ABSTRACT
Aim: Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS. Methods: Eight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis. Results: DA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and ß-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats. Conclusion: We present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.
Subject(s)
Insulin-Secreting Cells , Wolfram Syndrome , Humans , Rats , Animals , Infant , Incretins/pharmacology , Wolfram Syndrome/drug therapy , Glucagon-Like Peptide 1/pharmacology , Gastric Inhibitory PolypeptideABSTRACT
AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. METHODS: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. RESULTS: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. CONCLUSIONS/INTERPRETATION: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome.
Subject(s)
Induced Pluripotent Stem Cells , Insulin-Secreting Cells , Optic Atrophy , Wolfram Syndrome , Humans , Animals , Mice , Wolfram Syndrome/drug therapy , Wolfram Syndrome/genetics , Exenatide/therapeutic use , Optic Atrophy/pathology , Insulin-Secreting Cells/pathology , Mice, KnockoutABSTRACT
Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.
Subject(s)
Human Embryonic Stem Cells , Wolfram Syndrome , Animals , Mice , Humans , Wolfram Syndrome/drug therapy , Wolfram Syndrome/genetics , Wolfram Syndrome/metabolism , Riluzole/pharmacology , Riluzole/metabolism , Calcium/metabolism , Human Embryonic Stem Cells/metabolism , Neurons/metabolism , Mice, Knockout , Synapses/metabolismABSTRACT
Wolfram syndrome is a rare genetic disorder characterized by endocrine dysfunction and progressive neurodegeneration. By targeting intracellular calcium dysregulations, a sigma-1 receptor agonist rescued neurological deficits in preclinical models of Wolfram syndrome.
Subject(s)
Wolfram Syndrome , Calcium , Humans , Mitochondria , Wolfram Syndrome/drug therapy , Wolfram Syndrome/geneticsABSTRACT
Wolfram syndrome (WS) 1 is a rare monogenic neurodegenerative disorder caused by mutations in the gene encoding WFS1. Knowledge of the pathophysiology of WS is incomplete and to date, there is no treatment available. Here, we describe early deviations in the renin-angiotensin-aldosterone system (RAAS) and bradykinin pathway (kallikrein kinin system, KKS) observed in a rat model of WS (Wfs1 KO) and the modulative effect of glucagon-like peptide-1 receptor agonist liraglutide (LIR) and anti-epileptic drug valproate (VPA), which have been proven effective in delaying WS progression in WS animal models. We found that the expression of key receptors of the RAAS and KKS, Agtr2 and Bdkrb1, were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in Wfs1, KO serum aldosterone levels were substantially decreased and bradykinin levels increased compared to WT animals. Neither treatment nor their combination affected the gene expression levels seen in the Wfs1 KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the Wfs1 KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that Wfs1 deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems.
Subject(s)
Calmodulin-Binding Proteins/genetics , Down-Regulation , Membrane Proteins/genetics , Receptor, Angiotensin, Type 2/genetics , Receptor, Bradykinin B1/genetics , Wolfram Syndrome/genetics , Aldosterone/blood , Animals , Cells, Cultured , Disease Models, Animal , Down-Regulation/drug effects , Gene Knockout Techniques , Liraglutide/pharmacology , Liraglutide/therapeutic use , Male , Rats , Renin-Angiotensin System/drug effects , Valproic Acid/pharmacology , Valproic Acid/therapeutic use , Wolfram Syndrome/blood , Wolfram Syndrome/drug therapyABSTRACT
Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Glucagon-Like Peptide-1 Receptor/agonists , Hearing Loss, Sensorineural/drug therapy , Liraglutide/therapeutic use , Nerve Degeneration/drug therapy , Visual Pathways/pathology , Wolfram Syndrome/drug therapy , Animals , C-Peptide/metabolism , Diabetes Mellitus, Experimental/complications , Disease Models, Animal , Glucagon-Like Peptide-1 Receptor/metabolism , Hearing Loss, Sensorineural/complications , Liraglutide/pharmacology , Male , Nerve Degeneration/complications , Optic Nerve/drug effects , Optic Nerve/pathology , Optic Nerve/ultrastructure , Phenotype , Rats , Visual Pathways/drug effects , Wolfram Syndrome/complicationsABSTRACT
BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic ß cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, ß cell functions were not significantly improved, but there was a significant correlation between baseline ß cell functions and change in ß cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1ß, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.
