Yoni Freedhoff, MD, reviews the new book 'Food Intelligence,' which details the impact of food on nutrition, biochemistry, metabolism, and health.

AbstractBackground and Aims. Anti-obesity therapies co-targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor achieve greater weight los

The SWEET project is a multicenter, randomized, controlled trial that shows that long-term consumption of sweeteners and sweetness enhancers improves body weight control and elicits beneficial gut microbiota changes in adults with overweight or obesity.

β-cell dysfunction and dedifferentiation towards an α-cell-like phenotype are hallmarks of type 2 diabetes. Her,e the authors detect five α-cell subpopulations, find differences between healthy and diabetic donors, and identify SMOC1 as an inducer of human β-cell dysfunction and dedifferentiation.

Nimacimab monotherapy did not meet its primary endpoint for weight loss; preliminary pharmacokinetic analysis showed lower than expected…...

Objective This study aimed to characterize the reasons for treatment discontinuation with injectable semaglutide or tirzepatide for obesity in regular clinical practice. Methods This cross-section...

Obesity and its related disorders, including type 2 diabetes and liver, kidney, and cardiovascular diseases, are now recognized as chronic inflammator…

Evidence is emerging that glucagon-like peptide-1 (GLP-1) receptor agonists have anti-inflammatory and chondroprotective properties independent of their effects on weight loss. In this Review, the authors discuss the potential effects of GLP-1 receptor agonists on the incidence, disease activity and progression of various forms of arthritis, as well as practical considerations for their use in this context.

This cohort study investigates the comparative risks of male external genital infections in adult male patients with type 2 diabetes treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors vs g...

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure. This study shows that prolonged glucagon exacerbates lipid accumulation, promoting renal injury in early DKD, rather than lipid oxidation. Targeting glucagon signaling significantly inhibits DKD progression.

Aims/hypothesis Genetic association studies have demonstrated that partial loss of SLC30A8 Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of SLC30A8 Function on type 2 diabetes risk and related phenotypes in humans. Methods The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with SLC30A8 loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of SLC30A8 LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs. Results We identified 18 SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in SLC30A8 LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (ORadditive=0.62; 95% CI 0.53, 0.72; p=1.1×10–9; ORrecessive=0.34; 95% CI 0.12, 0.93; p=0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin. Conclusions/interpretation The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of SLC30A8, up to and including complete knockout, may treat type 2 diabetes safely and effectively. Graphical Abstract

Glucagon-like peptide-1 (GLP-1) supports beta cell health and function by potentiating glucose-dependent insulin production and secretion. While GLP-1…

Transparency in clinical research is essential for advancing medical knowledge, informing healthcare decisions, and maintaining public trust. The Food and Drug Administration Amendments Act (FDAAA) of...

Pilot study met key 3-month efficacy endpoint with strong statistical significance (p=0.014); Revita-treated patients lost an additional 2.5% total body weight after stopping GLP-1 drugs vs. 10% regai...

Hepatocyte caspase-8 in MASH promotes the activation of hepatic stellate cells and liver fibrosis through an apoptosis-independent mechanism

Aims/hypothesis The loss of pancreatic beta cell mass and identity is a hallmark of diabetes. While factors such as beta cell overwork (insulin hypersecretion) and elevated intracellular calcium have been implicated, beta cell identity loss also occurs in KATP gain-of-function (KATP-GOF) mice, a model of human neonatal diabetes, even in the absence of these factors. This suggests additional underlying mechanisms. Autophagy, a key process for cellular homeostasis, is impaired in the islets and beta cells of both type 1 and type 2 diabetes, but its role in monogenic diabetes with insulin secretory deficiency remains unclear. We hypothesise that autophagy dysfunction contributes to beta cell identity loss in KATP-GOF mice, and that intermittent fasting (IF) can restore autophagic flux, thereby preserving functional beta cell mass. Methods To test this, adult tamoxifen-inducible KATP-GOF mice and littermate controls were randomly assigned to two groups: (1) chow diet ad libitum; and (2) chow diet with alternate-day IF. Results KATP-GOF mice fed ad libitum developed severe hyperglycaemia due to impaired insulin secretion. This was followed by a reduction in insulin content, disruption of beta cell autophagic flux, autophagosome accumulation and, ultimately, the loss of beta cell identity and dedifferentiation. In contrast, KATP-GOF mice subjected to alternate-day IF exhibited lower blood glucose levels, improved mitochondrial morphology, restoration of autophagic flux and reestablishment of beta cell identity. Conclusions/interpretation This study provides the first evidence of autophagy impairment in non-obese, insulin secretory-deficient, KATP-induced diabetes mice and demonstrates that IF restores both autophagic flux and beta cell identity. This finding suggests that similar mechanisms may contribute to beta cell dysfunction in other forms of diabetes. Graphical Abstract

Eli Lilly has halted a study of an experimental drug, designed to prevent obesity patients from losing too much muscle, due to strategic business reasons, according to a U.S. registry of clinical trials.

The glucagon-like peptide 1 receptor agonist (GLP-1RA) class of medicines has emerged as transformative for the treatment of diabetes, obesity and other diseases. On the twentieth anniversary of the approval of exenatide (Byetta), three former employees of Amylin Pharmaceuticals acknowledge the contributions of some of the individuals and the innovation responsible for delivering the first approved GLP-1RA — the forerunner to the modern blockbuster drugs.

Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging, we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient-sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgrhep−/−). Liver-specific deletion of the glucagon receptor decreases hepatic AMP kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice but not in Gcgrhep−/− mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction. Graphical Abstract