Gerrit van Hall

The dynamics of human tendon protein synthesis in response to short‐term exercise and injury is poorly understood, and whether this occurs heterogeneously in the tendon remains an enigma. This study aimed to determine whether protein synthesis is affected by short‐term exercise, and whether it is altered in patellar tendinopathy. Protein synthesis was studied in humans using an 8 day intake of deuterated water (D ₂ O), and analyses of blood and tendon biopsies. Eighteen patients with chronic uni‐ or bilateral patellar tendinopathy (8 females and 10 males) and 18 healthy, matched participants (8 females and 10 males) were included. Both patellar tendons investigated in all participants, and the healthy participants additionally completed three bouts of unilateral heavy resistance training prior to biopsy sampling. Tendon protein synthesis rates were markedly higher (10–20 fold) in the soluble matrix fraction compared to the insoluble collagen fraction. Protein synthesis did not differ between tendinopathic and healthy tendons in either fraction. Unilateral resistance exercise had no significant impact on protein synthesis in either tendon fraction. Protein synthesis was not influenced by biological sex. The present study demonstrates that tendon protein synthesis predominantly occurs in the soluble matrix fraction compared to the insoluble collagen fraction of human patellar tendon, and chronic tendinopathy and short‐term exercise do not appear to alter synthesis rates in healthy, physically active humans. These data increase our understanding of tendon protein synthesis, and could help explain why patellar tendinopathy becomes a chronic condition. image Key points: The dynamics of human tendon protein synthesis in different protein fractions are not well‐understood, and the effect of short‐term exercise or tendinopathy remains largely unknown. In this study, protein synthesis was significantly higher in the soluble matrix proteins compared to the insoluble collagen fraction. No apparent differences in tendon protein synthesis in either fraction were observed between healthy and tendinopathic tendons. Unilateral short‐term exercise had no measurable impact on tendon protein synthesis in either protein fraction. The results increase our understanding of protein dynamics in human tendon and suggest that neither chronic tendinopathy nor short‐term exercise measurably alters tendon protein synthesis over an 8 day period.

In a randomized, placebo-controlled crossover study, intravenous ghrelin infusion impaired insulin sensitivity and β-cell function in individuals with previous sleeve gastrectomy as well as in matched controls. Ghrelin reduced peripheral insulin sensitivity by 25%–29% and decreased β-cell function (disposition index) by 48%–49%. These findings suggest that the postoperative reduction in circulating ghrelin following sleeve gastrectomy may contribute to improved glucose metabolism, while underscoring the complex role of ghrelin in human glucose homeostasis.

Mitochondrial dysfunction has long been associated with insulin resistance (IR), yet the causal relationship in humans remains unresolved. Here, to probe causality and delineate the underlying molecular mechanisms, we leveraged carriers of the m.3243A>G mtDNA variant as a human genetic model of primary mitochondrial dysfunction linked to diabetes. Deep metabolic phenotyping revealed selective skeletal muscle IR featuring preserved insulin-stimulated Akt-TBC1D4 signaling but blunted mTORC1 activation. Integrated muscle proteomic and bioenergetic profiling demonstrated broad mitochondrial protein depletion, OXPHOS- and complex I-specific deficits, and concomitant AMPKγ2 downregulation. An exercise-based intervention improved muscle insulin sensitivity, partially rescued mitochondrial defects, and increased AMPKγ2 abundance, without altering Akt-TBC1D4 or mTORC1 signaling. An integrative framework linking phenotypic features and exercise-induced remodeling signatures confirmed rescue of m.3243A>G-related molecular alterations and their association with muscle insulin sensitivity. These findings define an exercise-modifiable mitochondrial basis for skeletal muscle IR and identify specific mitochondrial defects as candidate targets for improving glucose homeostasis in common insulin-resistant states.

Aims/hypothesis Sodium–glucose co-transporter 2 (SGLT2) inhibitors improve beta cell function in individuals with type 2 diabetes. It has been suggested this is due to relief of glucotoxicity, but the mechanism is unknown. The objective of the present study was to evaluate the effect of the SGLT2 inhibitor empagliflozin, compared with NPH insulin treatment, on beta cell function, and, secondarily, on insulin sensitivity. Methods In this open-label, randomised, cross-over study, 17 individuals with non-insulin-treated type 2 diabetes were randomised to receive 5 weeks of treatment with either empagliflozin or insulin titrated to a similar level of glycaemic control as with empagliflozin before crossing over to the other treatment. Key inclusion criteria included age ≥18 years, BMI ≥ 28 kg/m², and a diabetes duration of more than 3 months. Treatments were preceded by a 3 week washout. Fasting and post-OGTT (5 h) metabolism were studied before and during treatments. Beta cell glucose sensitivity (bGS) was calculated as the slope of the linear relationship between the pre-hepatic insulin secretion rate and the corresponding plasma glucose value, and insulin sensitivity was calculated as glucose clearance relative to insulin concentrations. Endogenous glucose production, tissue glucose disposal and lipolysis were measured using stable isotopes. The disposition index was calculated as bGS × insulin sensitivity to assess beta cell function. Data for the present study were collected at the Department of Endocrinology, Hvidovre Hospital, Denmark. Results All participants who completed the study were included in the analyses. With equipoised glycaemic control, insulin concentrations were higher during insulin treatment than during empagliflozin treatment. bGS and insulin sensitivity were higher during empagliflozin treatment than during insulin treatment. The disposition index thus improved during empagliflozin treatment compared with insulin treatment. Conclusions/interpretation With similar glycaemic control, insulin sensitivity was higher and beta cell function improved during empagliflozin compared with insulin treatment, possibly due to a disinhibitory effect of lower insulin concentrations. Trial registration EudraCT 2017-002101-35. Funding This study was supported by Boehringer Ingelheim. Additional funding was provided by the Grosserer L.F. Foghts Fond, Charlottenlund, Denmark. Graphical Abstract

