2026-08-14 | Evaluating the use of GLP-1 receptor agonists in Wolfram syndrome patients.
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene and characterized by early-onset, insulin-dependent diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration driven by chronic endoplasmic reticulum (ER) stress; no proven disease-modifying therapy currently exists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) augment glucose-dependent insulin secretion and, in preclinical models, preserve β-cell mass, attenuate ER stress, and confer neuroprotection - properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study, with additional longitudinal data for participants co-enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study. We characterized the prevalence of GLP-1 RA use and the documented rationale for initiation, and evaluated within-participant pre-post changes in glycemic (HbA1c, body mass index) and visual (LogMAR best-corrected visual acuity, retinal nerve fiber layer thickness) parameters, along with adverse effects and reasons for discontinuation. Thirty of the 84 participants (35.7%) had received a GLP-1 RA in addition to insulin. No statistically significant changes in HbA1c or body mass index were observed at one or two years. Best-corrected visual acuity (LogMAR) declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common (56.7% of users) and were the leading cause of discontinuation. In this largest reported evaluation of GLP-1 RA use in Wolfram syndrome, these agents were already integrated into clinical care and were generally tolerated, but showed no glycemic or visual benefit over one to two years. Given the retrospective, uncontrolled design, the small number of participants with paired pre-post measurements, and the absence of a longitudinally followed comparator group, these findings are preliminary and hypothesis-generating rather than definitive, and provide a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.
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2026-08-12 | Anti-GAD65 antibody-associated cerebellar ataxia in a young adult with type 1 diabetes: a case report and literature review.
Anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia (anti-GAD-CA) is a rare autoimmune neurological disorder. Although frequently associated with latent autoimmune diabetes in adults (LADA), it can occasionally coexist with type 1 diabetes mellitus (T1DM). We report a 27-year-old woman with a 14-year history of T1DM who presented with subacute onset of balance impairment, vertigo, and hypophonic speech. Neurological examination and laboratory investigations were consistent with cerebellar ataxia. The patient exhibited high titers of anti-glutamic acid decarboxylase (anti-GAD) in both serum (619 IU/mL) and cerebrospinal fluid. Brain MRI was unremarkable. After a 5-day intravenous immunoglobulin (IVIG) therapy, the patient showed notable improvement in tandem gait and speech fluency. Her glycemic control also improved significantly, with the glycated hemoglobin (HbA1c) dropping from 9.7 to 6.8% over two months. Follow-up testing showed a steady decline in serum anti-GAD levels to 229 IU/mL. This case represents one of the youngest reported patients with anti-GAD-CA in the context of long-standing T1DM. The case emphasizes the importance of considering anti-GAD-CA in patients with unexplained cerebellar signs and autoimmune diabetes, even in younger individuals. Furthermore, the observed parallel improvements in neurological and glycemic parameters following immunotherapy may provide insight into the interplay between anti-GAD autoimmunity and metabolic control. Further studies are required to better understand the pathophysiological mechanisms and optimize management strategies.
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2026-06-22 | β-Hydroxybutyrate Improves Glucose Metabolism in Streptozotocin-Induced Type 1 Diabetes by Inhibiting Gut and Liver Glucose Transporters via GPR109A.
Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabetes exhibited reduced fasting blood glucose and increased fasting blood ketone levels, negatively correlated. Another clinical study using continuous glucose and ketone monitoring confirmed inverse glucose-ketone fluctuations. To test causality, we conducted animal and cellular studies. In streptozotocin-induced T1D mice, 7-week oral 3HB administration improved glucose metabolism and alleviated glycogenic hepatopathy. Imaging with 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography/computed tomography demonstrated reduced hepatic and intestinal glucose uptake. Western blotting confirmed 3HB suppressed glucose transporter (sodium-glucose cotransporter 1, GLUT2, GLUT5) overexpression and normalized glycogen metabolism. In vitro, 3HB dose-dependently inhibited glucose transporter expression and glucose uptake in primary hepatocytes and IEC-6 cells. G protein-coupled receptor 109A (GPR109A) serves as the primary receptor for 3HB. Mechanistic studies using the GPR109A inhibitor mepenzolate bromide, the mTOR inhibitor rapamycin, and siRNA-mediated gene silencing revealed that these effects were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. Overall, this study provides new insights into the role of ketone bodies in T1D, establishing 3HB as a modulator of glucose homeostasis through GPR109A-mediated suppression of glucose transporters in the liver and intestine.