Subject(s)
Dantrolene , Insulin-Secreting Cells , Interleukin-18/analysis , Interleukin-1beta/analysis , Quality of Life , Visual Acuity/drug effects , Wolfram Syndrome , Adolescent , Adult , Biological Availability , Calcium Signaling/drug effects , Child , Dantrolene/administration & dosage , Dantrolene/adverse effects , Dantrolene/pharmacokinetics , Dose-Response Relationship, Drug , Drug Monitoring/methods , Humans , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/physiology , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/statistics & numerical data , Muscle Relaxants, Central/administration & dosage , Muscle Relaxants, Central/adverse effects , Muscle Relaxants, Central/pharmacokinetics , Neurologic Examination/drug effects , Treatment Outcome , Wolfram Syndrome/diagnosis , Wolfram Syndrome/drug therapy , Wolfram Syndrome/metabolism , Wolfram Syndrome/physiopathologyABSTRACT
OBJECTIVES: Wolfram syndrome (WS) is a rarely seen autosomal recessive multisystem neurodegenerative disorder caused by mutations in the WFS1 gene. CASE PRESENTATION: Three sisters with WS had diabetes mellitus (DM) at 4 years of age and optic atrophy. In addition, the first case had hearing impairment, and the second case had diabetes insipidus and urinary incontinence. Linagliptin was administered to the first case as add-on therapy to intensive insulin treatment 15 years after the onset of DM, and her insulin need showed a dramatic decrease. The third case had a remission phase one month after the onset of DM. CONCLUSIONS: Even in cases with the same mutation, symptoms and findings may widely vary in WS. Remission of diabetes has rarely been reported in WS. Also, this report describes the first trial of a dipeptidyl peptidase-4 inhibitor in a patient with WS which provided a decrease in exogenous insulin need.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Insulin/therapeutic use , Membrane Proteins/genetics , Mutation , Wolfram Syndrome/drug therapy , Adolescent , Child , Child, Preschool , Drug Therapy, Combination , Female , Humans , Hypoglycemic Agents/therapeutic use , Male , Pedigree , Prognosis , Remission Induction , Wolfram Syndrome/metabolism , Wolfram Syndrome/pathologyABSTRACT
Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5-8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.
Subject(s)
Blindness/drug therapy , Blindness/prevention & control , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/prevention & control , Flavones/therapeutic use , Liraglutide/therapeutic use , Wolfram Syndrome/drug therapy , Animals , Blindness/blood , Blindness/physiopathology , Blood Glucose/metabolism , Body Weight , Calmodulin-Binding Proteins/deficiency , Calmodulin-Binding Proteins/metabolism , Cognitive Dysfunction/blood , Disease Models, Animal , Disease Progression , Drug Therapy, Combination , Fasting/blood , Flavones/pharmacology , Gene Expression Regulation/drug effects , Gene Knockout Techniques , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Hyperglycemia/pathology , Learning/drug effects , Liraglutide/pharmacology , Male , Membrane Proteins/deficiency , Membrane Proteins/metabolism , Nerve Degeneration/complications , Nerve Degeneration/pathology , Optic Nerve/drug effects , Optic Nerve/pathology , Optic Nerve/physiopathology , Optic Nerve/ultrastructure , Rats , Remyelination , Visual Acuity/drug effects , Wolfram Syndrome/bloodABSTRACT
BACKGROUND: Wolfram syndrome is a rare neurodegenerative disorder, characterized by the presence of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. The majority of cases are due to autosomal recessive biallelic variants in the WFS1 gene; however, pathogenic autosomal dominant (AD) mutations have also been described. Glucagon-like peptide (GLP-1) agonists have been studied in both animal models and humans with classic Wolfram syndrome. CASE: We present a 15-year-old female with a personal and family history of congenital strabismus, bilateral cataracts, low-frequency sensorineural hearing loss, and diabetes mellitus. Trio whole exome sequencing revealed a previously unknown maternally inherited heterozygous variant in exon 8 of the WFS1 gene c.2605_2616del12 p.Ser869_His872del, leading to the diagnosis of AD WFS1-related disorder. Treatment with a GLP-1 agonist resulted in marked improvement in glycemic control and discontinuation of insulin therapy. This patient's response to a GLP-1 agonist provides suggestive indirect evidence for a role of WFS1 on ß-cell endoplasmic reticulum stress and suggests that treatment with a GLP-1 agonist should be considered in patients with dominant forms of WS.
