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Background Events of cardiovascular disease (CVD) remain a critical concern in patients with Type 2 diabetes mellitus (T2D). Over 17 years, this study analyzed time changes in the 5‐year incidence of myocardial infarction (MI), chronic coronary heart disease (CHD), transient ischemic attack (TIA), and ischemic stroke (IS). Methods This retrospective cohort study was conducted using the Disease Analyzer database, including patients aged ≥ 18 years with at least 12 months of no prior CVD with new‐onset T2D in 2001–2006 (n = 10 162) and in 2013–2018 (n = 30 486), matched 1:3 by age and sex. Kaplan–Meier survival analysis estimated the 5‐year cumulative incidence of the outcomes. Multivariable Cox regression models assessed temporal changes, adjusted for comorbidities. Results The incidence of CHD and TIA significantly declined in 2013–2018 compared to 2001–2006, with HRs of 0.68 (95% CI: 0.63–0.73; p < 0.001) and 0.63 (95% CI: 0.52–0.76; p < 0.001), respectively. Reductions were more pronounced in women and older patients. Surprisingly, MI incidence showed only a trend of reduction (HR: 0.82; 95% CI: 0.68–0.99; p = 0.045) and IS incidence was not different (HR: 0.97; 95% CI: 0.85–1.12; p = 0.722) between time periods. Conclusions This study is the first to report time trends in CVD incidence in new‐onset T2D in Germany. From 2001 to 2018, the 5‐year incidence of CHD and TIA decreased in new‐onset T2D, reflecting demographic‐specific advancements in diabetes and cardiovascular care. However, the stable incidence of IS and MI underscores a persistent challenge in prevention strategies in patients with prediabetes and T2D.

Diabetes mellitus (DM) is a growing global health concern linked to increased hospitalization rates, longer hospital stays, and higher mortality. Older adults with DM are particularly prone to intracranial injuries due to frailty and DM-related complications such as neuropathy and cardiovascular diseases. This study explores the impact of DM on in-hospital outcomes in patients with intracranial injuries. This retrospective cohort study used data from 45 hospitals in Germany, including 12,720 patients aged ≥40 years hospitalized between January 2019 and December 2023 with a primary diagnosis of intracranial injury. Patients were categorized based on the secondary presence of DM diagnosis (ICD-10 E10-E14). Outcomes included in-hospital mortality, rehospitalization within 1 year and hospital length of stay (LOS). Multivariable logistic regression models were used to analyze associations between DM and the different outcomes, adjusting for age, sex, hospitalization year, and comorbidities. Among 12,720 patients, 2394 had a known DM diagnosis. The median age was higher in DM patients (82 vs. 79 years). In-hospital mortality rates were similar for patients with and without DM (4.7% vs. 4.6%; OR: 0.98; 95% CI: 0.78-1.22). DM was not associated with rehospitalization risk (OR: 1.06; 95% CI: 0.89-1.26) but showed a trend toward longer hospital stays (≥7 days: OR: 1.13; 95% CI: 1.01-1.26). While DM did not significantly influence mortality or rehospitalization after intracranial injuries, it showed a non-significant trend towards extended LOS (≥7 days). These findings underscore the importance of targeted management strategies to optimize outcomes in this population.

Aims/hypothesisEnergy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling.MethodsIn a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic–euglycaemic clamps with d-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals.ResultsSAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05).Conclusions/interpretationLipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling.Trial registrationClinicalTrials.gov.NCT01736202.FundingGerman Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research.