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2026-06-19 | Phenylketonuria and type 1 diabetes: a clinical and nutritional challenge in a young adult-a case report.
Phenylketonuria and type 1 diabetes are lifelong metabolic disorders requiring complex and potentially conflicting nutritional strategies. Their coexistence is rare, yet management may become particularly challenging during transition from pediatric to adult care. We describe the case of a young adult with phenylketonuria who developed type 1 diabetes. A 27-year-old man with longstanding phenylketonuria was referred to an adult metabolic-diabetes center after the diagnosis of type 1 diabetes. Clinical, biochemical, nutritional, and continuous glucose monitoring data were reviewed. The intervention included structured therapeutic education, transition from fixed insulin doses to a dynamic regimen based on carbohydrate counting, and revision of medical nutrition therapy using phenylketonuria-adapted low-protein foods and sugar-free phenylalanine-free amino acid supplements. At diagnosis, HbA1c was 11.5%, with markedly reduced C-peptide levels and high titer anti-GAD antibodies. Initial diabetes management was associated with poor adherence to the phenylketonuria diet, increased intake of conventional protein sources, and elevated phenylalanine levels. After individualized insulin titration and nutritional intervention, HbA1c improved from 11.5% to 7.8%, phenylalanine levels decreased from 842 to 705 μmol/L, insulin requirement declined from 0.55 to 0.3 IU/kg/day, and continuous glucose monitoring showed improved glycemic control without increased hypoglycemia. The Glycemia Risk Index improved from high-risk Zone E to low-intermediate-risk Zone B. This case highlights the need for personalized multidisciplinary care integrating continuous glucose monitoring, carbohydrate counting, and phenylketonuria specific nutrition to optimize both metabolic conditions.
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2026-06-08 | DIABETES MELLITUS IN WOLFRAM SYNDROME 1: CHARACTERISTICS AND PERSPECTIVES IN TREATMENT
Wolfram syndrome 1 is a rare autosomal recessive disorder caused by mutations in the WFS1 gene related to endoplasmic reticulum (ER) function. The course of the disease most often begins with diagnosis of insulin-dependent non-autoimmune diabetes mellitus with an early onset. Its clinical character is presented with an acronym DIDMOAD: diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA) and deafness (D). This article focuses on the clinical features of diabetes mellitus in Wolfram syndrome. We also describe current approach to its therapy and discuss possible treatment options placing the main emphasis on the GLP1 receptor agonists and cell regenerative therapy. Methods and materials: A qualitative synthesis of the data focusing on GLP-1 agonists, cell regenerative therapy and diabetes mellitus in Wolfram syndrome was performed. This literature review of GLP-1 receptor agonists and cell regenerative therapy effect on metabolic control, and current perspectives of treatment in patients with Wolfram syndrome, a monogenic type of diabetes, included recent publications, primarily from the past 10 years, and was conducted from November 2025 to April 2026 using the PubMed database. A systematic search was performed using specific keywords and medical subject headings (MeSH terms) related to GLP-1 agonists and Wolfram syndrome. The primary search terms included: “diabetes mellitus”, “GLP-1 agonists”, “Wolfram syndrome”, “WFS1”, “monogenic diabetes”, “islet transplantation”, and “cell regenerative therapy”. The criteria for inclusion of articles were as follows: published before April 2026, written in English, peer-reviewed original research articles. Exclusion criteria included publications not available in full text, articles in languages other than English. Editorials, commentaries, and conference abstracts without full data were also excluded. Titles and abstracts of the retrieved articles were screened to determine eligibility based on the inclusion and exclusion criteria.
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