Subject(s)
Glucagon-Like Peptides/analogs & derivatives , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Wolfram Syndrome/drug therapy , Adolescent , Female , Genes, Dominant , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptides/therapeutic use , Humans , Membrane Proteins/genetics , Treatment Outcome , Wolfram Syndrome/geneticsABSTRACT
Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic ß cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1's interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.
Subject(s)
Antineoplastic Agents/pharmacology , Calmodulin-Binding Proteins/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Insulin-Secreting Cells/drug effects , Membrane Proteins/metabolism , Pyridines/pharmacology , Wolfram Syndrome/drug therapy , Animals , Calcium/metabolism , Calmodulin-Binding Proteins/genetics , Cell Survival/drug effects , Disease Models, Animal , Endoplasmic Reticulum/metabolism , Gene Expression Regulation , Gene Knockout Techniques , Glycoproteins , Homeostasis , Hyperglycemia , Insulin Secretion , Membrane Proteins/genetics , Receptor, Insulin , Transcriptome , Wolfram Syndrome/geneticsABSTRACT
Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.
Subject(s)
Glucagon-Like Peptide-1 Receptor/agonists , Liraglutide/therapeutic use , Neuroprotective Agents/therapeutic use , Wolfram Syndrome/drug therapy , Animals , Apoptosis/drug effects , Calmodulin-Binding Proteins/deficiency , Calmodulin-Binding Proteins/genetics , Disease Models, Animal , Endoplasmic Reticulum Stress/drug effects , Glucose Tolerance Test , Hyperglycemia/pathology , Hyperglycemia/prevention & control , Liraglutide/pharmacology , Male , Membrane Proteins/deficiency , Membrane Proteins/genetics , Neurons/physiology , Neuroprotective Agents/pharmacology , Optic Nerve/metabolism , Rats , Rats, Transgenic , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Wolfram Syndrome/metabolism , Wolfram Syndrome/pathologyABSTRACT
Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder.
Subject(s)
Genetic Therapy/methods , Regenerative Medicine/methods , Wolfram Syndrome/therapy , Animals , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Humans , Molecular Targeted Therapy , Wolfram Syndrome/drug therapy , Wolfram Syndrome/genetics , Wolfram Syndrome/metabolismSubject(s)
Diabetes Mellitus, Type 1/genetics , Vision, Low/genetics , Wolfram Syndrome/genetics , Biphasic Insulins/therapeutic use , Child , Diabetes Mellitus, Type 1/drug therapy , Frameshift Mutation/genetics , Homozygote , Humans , Hypoglycemic Agents/therapeutic use , Male , Membrane Proteins/genetics , Treatment Outcome , Vision, Low/drug therapy , Wolfram Syndrome/drug therapySubject(s)
Optic Atrophy/diagnosis , Wolfram Syndrome/diagnosis , Adolescent , Adrenocorticotropic Hormone/blood , Growth Hormone/blood , Hormone Replacement Therapy , Humans , Male , Optic Atrophy/blood , Optic Atrophy/drug therapy , Testosterone/blood , Thyrotropin/blood , Wolfram Syndrome/blood , Wolfram Syndrome/drug therapyABSTRACT
Wolfram syndrome is a rare monogenic cause of juvenile onset diabetes mellitus. It is a non-autoimmune, insulin-deficient state with concurrent or consequent optic atrophy. Here we depict the case of a 16-year-old young girl afflicted with this condition, who presented with parasuicide on a background of depressive disorder. The aetiology of this presentation was attributable to multiple physical ailments and a genetic predisposition conferred by the disease-causing mutation for which she tested positive. She was managed with intensive insulin therapy and specific psychotherapy. Her case highlights the importance of recognising and addressing these comorbidities associated with Wolfram syndrome, so as to curtail disastrous consequences.
