Obesity is a chronic, multifactorial disease that has reached epidemic status. The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is a key therapeutic target to achieve weight loss and glycemic control in obesity and type 2 diabetes mellitus. Tirzepatide and retatrutide, the latest generation of GLP-1-incorporating multi-agonists, target multiple receptors in complementary systems to achieve marked and sustained weight loss. However, the associated gastrointestinal (GI) side effects (e.g., nausea, vomiting, diarrhea, abdominal pain) that often hinder patient compliance underscore a remaining need for therapies with better tolerability. GEP44, a novel, monomeric, chimeric peptide structurally based on native GLP-1, the GLP-1RA exendin-4 (Ex-4), and the gut-derived hormone peptide YY3-36 (PYY3-36), is an agonist at the GLP-1R and multiple neuropeptide Y (NPY) receptors. This review summarizes the design rationale for GEP44 and preclinical evidence supporting its beneficial metabolic effects and tolerability. Like GLP-1, PYY3-36 is associated with decreased food intake (FI), and co-administration of GLP-1RA and PYY3-36 elicits synergistic food intake (FI)- and body weight (BW)-reducing effects with similar or enhanced blood glucose (BG)-lowering effects. Studies examining the efficacy of GEP44 to promote weight loss and improve glucoregulation in lean vs. diet-induced obese rodents report that peripheral administration generally decreases BW, FI, and insulin resistance and increases EE at equivalent or greater magnitudes than those observed with single GLP-1RAs in a GLP-1R-dependent manner with improved GI tolerability. These beneficial actions reflect GEP44's potential to expand the mechanistic scope of anti-obesity medications.

Whipple disease is a rare systemic infection caused by Tropheryma whipplei that often presents with nonspecific gastrointestinal symptoms and may mimic other disorders. We report the case of a 75-year-old woman with type 2 diabetes mellitus who presented with chronic diarrhoea and a 15 kg unintentional weight loss over 6 months despite preserved appetite. Laboratory investigations revealed iron-deficiency anaemia, hypoproteinaemia, mild inflammatory and liver function abnormalities, and peripheral eosinophilia. Extensive infectious, autoimmune, and gastrointestinal investigations were unrevealing. Abdominal computed tomography demonstrated mesenteric lymphadenopathy, raising suspicion for lymphoma. Histopathological examination of duodenal biopsies revealed numerous foamy macrophages containing periodic acid-Schiff-positive, diastase-resistant granular material, consistent with Whipple disease. Ziehl-Neelsen staining additionally demonstrated acid-fast bacilli, and subsequent investigations confirmed concomitant Mycobacterium szulgai infection. The significance of this finding remains uncertain, as it may represent either true coinfection or incidental colonisation. A potential explanation is that T. whipplei-induced macrophage dysfunction creates a permissive intracellular niche for nontuberculous mycobacteria, although supporting evidence is lacking. Following antimicrobial therapy, the patient experienced marked clinical improvement with resolution of symptoms and an 8 kg weight gain. This case highlights the diagnostic challenges of Whipple disease and the need to consider concomitant mycobacterial infection when acid-fast organisms are identified.

Mpox (monkeypox) is an emerging viral infection with a broad and evolving clinical spectrum that increasingly spans beyond its characteristic cutaneous manifestations. Anorectal manifestations are well recognized in patients with Mpox in recent outbreaks. However, the gastrointestinal (GI) or anorectal symptoms may precede the typical rash, creating significant diagnostic challenges and delaying appropriate infection control measures. We describe a quinquagenarian man with poorly controlled diabetes mellitus who presented with fever, diarrhea, tenesmus, and severe perianal pain. Cross-sectional imaging demonstrated diffuse rectosigmoid inflammation, while endoscopy revealed severe ulcerative proctitis. Initial evaluation favored acute infectious proctitis, and treatment was directed accordingly. However, the subsequent development of disseminated pustular skin lesions prompted consideration of Mpox, which was ultimately confirmed by polymerase chain reaction testing of the lesions. Extensive testing excluded concurrent human immunodeficiency virus (HIV) infection and other common sexually transmitted infections, and rectal biopsy demonstrated nonspecific acute colitis. The patient recovered with supportive management and had complete endoscopic resolution on follow-up colonoscopy. This case illustrates the relevance of considering Mpox in the differential diagnosis of acute proctitis and lower GI symptoms, even before characteristic skin lesions appear. It also underscores the diagnostic value of maintaining a high index of suspicion in patients presenting with severe anorectal disease and points out that diabetes-associated immune dysfunction may play a role in such cases. Early recognition of atypical GI manifestations is essential for timely diagnosis, appropriate patient isolation, avoidance of unnecessary interventions, and optimal clinical outcomes.

