Jens J. Holst

Altered glucagon and GIP responses in South Asian versus Nordic women after gestational diabetes mellitus

Aims/hypothesis We aimed to compare ethnic differences in levels of glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) following a pregnancy complicated by gestational diabetes mellitus (GDM), and to assess whether the higher insulin levels observed in South Asian compared with Nordic women could be explained by differences in the hormone secretory responses. Methods We measured glucagon, GIP and GLP-1 in 178 South Asian and 107 Nordic women during an OGTT, and stratified participants by glycaemic status. Glucagon and total GLP-1 and GIP responses when fasting and post-OGTT were assessed by linear mixed models. Ethnic differences in incretin and glucagon levels were evaluated by linear regression analyses. Pre-hepatic insulin levels were estimated using deconvolution of C-peptide kinetics. Results Ethnic differences in glucagon and incretin levels varied by glycaemic status. In the normoglycaemic South Asian group, early (0–15 min) glucagon suppression post-OGTT was significantly attenuated compared with the Nordic group ( p =0.002). Fasting glucagon levels did not differ ( p =0.139), but total glucagon exposure (including fasting levels) was higher in South Asian women ( p =0.013). No differences in GIP and GLP responses to the OGTT were observed ( p =0.490 and p =0.802). In women with prediabetes or diabetes, fasting glucagon was higher in the South Asian group ( p =0.010), but there were no significant differences in early glucagon suppression post-OGTT ( p =0.986). GIP responses to the OGTT were lower among South Asian women ( p <0.001), despite higher insulin responses compared with the Nordic women. GLP-1 responses did not differ between the ethnic groups ( p =0.661). The higher pre-hepatic insulin levels in South Asian vs Nordic normoglycaemic women were not associated with differences in incretin levels, but were associated with lower insulin sensitivity in the regression analyses ( p <0.001). Conclusions/interpretation When examined 1–3 years post-GDM, normoglycaemic South Asian women had less early glucagon suppression and higher total glucagon exposure post-OGTT compared with Nordic women. The higher pre-hepatic insulin levels were not associated with higher incretin levels, but were associated with lower insulin sensitivity.

OCT 1HolstThe Lancet

Retatrutide in adults with obesity and type 2 diabetes: what have we learned from TRIUMPH-2?

Additive Glucagonotropic and Insulinotropic Effects of Glucose‐Dependent Insulinotropic Polypeptide and Alanine in Fasted Healthy Men

Randomized double-blind crossover trial reveals additive glucagon and C-peptide increases with co-infused GIP and alanine in fasted healthy men, indicating amino acid modulation of GIP action.

Intravenous Oxytocin Does Not Affect Glucose‐Regulating Hormones or Markers of Bone Turnover During Graded Glucose Infusion in Healthy Men

Randomized double-blind trial finds intravenous oxytocin does not alter metabolic hormones or bone turnover in healthy men, indicating limited acute metabolic effects.

Endotrophin Measured by PRO ‐ C6 as a Prognostic Biomarker for Liver‐Related Events in Patients With Advanced Chronic Liver Disease

Trial analysis demonstrates that elevated baseline PRO-C6 predicts liver-related events in advanced hepatitis C, indicating its potential for risk stratification.

Acute glucagon infusion induces natriuresis and diuresis via direct tubular GCGR and GLP-1R pathways.

Animal findings on glucagon's tubular natriuresis via GCGR/GLP-1R remain hypothesis-generating; human studies needed before clinical consideration.

Secretin receptor knockout diminishes urine alkalization and increases blood base retention in mice during base-loading.

SCTR loss impairs prolonged base excretion in mice; leaves open any role in human metabolic alkalosis.

Chronic, but not acute, treatment with GLP ‐2 and GIP in combination increases glucose absorption in the isolated vascularly perfused rat intestine

Animal study reveals that chronic GLP-2 receptor stimulation increases intestinal glucose absorption while GIP enhances blood flow in rats, indicating distinct gut regulatory roles.

The effect of GIP and GLP-2 on bone turnover in children with Cerebral Palsy or Spinal Muscular Atrophy

Randomized trial investigates bone turnover impact of GIP and GLP-2 in children with CP or SMA, suggesting limited effects.

A short-term randomized clinical trial testing feasibility of and physiological responses to a Ruminococcus torques strain in healthy overweight humans

Randomized trial investigates physiological effects of Ruminococcus torques in overweight humans, suggesting implications for gut health.

EGF and NRG1β elicit shared core signaling alongside ligand-specific kinase phosphorylation differences in mouse hearts.

In vivo phosphoproteomics maps distinct and shared acute cardiac phosphorylation responses to EGF and NRG1β, providing mechanistic insights into how ErbB-targeted therapies may influence cardiac function.