Atrial natriuretic peptide (ANP) is suggested to stimulate lipolysis, which has been demonstrated using supraphysiological doses of ANP. We explored the effects of physiological doses of ANP, as observed during an acute exercise bout, on lipolysis, ketogenesis, and glucose metabolism. Ten healthy men was randomized to infusion of ANP vs. placebo using stable isotope labeled tracers. The present study indicates that lipid metabolism does not seem to be regulated by ANP in men.

Aims/hypothesis: The aim of this work was to investigate tissue-specific insulin resistance in South Asian and Nordic women with previous gestational diabetes mellitus (pGDM) and to evaluate potential ethnic differences contributing to type 2 diabetes risk. Methods: A cross-sectional study using a two-step hyperinsulinaemic–euglycaemic clamp with a glucose tracer was conducted to assess insulin sensitivity in muscle, liver and adipose tissue in 19 South Asian and 16 Nordic women with pGDM and prediabetes (impaired glucose tolerance and/or impaired fasting glucose), along with 16 ethnicity-specific control women. We assessed inflammation and mitochondrial genes by mRNA sequencing of adipose tissue. Results: Both South Asian and Nordic women with pGDM showed reduced total glucose disposal (mainly due to muscle insulin resistance) and hyperinsulinaemia compared with the control group. Endogenous glucose production (mainly due to hepatic insulin resistance) was elevated in Nordics with pGDM, while South Asians with pGDM showed pronounced adipose tissue insulin resistance (reduced suppression of glycerol during clamp). mRNA sequencing of adipose tissue indicated increased tissue inflammation in South Asian women compared with Nordic women with pGDM. Furthermore, we observed a differential response to hyperinsulinaemia in South Asians vs Nordics related to mitochondrial mRNA, such as thymidine kinase 2 ( TK2 ). Correlations between adiposity markers and insulin sensitivity also differed by ethnicity, suggesting that the pathways leading to type 2 diabetes may vary across populations. Conclusions/interpretation: South Asian and Nordic women with pGDM exhibited differences in insulin resistance profiles, with South Asians showing greater adipose tissue insulin resistance and inflammation. Graphical

The main objective of the study was to investigate the effects of prenatal exercise interventions on maternal body composition at 28 weeks gestation and 7–14 days after delivery. We also explored associations between physical activity (PA) per se and body composition. This study presents secondary outcomes of the FitMum randomized controlled trial, which included healthy inactive pregnant women at gestational age ≤ 15+0 weeks. They were randomized to structured supervised exercise training, motivational counselling on PA, or standard care. Maternal body composition was measured by doubly labeled water at 28 weeks gestation (n = 134) and by dual-energy X-ray absorptiometry scan 7–14 days after delivery (n = 117). PA, including moderate-to-vigorous-intensity PA (MVPA), active kilocalories, and steps, were measured continuously from inclusion to delivery by a wrist-worn activity tracker. One hundred fifty pregnant women were included with a median pre-pregnancy body mass index (BMI) of 24.1 (21.6–27.9) kg/m². We found no differences between groups in fat mass, fat percentage or fat-free mass at 28 weeks gestation or 7–14 days after delivery. Visceral adipose tissue mass and bone mineral density measured 7–14 days after delivery did not differ between groups either. Linear regression analyses adjusted for pre-pregnancy BMI showed that a higher number of daily steps was associated with lower fat mass, fat percentage, and visceral adipose tissue mass at 28 weeks gestation and 7–14 days after delivery. Active kilocalories during pregnancy was positively associated with fat-free mass 7–14 days after delivery. Neither structured supervised exercise training nor motivational counselling on PA during pregnancy affected maternal body composition at 28 weeks gestation or 7–14 days after delivery compared to standard care. Interestingly, when adjusted for pre-pregnancy BMI, higher number of daily steps was associated with lower fat content during pregnancy and after delivery, whereas MVPA and active kilocalories were not. Trial registration: ClinicalTrials.gov; NCT03679130; 20/09/2018.

Background: Sarcopenia is thought to be underlined by age-associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageing per se or other confounding factors. Methods: Lean and healthy young (n=10, 22 ± 3 yrs, BMI; 23.4 ± 0.8 kg/m ² ) and old men (n=10, 70 ± 3 yrs, BMI; 22.7 ± 1.3 kg/m ² ) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after, as well as 60 and 180 minutes after EAA intake. Muscle samples were analyzed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signaling. Results: Following exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was ∼11% and ∼28% lower in Young (p-1 to 0.056%·h ^-1 , p-1 to 0.083%·h ^-1 , pThr389 increased to a similar extent in the exercising leg in both groups but was 2.8-fold higher in the resting leg of Old at the 60 min timepoint (pSer65 increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (pThr56 was reduced (∼ 66 and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (pper se does not appear to cause AR in human skeletal muscle.