Bankstown Hospital - Grand Rounds - Further Reading

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Born to Beta Cell

Amo-Shiinoki, K., et al. (2025). "β cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome." Science Translational Medicine 17(786): eadp2332  https://www.science.org/doi/abs/10.1126/scitranslmed.adp2332 REQUEST ARTICLE

        Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by WFS1 gene mutations. However, the pathological process of ER stress–associated β cell failure remains to be fully elucidated. Our results indicate loss of β cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of β cells and subsequent decrease in α cells, suggesting loss of endocrine function. Wfs1-deficient mice displayed dysfunction, gradual loss, and dedifferentiation of β cells, leading to permanent hyperglycemia. Impairment of the β cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced β cells. Islets of Wfs1-deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically, Wfs1-null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS β cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress–induced protein up-regulated in Wfs1 deficiency. Txnip deletion preserved functional β cells and prevented diabetes progression in Wfs1-deficient mice. Together, this study deciphered pathological mechanisms of β cell dedifferentiation in β cell failure and has implications for Txnip inhibition in WS therapy. β cell dedifferentiation underlies diabetes mellitus in Wolfram syndrome, and Txnip inhibition prevents β cell regression in Wfs1-deficient mice. Wolfram syndrome can be caused by inherited mutations in WFS1, leading to diabetes driven by loss of β cells. Amo-Shiinoki et al. found that endocrine dysfunction is promoted by β cell dedifferentiation and loss of cellular identity in this genetic disorder. The authors further showed that inhibition of thioredoxin-interacting protein (Txnip), a protein involved in metabolic stress response, preserved functional β cells and ameliorated metabolic dysfunction in a Wfs1-knockout mouse model of Wolfram syndrome. This study therefore identifies a potential therapeutic strategy for treating this disorder. —Catherine Charneski.

Bonnycastle, L. L., et al. (2013). "Autosomal Dominant Diabetes Arising From a Wolfram Syndrome 1 Mutation." Diabetes 62(11): 3943-3950  https://doi.org/10.2337/db13-0571 PDF AVAILABLE AT URL

 We used an unbiased genome-wide approach to identify exonic variants segregating with diabetes in a multigenerational Finnish family. At least eight members of this family presented with diabetes with age of diagnosis ranging from 18 to 51 years and a pattern suggesting autosomal dominant inheritance. We sequenced the exomes of four affected members of this family and performed follow-up genotyping of additional affected and unaffected family members. We uncovered a novel nonsynonymous variant (p.Trp314Arg) in the Wolfram syndrome 1 (WFS1) gene that segregates completely with the diabetic phenotype. Multipoint parametric linkage analysis with 13 members of this family identified a single linkage signal with maximum logarithm of odds score 3.01 at 4p16.2-p16.1, corresponding to a region harboring the WFS1 locus. Functional studies demonstrate a role for this variant in endoplasmic reticulum stress, which is consistent with the β-cell failure phenotype seen in mutation carriers. This represents the first compelling report of a mutation in WFS1 associated with dominantly inherited nonsyndromic adult-onset diabetes.

Hu, R., et al. (2024). "ISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models." Cell Death & Differentiation 31(3): 322-334   https://doi.org/10.1038/s41418-024-01258-w PDF AVAILABLE AT URL

Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS β-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed β-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with β-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.

Kinsley, B. T., et al. (1995). "Morbidity and Mortality in the Wolfram Syndrome." Diabetes Care 18(12): 1566-1570  https://doi.org/10.2337/diacare.18.12.1566  PDF AVAILABLE AT URL

 To determine the major causes of morbidity and mortality in the autosomal recessive Wolfram syndrome, which is defined by diabetes and bilateral progressive optic atrophy with onset in childhood or adolescence.We abstracted and reviewed the medical records of 68 confirmed cases of Wolfram syndrome identified through a nationwide survey of endocrinologists, ophthalmologists, institutes, and homes for the blind. We also reviewed all available autopsy records.The most common causes of morbidity and mortality were the neurological manifestations of this syndrome and the complications of urinary tract atony. There was a lower frequency of diabetic ketoacidosis, no histologically proven diabetic glomerulosclerosis, and less severe, more slowly progressive, diabetic retinopathy than in classic type I diabetic patients. Mortality in Wolfram syndrome is much higher than in type I diabetes; 60% of Wolfram syndrome patients die by age 35. Recognition of these clinical differences from classic type I diabetes is important for the proper management of Wolfram syndrome patients.Identification of Wolfram syndrome patients among all diabetic patients presenting in childhood or adolescence is important because the management of patients with this syndrome is different from that of patients with classic type I diabetes.

Morikawa, S. and F. Urano (2023). "The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome." International Journal of Molecular Sciences 24(1): 230  https://www.mdpi.com/1422-0067/24/1/230 PDF AVAILABLE AT URL

The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of “poorly folded proteins”, namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction.

Rohayem, J., et al. (2011). "Diabetes and Neurodegeneration in Wolfram Syndrome: A multicenter study of phenotype and genotype." Diabetes Care 34(7): 1503-1510  https://doi.org/10.2337/dc10-1937 PDF AVAILABLE AT URL

 To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation.The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes.WSD was diagnosed earlier than type 1 diabetes (5.4 ± 3.8 vs. 7.9 ± 4.2 years; P < 0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P = 0.049). Mean duration of remission in WSD was 2.3 ± 2.4 vs. 1.6 ± 2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P < 0.001). Neurologic disease progression was faster in the WSD group with a mean HbA1c >7.5% (P = 0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P = 0.028).Endoplasmic reticulum stress–mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.

Toppings, N. B., et al. (2018). "Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies." Case Reports in Endocrinology 2018(1): 9412676  https://onlinelibrary.wiley.com/doi/abs/10.1155/2018/9412676 PDF AVAILABLE AT URL

                Background. Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in WFS1, a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care. Case. We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations in WFS1 were identified, supporting a diagnosis of classical WS. Conclusions. The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserve β-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies for β-cell preservation for individuals with type 1 and 2 diabetes.

Urano, F. (2016). "Wolfram Syndrome: Diagnosis, Management, and Treatment." Current Diabetes Reports 16(1): 6  https://doi.org/10.1007/s11892-015-0702-6 PDF AVAILABLE AT URL

 Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome.

. Available via CIAP

• UptoDate: Endocrinology and Diabetes. Available via CIAP (including mobile access).
• Therapeutic Guidelines: Diabetes. Available via CIAP (including mobile access)