Maturity-Onset Diabetes of the Young (MODY): Genetic and Clinical Characteristics

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Abstract

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of familial diabetes mellitus characterized by early onset, autosomal dominant inheritance and primary defects of insulin secretion. Mutations in six genes cause most of the MODY cases. These genes encode the enzyme glucokinase and the transcription factors hepatocyte nuclear factor 4α, hepatocyte nuclear factor 1α, insulin promoter factor-1, hepatocyte nuclear factor 1β and neuroD1. Additional MODY genes remain to be identified. The study of families with MODY has shown that the different MODY subtypes present different metabolic and clinical profiles.

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The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.

A T Hattersley, J. E. Tooke (1999)

Low birthweight is associated with insulin resistance, hypertension, coronary-artery disease, and non-insulin-dependent diabetes (NIDDM). A suggested explanation for this association is intrauterine programming in response to maternal malnutrition. We propose, however, that genetically determined insulin resistance results in impaired insulin-mediated growth in the fetus as well as insulin resistance in adult life. Low birthweight, measures of insulin resistance in life, and ultimately glucose intolerance, diabetes, and hypertension could all be phenotypes of the same insulin-resistant genotype. There is evidence to support this hypothesis. Insulin secreted by the fetal pancreas in response to maternal glucose concentrations is a key growth factor. Monogenic diseases that impair sensing of glucose, lower insulin secretion, or increase insulin resistance are associated with impaired fetal growth. Polygenic influences resulting in insulin resistance in the normal population are therefore likely to result in lower birthweight. Abnormal vascular development during fetal life and early childhood, as a result of genetic insulin resistance, could also explain the increased risk of hypertension and vascular disease. The predisposition to NIDDM and vascular disease is likely to be the result of both genetic and fetal environmental factors.

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Cloning and characterization of the thyroid iodide transporter.

J-G Dai, N Carrasco, O Levy (1996)

Iodide (I-) is an essential constituent of the thyroid hormones T3 and T4, and is accumulated by the thyroid. The transport of iodide, the first step in thyroid hormogenesis, is catalysed by the Na+/I- symporter, an intrinsic membrane protein that is crucial for the evaluation, diagnosis and treatment of thyroid disorders. Although several other important thyroid proteins involved in hormogenesis have been characterized, the Na+/I- symporter has not. Here we report the isolation of a complementary DNA clone that encodes this symporter, as a result of functional screening of a cDNA library from a rat thyroid-derived cell line (FRTL-5) in Xenopus laevis oocytes. Oocyte microinjection of an RNA transcript made in vitro from this cDNA clone elicited a more than 700-fold increase in perchlorate-sensitive Na+/I- symport activity over background. To our knowledge, this is the first iodide-transporting molecule to have its cDNA cloned, providing a missing link in the thyroid hormone biosynthetic pathway.

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Mutations in the glucokinase gene of the fetus result in reduced birth weight.

E Ballantyne, S Ellard, Alan R. Harvey … (1998)

Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood. It has been proposed that this association results from fetal programming in response to the intrauterine environment. An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P=0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P=0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISBN: 978-3-8055-7415-0

ISBN: 978-3-318-00844-9

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2002

Publication date (Print): 2002

Publication date (Electronic): 17 November 2004

Volume: 57

Issue: Suppl 1

Pages: 29-33

Affiliations

^aINSERM U-342, Hôpital Saint-Vincent-de-Paul, and ^bUnité de Diabétologie de l’Enfant, Hôpital Necker – Enfants Malades, Paris, France

Article

Publisher ID: 53309 Other ID: Horm Res 2002;57(suppl 1):29–33

DOI: 10.1159/000053309

PubMed ID: 11979019

SO-VID: 744aa322-2c7a-4759-93cf-793928e76f63

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Maturity-Onset Diabetes of the Young (MODY): Genetic and Clinical Characteristics

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Karger: Endocrinology

Most cited references 10

The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.

Cloning and characterization of the thyroid iodide transporter.

Mutations in the glucokinase gene of the fetus result in reduced birth weight.

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