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      Identification of a novel hepatocyte nuclear factor-1 alpha ( HNF1A) variant in maturity onset diabetes of the young type 3 (HNF1A-MODY)


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          We identified an adolescent young woman with new-onset diabetes. Due to suspicious family history, she underwent genetic testing for common monogenic diabetes (MODY) genes. We discovered that she and her father carry a novel variant of uncertain significance in the HNF1A gene. She was successfully transitioned from insulin to a sulfonylurea with excellent glycemic control. Based on her family history and successful response to sulfonylurea, we propose that this is a novel pathogenic variant in HNF1A. This case highlights the utility of genetic testing for MODY, which has the potential to help affected patients control their diabetes without insulin.

          Learning points
          • HNF1A mutations are a common cause of monogenic diabetes in patients presenting with early-onset diabetes and significant family history.

          • Genetic testing in suspected patients allows for the identification of mutations causing monogenic diabetes.

          • First-degree relatives of the affected individual should be considered for genetic testing.

          • The use of sulfonylurea agents in patients with HNF1A-MODY can reduce dependence on insulin therapy and provide successful glycemic control.

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          Precision diabetes: learning from monogenic diabetes

          The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed <6 months of age). In contrast, in MODY it was more complex and slow because of the lack of single criteria to identify patients, but it was greatly assisted by the development of a diagnostic probability calculator and associated smartphone app. Experience in monogenic diabetes suggests that successful adoption of a precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4226-2) contains a slideset of the figures for download, which is available to authorised users.
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            Genetic cause of hyperglycaemia and response to treatment in diabetes.

            Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1alpha diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity. We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1alpha mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance. Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4.7 vs 0.9 mmol/L, p=0.0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0.002). Patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups. The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1alpha diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.
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              Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.

              Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the commonest cause of MODY. Individual patients with HNF-1alpha mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1alpha mutations that show marked hypersensitivity to sulphonylureas. In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. HNF-1alpha MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1alpha MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                21 March 2022
                : 2022
                : 21-0118
                [1 ]Department of Pediatrics , Endocrinology and Diabetes, Washington University School of Medicine, St. Louis, Missouri, USA
                [2 ]Saint Louis University School of Medicine , St. Louis, Missouri, USA
                Author notes
                Correspondence should be addressed to S I Stone; Email: sstone@ 123456wustl.edu

                *Current affiliation: Saint Louis University School of Medicine, St.Louis, Missouri, USA.

                Author information
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                : 26 January 2022
                : 21 March 2022
                Adolescent/young adult
                United States
                Insight into Disease Pathogenesis or Mechanism of Therapy
                Insight into Disease Pathogenesis or Mechanism of Therapy

                adolescent/young adult,male,female,white,united states,pancreas,diabetes,insight into disease pathogenesis or mechanism of therapy,april,2022


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