes. SMRT-seq revealed ∼67,000 isoforms originating from ∼14,000 unique genes; the isoform numbers per gene did not differ between participants with diabetes and matched control participants. Our data identified novel alternative splicing events, including two variants of the ATP5F1A gene encoding a subunit for ATP synthase. Among these, two novel transcripts were expressed exclusively in control participants. Our findings link transcriptomic changes to impaired mitochondrial respiration in type 2 diabetes, with the potential of providing novel therapeutic targets to improve metabolic health.

IntroductionShunting of glycolytic intermediates into the pentose phosphate pathway via transketolase activation by benfotiamine has been suggested to protect from hyperglycemia-induced microvascular damage, but the long-term effects of benfotiamine on diabetic sensorimotor polyneuropathy (DSPN) remain unclear.Research design and methodsThis 1:1 randomized double-blind, placebo-controlled parallel group monocentric phase II trial compared the efficacy and safety of 1-year treatment with benfotiamine 300 mg two times per day versus placebo over 12 months in participants with type 2 diabetes and mild-to-moderate symptomatic DSPN. The primary endpoint was the change in corneal nerve fiber length (CNFL) assessed by corneal confocal microscopy (CCM) from baseline to 12 months. Secondary endpoints included three other CCM parameters, skin biopsy (four parameters), nerve conduction studies (13 measures), quantitative sensory testing (six parameters), cardiovascular autonomic function tests (17 indices), sudomotor function tests (five parameters), 15 clinical scores and scales for neuropathic symptoms and signs and 13 health-related quality of life and depression instruments. Pharmacokinetics included measurement of six thiamine analytes in blood.ResultsA total of 57 participants underwent randomization. The changes from baseline to 12 months in CNFL did not differ between the two groups. The corresponding changes in the secondary morphometric, functional and clinical neuropathic outcomes as well as quality of life were also similar in the two groups. Only the Neuropathy Symptom Score tended to improve after benfotiamine treatment (p=0.098 vs placebo). Benfotiamine treatment increased the concentrations of all six thiamine analytes studied (p≤0.003 vs placebo). Safety analysis showed no relevant differences between the groups in the rates of adverse events.ConclusionsIn type 2 diabetes individuals with mild-to-moderate symptomatic DSPN, treatment with benfotiamine for 12 months was well tolerated, but had no significant effects on multiple morphometric, neurophysiological and clinical measures of neuropathy.Trial registration numberEuropean Clinical Trials Database (EudraCT) 2017-003054-16 registered on April 10 (https://eudract.ema.europa.eu/), 2018 and German Register for Clinical Trials DRKS00014832 registered on August 3, 2018 (https://drks.de/search/de).

This cross-sectional study examined a Lifestyle Risk Factor Index (LSRI) in relation to adiposity measures including visceral adipose tissue (VAT) in the German National Cohort (NAKO). Based on self-reports at baseline among 30,920 of > 205,000 NAKO eligible participants with magnetic resonance imaging (MRI) scans, one point each for not smoking, adhering to ≥ 3/7 diet recommendations, consuming ≤ 1 (women)/≤ 2 (men) alcoholic drinks/day, and ≥ 150 min/week physical activity was assigned. VAT volume, obtained from whole-body MRI at 3T, was analyzed by deep learning-based image segmentation. General linear models estimated adjusted geometric mean adiposity measures by LSRI and stratified analyses by sex and BMI. Of 18,508 participants aged 48.2 ± 12.2 years, the respective proportions for 0/1, 2, 3, and 4 LSRI points were 7%, 24%, 51%, and 18%. Participants with LSRI scores of 4 versus 0/1 had lower adjusted geometric mean volumes of VAT (2.3; 95% CI 2.2, 2.3 vs. 3.0; 95% CI 2.9, 3.1 L). These differences were slightly attenuated after adding BMI. This association was weaker for individuals with obesity than normal/overweight. A combination of lifestyle factors appears to be associated with lower VAT volume, but an elevated BMI may have a greater influence on VAT accumulation than lifestyle behaviors alone.

Abstract Type 2 diabetes (T2D) is a heterogeneous disease, yet current classifications fail to capture its complexity or enable precision care. Here, we introduce a clinically scalable, immune-based endotyping strategy using routine blood immune cell counts - neutrophils, lymphocytes, and monocytes - from over 1,500 individuals with newly diagnosed T2D across three independent longitudinal European cohorts. Unsupervised clustering identified four consistent and clinically meaningful immune endotypes: Severe Inflammatory Diabetes (SIND), Mild Inflammatory Diabetes (MIND), Lymphocyte-Rich Diabetes (LYRD), and Lymphocyte-Deficient Diabetes (LYDD), that named immunotypes. These endotypes were associated with divergent long-term outcomes, with SIND and LYDD showing increased cardiovascular, renal, and mortality risks, and MIND and LYRD linked to more favorable trajectories. Multi-omic profiling revealed endotype-specific inflammatory signatures, including selective expansion of CCR2hi and CD39hi classical monocytes in the SIND endotype. Integration with single-cell RNA-seq uncovered distinct monocyte subsets in SIND, enriched for chemotaxis and myeloid activation transcriptional programs, alongside skewed adaptive immunity. Strikingly, this pro-inflammatory immune profile was attenuated by IL-1β antagonism and bariatric surgery-induced diabetes remission, underscoring its therapeutic relevance. These findings position immune-based endotyping as a robust and accessible tool to stratify risk, uncover disease mechanisms, and guide personalized intervention strategies in T2D.