Effects of Sativex® Versus Placebo on Glucagon-like Peptide-1, Total Ghrelin, and Subjective Appetite in Older Adults with Poor Appetite: A Protocolized Secondary Analysis of a Double-Blind, Randomized, Placebo-Controlled Crossover Trial

Background: Poor appetite, a major contributor to malnutrition, is highly prevalent among older adults and associated with adverse clinical outcomes. Nevertheless, there are currently no widely accepted or consistently effective pharmacological treatments targeting appetite that are routinely recommended alongside nutritional interventions. Medical cannabis has been proposed as a potential appetite stimulant in older adults with poor appetite through modulation of appetite-regulating hormones such as glucagon-like peptide-1 (GLP-1) and total ghrelin, but the evidence remains limited. Aims: To investigate the effects of Sativex® versus placebo on postprandial GLP-1 and total ghrelin concentrations following a single dose (8.1 mg Δ9-tetrahydrocannabinol (THC) and 7.5 mg cannabidiol (CBD)), and on subjective appetite following two separated doses, in older adults with poor appetite, and to investigate the associations between plasma concentrations of THC and its metabolites on these outcomes. Methods: This protocolized secondary analysis included 17 participants (≥65 years) with poor appetite from a double-blind, randomized, placebo-controlled crossover trial. Participants received Sativex® or placebo on two separate study days. GLP-1 and total ghrelin were measured following one dose of Sativex®/placebo and a standardized breakfast, and subjective appetite was assessed repeatedly using visual analog scales throughout the administration of two separate doses of Sativex®/placebo, the consumption of a standardized breakfast, and an ad libitum lunch meal. Effects/associations were analyzed using linear mixed-effects models. Results: Compared with placebo, Sativex® produced an estimated 2.38 pmol/L (95% confidence intervals (CI): −0.71 to 5.46; Bonferroni-corrected p = 0.274) reduction in mean GLP-1 and time-dependent changes in mean total ghrelin (Bonferroni-corrected p = 0.054). Compared with placebo, Sativex® produced minimal changes in separate subjective appetite sensations (all Bonferroni-corrected p = 1.00) and a slightly lower combined appetite score (−5.2 mm; 95% CI: −24.4 to 4.0; Bonferroni-corrected p = 1.00). Increased plasma concentrations of THC and metabolites were associated with reduced estimates of mean GLP-1 concentrations and subjective appetite, as well as increased mean total ghrelin concentrations. However, no statistically significant differences were detected for any analyses, and estimates had wide CIs, warranting cautious interpretation. Conclusions: In conclusion, no statistically significant differences were detected between Sativex® and placebo in postprandial GLP-1, total ghrelin, or subjective appetite over time in older adults with poor appetite. Similarly, no statistically significant associations were observed between plasma concentrations of THC and its metabolites and GLP-1, total ghrelin, or subjective appetite. Trial registration: ClinicalTrials.gov ID: NCT05503147; EudraCT nr.: 2021-002318-15.

During a 52-week weight maintenance phase, exercise alone or in combination with liraglutide significantly reduced carotid intima-media thickness by 7% and 6% respectively, whereas liraglutide alone did not.

Exercise should be prioritized in obesity weight-maintenance regimens for vascular benefit; challenges weak prior evidence favoring liraglutide monotherapy.

Ghrelin predicts food consumption up to three hours prior to eating: A randomised controlled trial

Eating triggers a cascade of metabolic, neural, and subjective signals that unfold and interact over several hours, typically suppressing the motivation to eat until the next meal. Which of these signals predict next-meal intake is not well understood. In a cross-over, double-blinded, and repeated measures factorial design over four separate test days, we manipulated both the protein and caloric content of four preload meals to experimentally induce differences in satiety. We investigated how the neural, subjective, hormonal, and metabolite states unfolded after a meal and how much each of them predicted the next meal intake 3 h later. Bayesian analysis revealed an extreme level of evidence for the inclusion of the peptide hormone ghrelin as a predictor of next meal energy intake. This predictive effect was consistently found for all time points, including also the time point immediately preceding preload consumption. When measured immediately before the ad libitum test meal, the plasma level of the gut hormone Glucagon-like Peptide-1 (GLP-1) and the subjective report of estimated consumption also predicted next-meal intake. No other measure, including the protein and caloric content of the preload, adequately predicted next-meal intake. Our results link ghrelin levels with the regulation of food intake several hours later.

Physical Fitness with Exercise and GLP-1 Receptor Agonist Treatment Alone or Combined After Diet-Induced Weight Loss: A Secondary Analysis of a Randomized Controlled Trial in Adults with Obesity

Secondary analysis shows combined exercise and GLP-1 treatment improves physical fitness in adults with obesity, suggesting a beneficial approach for weight maintenance.