Cases involving both diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) may present with a more severe condition at the start of treatment compared to cases involving either condition alone. However, gastrointestinal infections are a relatively rare cause of mixed DKA/HHS in adults. A 66-year-old man with untreated diabetes was admitted with impaired consciousness after several days of diarrhea and poor oral intake. Laboratory findings confirmed mixed DKA/HHS; blood cultures identified Aeromonas caviae (A. caviae), and stool cultures identified Escherichia coli (E. coli) O125. Mixed DKA/HHS and infection resolved following continuous intravenous insulin, fluid resuscitation, and appropriate antimicrobial therapy, but refeeding syndrome developed. In cases of malnutrition or hyperglycemia, an immunocompromised state serves as a risk factor for multiple infections. If concomitant infections or microbiological findings are present, they may exacerbate metabolic decompensation in mixed DKA/HHS. To our knowledge, this is the first reported case of adult mixed DKA/HHS associated with A. caviae bacteremia and pathogenic E. coli O125 detected in stool. Clinicians should be aware that gastrointestinal infections can trigger DKA and consider the possibility of concomitant infections and bacteremia.

A 5-year-old spayed female domestic shorthair cat was referred to the Clinical Nutrition Service at the Ontario Veterinary College (Guelph, Ontario) for management of chronic, nonresponsive enteropathy and recently diagnosed diabetes mellitus. The cat was presented with persistent diarrhea, perianal ulceration, weight loss, and poor glycemic control despite treatment with prednisolone, cobalamin injections, a hydrolyzed diet, and short antimicrobial trials. Once hospitalized, the cat was transitioned to a high-protein, low-carbohydrate commercial veterinary therapeutic diet containing mixed protein sources. Nutritional support was initiated via a nasogastric tube but discontinued after 48 h when voluntary oral intake resumed. Clinical signs improved gradually over 5 d, blood glucose stabilized below the renal threshold, and insulin therapy was discontinued at discharge after 6 d of hospitalization. The commercial veterinary therapeutic diet was maintained, and psyllium husk was later added to improve stool quality. Soft stools persisted for several months, with normalization occurring only after targeted fiber supplementation was introduced alongside ongoing medical management. This case highlights the importance of individualized nutritional management in chronic enteropathy, as clinical response to dietary intervention may evolve over time and long-term stabilization may require alternative strategies beyond hydrolyzed-protein diets. Key clinical message: Dietary responsiveness in feline chronic enteropathy is highly individualized. Hydrolyzed-protein diets are commonly recommended, but responses may vary between cases. Sequential and sustained dietary trials, guided by clinical response, may be necessary to achieve durable remission.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to obesity, insulin resistance, type 2 diabetes, and progressive liver fibrosis. Dual and triple glucagon-like peptide-1 (GLP-1)-based polyagonists may provide complementary hepatic and metabolic benefits, but their overall efficacy and safety have not been fully established. This systematic review and meta-analysis evaluated randomized controlled trials comparing dual or triple GLP-1-based polyagonists with placebo in adults with MASLD or MASH. PubMed, the Cochrane Central Register of Controlled Trials, ScienceDirect, and Google Scholar were searched from inception through May 19, 2026. Dichotomous outcomes were pooled as risk ratios (RRs), and continuous outcomes were analyzed as mean differences (MDs), using random-effects models. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Six randomized controlled trials involving 961 participants were included. The included GLP-1-based polyagonists-tirzepatide, survodutide, pemvidutide, retatrutide, and cotadutide-significantly increased MASH resolution or histological improvement without worsening of fibrosis (RR 3.32, 95% CI 2.28-4.84; I[2] = 20%) and fibrosis improvement without worsening of MASH (RR 1.49, 95% CI 1.15-1.94; I[2] = 0%). Treatment also produced a greater relative reduction in liver fat content (MD -44.60 percentage points, 95% CI -51.17 to -38.04; I[2] = 0%) and increased the likelihood of achieving at least a 30% relative reduction in liver fat by magnetic resonance imaging-proton density fat fraction (RR 4.71, 95% CI 3.04-7.30; I[2] = 22%). Body weight was significantly reduced, although heterogeneity was considerable (MD -9.14 percentage points, 95% CI -17.38 to -0.91; I[2] = 98%). Nausea, diarrhea, and vomiting were more frequent with polyagonists, but no statistically significant differences were observed in serious adverse events or adverse events leading to treatment discontinuation. In conclusion, dual and triple GLP-1-based polyagonists improve histological and imaging-based hepatic outcomes in MASLD and MASH and may simultaneously address underlying metabolic dysfunction. However, gastrointestinal intolerance, pharmacological heterogeneity, the small number of trials, and limited follow-up warrant cautious interpretation. Larger phase 3 trials are needed to clarify drug-specific efficacy, long-term safety, and effects on liver-related and cardiovascular outcomes.