Metabolic dysfunction-associated steatohepatitis (MASH) is an increasingly important contributor to morbidity and mortality. Little emphasis has been placed on its timely diagnosis and interventions to prevent adverse disease outcomes. The principal determinant of MASH outcomes is the liver fibrosis stage. The prevalence of MASH is higher among people living with obesity and/or type 2 diabetes, with MASH with moderate to advanced fibrosis affecting one in six adults. Delivering a paradigm shift in MASH diagnosis in the four countries studied will require an expansion of community-based diagnostic capability that will also foster prevention efforts and provide opportunities for treatment and care.

Heart transplantation (HTX) is the treatment of choice for advanced heart failure. Still, long-term survival needs to be improved. Recent studies showed that obesity and type 2 diabetes (T2D) as well as impaired renal and liver function are associated with mortality post-HTX. There are many open questions including (i) optimal metabolic surveillance post-transplant, (ii) association of metabolic deterioration and cardiac function, (iii) association with hepatic and renal deterioration, and (iv) optimal timing and choice of treatment. The METAB-HTX trial will address these open questions, hypothesizing that metabolic deterioration post-HTX is associated with impaired cardiac function and survival. METAB-HTX is a prospective, longitudinal cohort study, enrolling 400 patients post-HTX in a period of 5years. Time-series, deep cardiac, and metabolic phenotyping will be conducted. Cardiac function will be analysed by echocardiography as well as serial cardiac magnetic resonance imaging and spectroscopy (cMRI/MRS). Coronary angiography will be conducted to assess both macrovascular and microvascular coronary allograft vasculopathy (CAV). To evaluate allograft rejection, endomyocardial biopsies will be taken. Metabolic alterations will be investigated by (i) glucometabolic phenotyping including serial oral glucose tolerance tests, homeostasis model assessment, T2D endotyping, and muscle biopsies in selected cases; (ii) lipid disorders will be evaluated by classical lipid measurements in combination with evaluation of HDL function, plasma membrane lipid composition, fluidity analyses of circulating cells and MRI/MRS for adipose tissue distribution, and ectopic fat analysis. Kidney and liver function and structural alterations will be evaluated. Complex analyses will be conducted to evaluate (i) myocardial substrate utilization and energy metabolism by cardiac and circulating cell respirometry, (ii) impact of genetic (including immunogenetic) and transcriptomic factors by third- and fourth generation sequencing (short- and long-read sequencing), (iii) circulating signatures of future neoplasia by single-cell sequencing of circulating leucocytes, and (iv) evaluation of thromboinflammation in association with heart transplant events. The primary endpoint will be the incidence of heart transplant events, defined as worsening of systolic or diastolic left ventricular function, CAV, allograft rejection, worsening of kidney function, metabolic liver disease, infections, neoplasia, deterioration of glucose and lipid metabolism. Secondary outcomes include hospitalizations related to primary endpoints, re-HTX or ventricular assist device, cardiovascular mortality, and all-cause mortality. The METAB-HTX trial will identify early metabolic alterations potentially impairing cardiac function and outcome of HTX patients. This will identify patients at risk and allow precise planning of interventional trials to treat metabolic alterations post-HTX and improve outcome.

This study evaluated the incremental predictive value of proteomic biomarkers in assessing 10-year type 2 diabetes risk when added to the clinical Cambridge Diabetes Risk Score (CDRS). Data from 21,898 UK Biobank participants were used for model derivation and internal validation, and 4,454 Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung (ESTHER) cohort (Germany) participants were used for external validation. Proteomic profiling included the Olink Explore (2,085 proteins) and Olink Target 96 Inflammation panel (73 proteins). Adding 15 proteins from Olink Explore or 6 proteins from the Olink Inflammation panel improved the C-index of the CDRS by 0.029 or 0.016 in internal validation with net reclassification of 23.0% and 29.0%, respectively. External validation was only conducted for the six-protein-extended model, and the C-index improved by 0.014. The Olink Explore-based 15-protein model enhanced the CDRS model performance most, and this promising prediction model should be externally validated. Our successful external validation of the Olink Inflammation panel-based six-protein model shows that this is a promising endeavor.

BackgroundN-glycosylation is a complex, post-translational modification which influences protein function and is sensitive to physiological changes. Obesity is associated with alterations in protein function; however, little is known about the glycoproteome in obesity beyond observations of association with types and structures of selected glycopeptides. Most often, due to technical challenges, glycan composition and structure information are missing. Here, we combined label-free data-independent proteomics and targeted quantitative glycoproteomics to study N-glycosylation of plasma proteins in obesity. Using a monozygotic twin study design, we controlled for genetic variation and focused only on the acquired effects of obesity.MethodsUsing plasma samples of 48 monozygotic twin pairs discordant for BMI (intrapair difference > 2.5 kg/m2), we identified using mass spectrometry, differential protein and glycopeptide levels between heavier and leaner co-twins. We used a within-twin paired analysis model and considered p < 0.05 as significant.ResultsWe identified 48 protein and 33 N-glycosylation expression differences (p < 0.05) between co-twins. These differences occurred either both in the protein expression and glycoprotein (sometimes in opposing directions) or independently from each other. Haptoglobin protein was upregulated (Fold Change = 1.10, p = 0.001) in heavier co-twins along with seven upregulated glycan compositions at N-glycosylation site Asn241. The complement protein C3 was upregulated (Fold Change = 1.08, p = 0.014) along with one upregulated glycopeptide at Asn85. Additionally, many glycopeptides were upregulated despite non-significant differences in protein-backbone plasma levels.ConclusionDifferential protein expression related to cholesterol biosynthesis and acute phase signalling as well as N-glycosylation of proteins related to iron metabolism and inflammation can be linked to acquired obesity.

Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other—while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.