Empagliflozin improves beta cell function independently of relief of glucotoxicity in patients with type 2 diabetes: results from a randomised cross-over study with insulin as comparator

Study improved beta cell function with empagliflozin compared to insulin in type 2 diabetes patients, suggesting metabolic benefits beyond glucose relief.

GLP ‐2 and GIP acutely increase superior mesenteric artery blood flow in male rats, and the effect is independent of nitric oxide and vasoactive intestinal peptide

Acute effects of GLP-2 and GIP enhance splanchnic blood flow in anesthetized rats, indicating independence from nitric oxide and vasoactive intestinal peptide.

GLP‐1 Receptor Agonists for the Prevention of New‐Onset Heart Failure: A Systematic Review and Meta‐Analysis of Placebo‐Controlled Randomized Clinical Trials

Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) improve outcomes in heart failure (HF) with preserved ejection fraction. Whether GLP‐1 RA prevent new‐onset HF in Type 2 diabetes or obesity requires further investigation. Methods We performed an updated meta‐analysis of randomized placebo‐controlled trials (RCT) of treatment with GLP‐1 RA in participants without HF. The hazard ratio (HR) and 95% confidence intervals (95% CI) were extracted from the group without HF in each study. The primary outcome was time to first HF event (HF hospitalization or urgent visit for HF). The correlation between the effect of GLP‐1 RA on HF events and the effects on HbA1c, weight and major atherosclerotic cardiovascular events (MACE) was also investigated. We also evaluated the heterogeneity of effect according to study characteristics. Results A total of 52,752 participants without HF from six RCTs were included. Treatment with GLP‐1 RA (vs. placebo) decreased the risk of new‐onset HF (HR = 0.77 [95% CI 0.65–0.93], p < 0.001) and the composite of HF events or cardiovascular death (HR = 0.82 [95% CI 0.76–0.89], p < 0.001). The effect of GLP‐1 RA on HF events was independent of its effects on HbA1c or weight, but was correlated with its protective effects on MACE. The effects on HF prevention were more pronounced in studies restricted to patients with atherosclerotic cardiovascular disease and in trials with higher incidence rate of HF events. Conclusion Treatment with GLP‐1 RA decreases the risk of new‐onset HF in patients with Type 2 diabetes or obesity.

Influence of Diets Differing in Macronutrient Composition on Metabolic Regulation During Exercise in Adults with Type 1 Diabetes

Aim: To compare the effect of consuming three isocaloric diets that differed in macronutrient composition on substrate oxidation and glucose regulation during sustained submaximal exercise in adults with type 1 diabetes (T1D). Methods: In a randomised, crossover design, 12 adults with T1D (n = 4 female, age: 46 ± 15 years, HbA1c: 55.9 ± 7.8 mmol/mol) consumed three isocaloric diets over seven days: (i) HCLFLP (high-carbohydrate [48%], low-fat [33%], low-protein [19%]), (ii) LCHFLP (low-carbohydrate [19%]), high-fat [62%], low-protein [19%]), and (iii) LCLFHP (low-carbohydrate (19%), low-fat [57%], high-protein [24%]). On the morning of day eight, participants undertook 45 min of cycling (≈60% V.O2peak) whilst fasting. Venous-derived plasma glucose and free fatty acids (FFA) were measured throughout the trial period. Indirect calorimetry was used to determine rates of substrate oxidation during exercise. Data were analysed via repeated measures ANOVAs with p ≤ 0.05 accepted as significant. Results: During exercise, rates of lipid oxidation were higher (1.2-fold, p = 0.030) and carbohydrate oxidation lower (0.8-fold, p = 0.030) in LCHFLP versus HCLFLP. Concentrations of FFA after exercise were higher in LCHFLP compared to HCLFLP (by ≈22%, p = 0.019). Overall time spent in euglycaemia was higher (HCLFLP: 55.6 ± 43.9, LCHFLP: 87.3 ± 28.7, LCLFHP: 95.2 ± 7.9%, p = 0.003) and hyperglycaemia lower (HCLFLP: 44.4 ± 43.9, LCHFLP: 12.7 ± 28.7, LCLFHP: 4.8 ± 7.9%, p = 0.003) in both LC diets relative to HC. No differences in any measured biomarkers were observed between the two LC diets. Conclusions: One-week consumption of isocaloric diets that differed in their macronutrient composition shifted patterns of energy metabolism during a standardised bout of moderate intensity exercise performed in the fasted state in adults with T1D.

2′-Fucosyllactose supplementation results in a transient improvement in gut microbial resilience after vancomycin use in adults with overweight or obesity: a randomized, double-blind, placebo-controlled intervention

Randomized trial demonstrates transient improvements in gut microbial resilience in adults with obesity after 2′-FL supplementation, suggesting its potential post-antibiotic benefit.