Aims/hypothesisIt remains unclear whether and which modality of exercise training as a component of lifestyle intervention may exert favourable effects on somatosensory and autonomic nerve tests in people with type 2 diabetes.MethodsCardiovascular autonomic and somatosensory nerve function as well as intraepidermal nerve fibre density (IENFD) were assessed in overweight men with type 2 diabetes (type 2 diabetes, n = 20) and male glucose-tolerant individuals (normal glucose tolerance [NGT], n = 23), comparable in age and BMI and serving as a control group, before and after a supervised high-intensity interval training (HIIT) intervention programme over 12 weeks. Study endpoints included clinical scores, nerve conduction studies, quantitative sensory testing, IENFD, heart rate variability, postural change in systolic blood pressure and spontaneous baroreflex sensitivity (BRS).ResultsAfter 12 weeks of HIIT, resting heart rate decreased in both groups ([mean ± SD] baseline/12 weeks: NGT: 65.1 ± 8.2/60.2 ± 9.0 beats per min; type 2 diabetes: 68.8 ± 10.1/63.4 ± 7.8 beats per min), while three BRS indices increased (sequence analysis BRS: 8.82 ± 4.89/14.6 ± 11.7 ms2/mmHg; positive sequences BRS: 7.19 ± 5.43/15.4 ± 15.9 ms2/mmHg; negative sequences BRS: 12.8 ± 5.4/14.6 ± 8.7 ms2/mmHg) and postural change in systolic blood pressure decreased (−13.9 ± 11.6/−9.35 ± 9.76 mmHg) in participants with type 2 diabetes, and two heart rate variability indices increased in the NGT group (standard deviation of R–R intervals: 36.1 ± 11.8/55.3 ± 41.3 ms; coefficient of R–R interval variation: 3.84 ± 1.21/5.17 ± 3.28) (all p<0.05). In contrast, BMI, clinical scores, nerve conduction studies, quantitative sensory testing, IENFD and the prevalence rates of diabetic sensorimotor polyneuropathy and cardiovascular autonomic neuropathy remained unchanged in both groups. In the entire cohort, correlations between the changes in two BRS indices and changes in V̇O2max over 12 weeks of HIIT (e.g. sequence analysis BRS: r = 0.528, p=0.017) were observed.Conclusions/interpretationIn male overweight individuals with type 2 diabetes, BRS, resting heart rate and orthostatic blood pressure regulation improved in the absence of weight loss after 12 weeks of supervised HIIT. Since no favourable effects on somatic nerve function and structure were observed, cardiovascular autonomic function appears to be more amenable to this short-term intervention, possibly due to improved cardiorespiratory fitness.

Fasting requires complex endocrine and metabolic interorgan crosstalk, which involves shifting from glucose to fatty acid oxidation, derived from adipose tissue lipolysis, in order to preserve glucose for the brain. The glucose-alanine (Cahill) cycle is critical for regenerating glucose. In this issue of JCI, Petersen et al. report on their use of an innovative stable isotope tracer method to show that skeletal muscle-derived alanine becomes rate controlling for hepatic mitochondrial oxidation and, in turn, for glucose production during prolonged fasting. These results provide new insight into skeletal muscle-liver metabolic crosstalk during the fed-to-fasting transition in humans.

Abstract Context Vitamin B12 and folate deficiency are not only linked to hematological, neurological, and cardiovascular diseases, but are also associated with insulin resistance. Metformin can decrease vitamin B12 and folate concentrations. Objective To examine (1) effects of short-term metformin treatment on serum holotranscobalamin (holoTC) and folate and (2) their association with insulin sensitivity in recent-onset type 2 diabetes. Design This cross-sectional analysis comprised patients (known disease duration <12 months) on metformin monotherapy (MET, n = 123, 81 males, 53 ± 12 years) or nonpharmacological treatment (NPT, n = 126, 77 males, 54 ± 11 years) of the German Diabetes Study. Main Outcome Measures HoloTC (enzyme-linked immunosorbent assay), cobalamin, and folate (electrochemiluminescence); beta-cell function and whole-body insulin sensitivity, measured during fasting (HOMA-B, HOMA-IR) and intravenous glucose tolerance tests combined with hyperinsulinemic–euglycemic clamp tests. Results HoloTC (105.4 [82.4, 128.3] vs 97 [79.7, 121.9] pmol/L) and folate concentrations (13.4 [9.3, 19.3] vs 12.7 [9.3, 22.0] nmol/L) were similar in both groups. Overall, holoTC was not associated with fasting or glucose-stimulated beta-cell function and insulin-stimulated glucose disposal. Cobalamin measurements yielded similar results in representative subgroups. In NPT but not MET, folate levels were inversely correlated with HOMA-IR (r = –0.239, P = .007). Folate levels did not relate to insulin sensitivity or insulin secretion in the whole cohort and in each group separately after adjustment for age, body mass index, and sex. Conclusions Metformin does not affect circulating holoTC and folate concentrations in recent-onset type 2 diabetes, rendering monitoring of vitamin B12 and folate dispensable, at least during the first 6 months after diagnosis or initiation of metformin.

Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future.

