Daniel Drucker

Reasons for Discontinuation of Obesity Pharmacotherapy With Semaglutide or Tirzepatide in Clinical Practice 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...

Among reasons for discontinuation of GLP-1 medicines initiated for #weightlossdue cost or insurance-related issues was the most common reason cited onlinelibrary.wiley.com/doi/10.1002/...

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

Inflammation is a key driver of the pathophysiology of cardiometabolic disorders #obesity #T2D and new metabolic medicines based on GLP-1 action exert their magic in part by reducing inflammation. A new review from Professor Donath summarizes the field www.sciencedirect.com/science/arti...?

Efferocytosis-associated reprogramming of the islet macrophages and the subsequent influence on the adaptive immune response could be beneficial in modulating diabetic autoimmunity #diabetes #T1D www.nature.com/articles/s41...

Glucagon-like peptide-1 receptor agonists in arthritis: current insights and future directions - Nature Reviews Rheumatology 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.

GLP-1 medicines and #arthritis www.nature.com/articles/s41...

Incoming nutritional epidemiology. Low Carbohydrate Diets may not be beneficial for primary prevention of #T2D unless they prioritize plant-based protein, healthy fats, and high-quality carbohydrates. diabetesjournals.org/care/article...

Novel insights into the molecular underpinnings of islet cell dysfunction in #T1D highlighting pathways that may be leveraged to preserve residual β-cell function and modulate α-cell activity @bcellorg.bsky.social www.jci.org/articles/vie...

SGLT2 Inhibitors and External Genital Infection in Male Patients With Diabetes 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...

Rare but real. Genital infections in males #T2D on SGLT2i jamanetwork.com/journals/jam...

Prolonged glucagon exposure rewires lipid oxidation and drives diabetic kidney disease progression - Nature Communications 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.

Prolonged glucagon exposure and the kidney-helpful or harmful? www.nature.com/articles/s41...

Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function - Diabetologia 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

Human #genetics implies that therapeutic inhibition of SLC30A8, mediating zinc transport up to and including complete knockout, may treat type 2 diabetes safely and effectively @diabetologiajnl.bsky.social link.springer.com/article/10.1...

Furin may contribute to proglucagon processing and Glucagon-Like Peptide-1 production in human alpha cells. Glucagon-like peptide-1 (GLP-1) supports beta cell health and function by potentiating glucose-dependent insulin production and secretion. While GLP-1…

Here it is proposed that furin plays an important role in liberation of GLP-1 from alpha cells www.sciencedirect.com/science/arti...

Sponsor-Level Compliance with ClinicalTrials.gov Reporting Requirements: A Comprehensive Analysis 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...

Clinical trial results reporting for industry-still room for improvement. Meanwhile in academia, home to many industry critics, the timely reporting rates remain abysmal publichealth.realclearjournals.org/research-art...

Some promising data for #weightloss maintenance after discontinulation of GLP-1 medicines using duodenal mucosal resurfacing ir.fractyl.com/news-release...

A non-apoptotic caspase-8–meteorin pathway in hepatocytes promotes MASH fibrosis - Nature Metabolism Hepatocyte caspase-8 in MASH promotes the activation of hepatic stellate cells and liver fibrosis through an apoptosis-independent mechanism

A therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin.
www.nature.com/articles/s42...

Restoration of pancreatic beta cell identity and autophagy in KATP-induced diabetes by intermittent fasting - Diabetologia 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

Based on studies of autophagy in non-obese, insulin secretory-deficient KATP-GOF mice the authors propose that #IntermittentFasting prevents the gradual loss of beta cell identity by enhancing autophagy link.springer.com/article/10.1...

Eli Lilly halts trial testing experimental muscle-preserving drug with Zepbound 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.

Bimagrumab exits stage left as the healthy #weightloss saga continues to unfold #obesity www.reuters.com/business/hea...

A salute to innovation: exenatide in diabetes and obesity drug development at Amylin Pharmaceuticals - Nature Metabolism 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.

From the lizard venom and John Eng, in licensing to clinical development and approval April 28 2005. The remarkable story of Amylin Pharma and exenatide www.nature.com/articles/s42...

Effects of Glucagon-Like Peptide 1 Receptor Agonist Initiation in Patients With Heart Failure With Reduced Ejection Fraction and Implantable Cardiac Devices:

Use of GLP-1 medicines in patients with HFrEF and implanted cardiac devices. Caution please www.jacc.org/doi/10.1016/...

