1,721,181 research outputs found
Pathophysiology of non-insulin-dependent diabetes and the search for candidate genes: Dangerous liaisons?
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Genetic causes and treatment of neonatal diabetes and early childhood diabetes
No full textDiabetes mellitus and impaired fasting glucose associated with single gene mutations are less rare than previously thought and may account for more than 6% of patients attending a pediatric diabetes clinic. The number of loci involved in monogenic diabetes exceed 25, and appropriate genetic diagnosis is crucial to direct therapy, for genetic counseling and for prognosis of short- and long-term complications. Among patients with neonatal diabetes (i.e. with onset within first 6 months of life) and patients with Maturity Onset Diabetes of the Young (MODY; an autosomal dominant form of diabetes), those carrying mutations in KCNJ11, ABCC8, HNF1A and HNF4A genes usually respond to oral therapywith sulphonylurea, while those bearing GCK mutations do not necessitate any treatment. Sensor-augmented continuous subcutaneous
insulin infusion has been successfully employed in neonatal diabetes, and long-lasting effectiveness of sulfonylurea in KCNJ11 mutation carriers with neonatal diabetes well documented
Role of proline 193 in the insulin receptor post-translational processing
No full textAims/hypothesis. A point mutation, P193L, in the insulin receptor alpha subunit, has been previously identified in a patient affected by an extreme form of insulin resistance due to reduced insulin binding. In our study we investigated the cellular mechanisms by which P193L substitution causes a reduction of insulin receptor numbers on the cell surface.Methods. Mutated insulin receptors have been generated and expressed in COS1 cells. Transcription as well as translation of P193L insulin receptor have been measured and compared with wild type insulin receptorResults. P193L insulin receptor is normally transcribed and progresses to the step of insulin proreceptor, which does not proceed to dimerization, resulting in the accumulation of the 210 kDa form. These findings suggest that the P193L insulin proreceptor is retained in the endoplasmic reticulum, where several molecular chaperones drive the folding of protein precursors. Therefore the interaction between mutated insulin receptor precursor and two endoplasmic reticulum resident chaperones (GRP78 and calnexin) were investigated. P193L insulin proreceptor co-immunoprecipitates with greater amounts of GRP78 and its interaction with calnexin is greatly delayed compared with wild type insulin receptor precursor, Co-transfection of wild type and mutated insulin receptors causes a considerable reduction of cell surface wild type insulin receptors,Conclusion/interpretation. P193 is critical for insulin propeceptor folding. The monomeric form of P193L insulin proreceptor is retained in the endoplasmic reticulum by a calnexin and GRP78 mediated mechanism that reduces mature insulin receptor expression on the cell surface
Insulin: Still a miracle after all these years
No full textThe discovery of insulin almost 100 years ago has resulted in a remarkable increase in lifespan and quality of life for patients with type 1 diabetes. The Joslin Medalist Study has allowed researchers to access and study patients (Medalists) with type 1 diabetes who have been insulin dependent for 50 years or more. In this issue of the JCI, Yu et al. evaluated HLA variants, autoantibody status, beta cell function, C-peptide release, and monogenetic diabetes genes in a cohort of Medalists. Postmortem analysis of pancreata from Medalists revealed the presence of insulin-positive beta cells in these patients. Moreover, some patients were still able to respond to metabolic stimuli despite long-term insulin dependence. Overall, the Medalist cohort was highly heterogenous, and genetic testing suggested that several patients would fall into categories other than type 1 diabetes on the basis of REVEL (rare exome variant ensemble learner) classification and may be able to transfer to other therapy options
Kir6.2 Activating Mutations Are a Common Finding in Italian Patients with Permanent Neonatal Diabetes (PNDM)
No full textMutations in hIAPP and NEUROG3 genes are not a common cause of permanent neonatal/infancy/childhood onset diabetes.
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