Background 31 P-magnetic resonance spectroscopy (MRS) saturation transfer (ST) allows for noninvasive investigation of liver energy metabolism by assessing flux rates of adenosine triphosphate (ATP) synthesis. However, this technique has rarely been applied at clinical field strengths because of long examination times and contamination from muscle tissue. Our aim was to establish a new method to robustly assess ATP synthesis using a clinical scanner. Methods A prospective single-center study was performed (January 2023–August 2024) within the German Diabetes Study. We established a suitable 31 P-MRS ST protocol, tested it in vitro and in vivo and assessed its reproducibility. We assessed the hepatic apparent spin-lattice relaxation time of inorganic phosphate ( T 1 , P i ′ ), equilibrium forward rate constant ( k f ), and forward ATP synthesis rate ( F A T P ) in nine control volunteers (CON) (six females) and eight patients (five females) with type 1 diabetes (T1D) and compared differences by ANOVA. Results Reproducibility assessment in nine CON, aged 27 ± 4 years (mean ± standard deviation), yielded coefficients of variation for repeated measurements of 7.1% and 21.3% for T 1 , P i ′ and k f , respectively. Group comparison revealed higher hepatic k f (0.34 ± 0.03 s -1 versus 0.16 ± 0.03 s -1 ; p  = 0.001) and F A T P (35.3 ± 3.5 mM/min versus 16.4 ± 3.5 mM/min; p  = 0.002) in CON than in T1D, aged 42 ± 15 years, respectively. Conclusion This 31 P-MRS ST method allowed for robust assessment of hepatic ATP synthesis at clinical field strength and was sensitive enough to detect differences between CON and T1D volunteers. Relevance statement Noninvasive methods to investigate hepatic energy metabolism are urgently needed to evaluate liver health while preventing unnecessary biopsies. For broad clinical applicability, the robustness shown by the proposed method at clinical field strength is crucial. Trial registration ClinicalTrials.gov: NCT01055093—Prospective study on diabetes mellitus and its complications in newly diagnosed adult patients (GDC), NCT01055093, Registered: 01/22/2010, https://clinicaltrials.gov/study/NCT01055093?term=NCT01055093&rank=1#study-overview . Key Points The proposed magnetic resonance spectroscopy method calculates hepatic ATP synthesis rates at clinical field strength. The protocol shows acceptable reproducibility and spectra without contamination from muscle. The method can detect differences between participants with type 1 diabetes and controls. Graphical Abstract

BACKGROUNDWhile saturated fat intake leads to insulin resistance and nonalcoholic fatty liver, Mediterranean-like diets enriched in monounsaturated fatty acids (MUFA) may have beneficial effects. This study examined effects of MUFA on tissue-specific insulin sensitivity and energy metabolism.METHODSA randomized placebo-controlled cross-over study enrolled 16 glucose-tolerant volunteers to receive either oil (OIL, ~1.18 g/kg), rich in MUFA, or vehicle (VCL, water) on 2 occasions. Insulin sensitivity was assessed during preclamp and hyperinsulinemic-euglycemic clamp conditions. Ingestion of 2H2O/acetaminophen was combined with [6,6-2H2]glucose infusion and in vivo 13C/31P/1H/ex vivo 2H-magnet resonance spectroscopy to quantify hepatic glucose and energy fluxes.RESULTSOIL increased plasma triglycerides and oleic acid concentrations by 44% and 66% compared with VCL. Upon OIL intervention, preclamp hepatic and whole-body insulin sensitivity markedly decreased by 28% and 27%, respectively, along with 61% higher rates of hepatic gluconeogenesis and 32% lower rates of net glycogenolysis, while hepatic triglyceride and ATP concentrations did not differ from VCL. During insulin stimulation hepatic and whole-body insulin sensitivity were reduced by 21% and 25%, respectively, after OIL ingestion compared with that in controls.CONCLUSIONA single MUFA-load suffices to induce insulin resistance but affects neither hepatic triglycerides nor energy-rich phosphates. These data indicate that amount of ingested fat, rather than its composition, primarily determines the development of acute insulin resistance.TRIAL REGISTRATIONClinicalTrials.gov NCT01736202.FUNDINGGerman Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, Portugal Foundation for Science and Technology, European Regional Development Fund, and Rede Nacional de Ressonancia Magnética Nuclear.