Subject(s)
Depressive Disorder/etiology , Diabetes Mellitus, Type 1/complications , Suicide, Attempted/psychology , Wolfram Syndrome/diagnosis , Adolescent , Depressive Disorder/complications , Depressive Disorder/psychology , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/psychology , Diagnosis, Differential , Female , Humans , Insulin/therapeutic use , Membrane Proteins/genetics , Psychotherapy/methods , Treatment Outcome , Wolfram Syndrome/complications , Wolfram Syndrome/drug therapy , Wolfram Syndrome/geneticsABSTRACT
Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 µg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.
Subject(s)
Blood Glucose/drug effects , Hypoglycemic Agents/pharmacology , Peptides/pharmacology , Venoms/pharmacology , Wolfram Syndrome/drug therapy , Animals , Biomarkers/blood , Blood Glucose/metabolism , Disease Models, Animal , Exenatide , Genetic Predisposition to Disease , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , Insulin/blood , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Time Factors , Wolfram Syndrome/blood , Wolfram Syndrome/geneticsABSTRACT
Wolfram syndrome is a rare neurodegenerative and genetic disorder, characterized by insulin-dependent diabetes mellitus, caused by non-autoimmune loss of ß cells, as well as optic atrophy; the disease is also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Patients that demonstrate diabetes mellitus are also affected by: optic atrophy in the first decade of their life, diabetes insipidus and sensorineural deafness in the second decade, and urinary tract and neurological abnormalities in the third decade of their life. Patients with Wolfram syndrome usually die due to central respiratory failures caused by brain stem atrophy in their third or at the beginning of their fourth decade of life. The authors present a case of two female siblings with diagnosed Wolfram syndrome that have been diagnosed with diabetes mellitus, optic atrophy, and urological abnormalities. Early diagnosis and adequate hormonal supplementation can improve their quality of life.
Subject(s)
Diabetes Mellitus/drug therapy , Optic Atrophies, Hereditary/drug therapy , Rare Diseases/diagnosis , Rare Diseases/drug therapy , Urologic Diseases/drug therapy , Wolfram Syndrome/diagnosis , Wolfram Syndrome/drug therapy , Adolescent , Diabetes Mellitus/etiology , Female , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Optic Atrophies, Hereditary/etiology , Poland , Treatment Outcome , Urologic Diseases/etiology , Wolfram Syndrome/complicationsABSTRACT
We report two cases emphasizing the importance of insulin assays for evaluation of hypoglycemia in diabetic patients. Case 1 was a 96/12-year-old female patient with type 1 diabetes mellitus and case 2 was a 1010/12-year-old male patient with DIDMOAD. Both patients were on a basal-bolus insulin regimen. Both were admitted because of persistent hypoglycemia. Analyses of serum samples obtained at the time of hypoglycemia initially showed low insulin and C-peptide levels. Recurrent episodes of unexplained hypoglycemia necessitated measurement of insulin levels by using different insulin assays, which revealed hyperinsulinemic hypoglycemia with low C-peptide levels, findings which confirmed a diagnosis of factitious hypoglycemia. Surreptitious administration of insulin should not be excluded in diabetic patients with hypoglycemia without taking into account the rate of cross-reactivity of insulin analogues with the insulin assay used.