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice - GeroScience 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

New from Jennifer Stern. A role for the glucagon receptor in the lifespan extending effects of caloric restriction link.springer.com/article/10.1...

New from Mark Ruszniak @vubasicsciences.bsky.social An essential role for the GLP-1R in hematopoietic stem cell engraftment academic.oup.com/jimmunol/adv...

Potential Impact of Next-Generation Weight Loss Drugs on Cancer Incidence with 10% #weightloss Projections from the USA pmc.ncbi.nlm.nih.gov/articles/PMC...

From strength to greater strength, terrific recruitment of Professor Klatt to @uoftmedicine.bsky.social

Site-specific adaptive nanovesicles for oral insulin delivery Milk-derived nanovesicles enable oral insulin delivery by crossing the gut barrier and targeting the liver.

The 100 year pursuit of oral #insulin delivery #diabetes continues-here is the latest technology and chapter www.science.org/doi/10.1126/...

Join us this Friday am, in person or online, for new insights into #Islet biology-what should we strive for in islet cell replacement therapy?-some thoughts from Professor Powers, a leader in the field in characterizing human islets across the lifespan #diabetes

Join us this Friday am, in person or online, for new insights into #Islet biology-what should we strive for in islet cell replacement therapy?-some thoughts from Professor Powers, a leader in the field in characterizing human islets across the lifespan #diabetes

A consensus guide to preclinical indirect calorimetry experiments - Nature Metabolism The authors highlight inconsistencies and divergencies in the literature reporting data on indirect calorimetry for studies on whole-body energy homeostasis, and propose harmonization of standards to facilitate data comparison and interpretation across different datasets.

Towards establishing consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results-the latest proposals www.nature.com/articles/s42...

More genetic evidence supporting
an association between GLP1R agonists and higher risk of chronic tubulo-interstitial nephritis journals.lww.com/md-journal/f...

Pancreatic cancer-related diabetes and type 2 diabetes differ in multiple aspects of glucose homeostasis - Diabetologia Aims/hypothesis Pancreatic ductal adenocarcinoma-related diabetes mellitus (PDAC-DM) is a paraneoplastic syndrome with a poorly understood pathophysiology. PDAC-DM is often clinically confused with type 2 diabetes, resulting in delayed cancer detection and poorly individualised hyperglycaemia treatment. We investigated whether these forms of diabetes can be distinguished at the metabolic level. Methods Adults with either cancer treatment-naive PDAC-DM (n=28) or type 2 diabetes (n=97), and with diabetes onset within 3 years, underwent mixed-meal tolerance tests to investigate glucose metabolism. Outcomes included insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), beta cell function (oral disposition index), insulin clearance, and postprandial glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) responses. Results Compared with type 2 diabetes, individuals with PDAC-DM showed ~2.5-fold greater insulin sensitivity, ~81% lower insulin secretion and ~40% lower beta cell function. Insulin clearance was higher in the PDAC-DM group than the type 2 diabetes group, with and without adjustment for insulin sensitivity. Glucagon and GLP-1 levels increased after a meal in both groups, but levels were higher in the PDAC-DM group. GIP levels were similar between groups. The metabolic differences between groups persisted after adjustment for age, sex and BMI. Conclusions/interpretation PDAC-DM and type 2 diabetes are metabolically distinct, with different defects responsible for hyperglycaemia. PDAC-DM is characterised predominantly by insulin deficiency and displays higher insulin sensitivity than type 2 diabetes. There are also differences in alpha cell regulation and insulin clearance compared with type 2 diabetes. These findings identify biological characteristics that may have implications for individualised treatment of PDAC-DM and guide diagnostic biomarker discovery for early PDAC diagnosis. Graphical Abstract

PDAC associated #diabetes vs #T2D greater insulin sensitivity, ~81% lower insulin secretion and ~40% lower beta cell function #pancreaticcancer link.springer.com/article/10.1...

Clinical implications of bone marrow adiposity identified by phenome-wide association and Mendelian randomization in the UK Biobank - Nature Communications Bone marrow adipose tissue accounts for almost 10% of human fat mass, but its roles remain unclear. Here, Xu et al. identify more than 45 diseases linked to marrow adiposity in over 48,000 people, including causal roles in musculoskeletal disease.

Here the authors propose bone marrow adipose tissue as a biomarker and/or therapeutic target for diverse human diseases www.nature.com/articles/s41...

The potential for a once monthly Amylin-GLP-1 medicine combination-early PK data

PK data support monthly dosing for MET-097i