Genetic cause of hyperglycaemia and response to treatment in diabetes

Pearson, Ewan R.; Starkey, B.J.; Powell, Roy; Gribble, Fiona M.; Clark, Penny; Hattersley, Andrew T.

doi:10.1016/s0140-6736(03)14571-0

Cited by 523 publications

(419 citation statements)

References 31 publications

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“…The mechanism for the increased glycaemic response to sulfonylureas observed in HNF1A MODY, compared with Type 2 diabetes, is thought to be attributable to increased pancreatic insulin secretory response to sulfonylureas and increased sensitivity to the insulin released 1.…”

Section: Monogenic Diabetes Pregnancymentioning

confidence: 99%

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Management of sulfonylurea‐treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer

et al. 2017

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The optimum treatment for HNF1A/HNF4A maturity‐onset diabetes of the young and ATP‐sensitive potassium (KATP) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established that glibenclamide crosses the placenta and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A maturity‐onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per conception either transfer to insulin before conception (at the risk of a short‐term deterioration of glycaemic control) or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800‐g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post‐delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed.

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Section: Monogenic Diabetes Pregnancymentioning

confidence: 99%

“…The key difference in sulfonylurea treatment in neonatal diabetes is the high dose of glibenclamide required (0.45 mg/kg/day) 3 compared with the low doses in HNF1A/HNF4A MODY (<0.01 mg/kg/day) 1, 2 or typical doses in Type 2 diabetes (0.06–0.2 mg/kg/day) 32.…”

Section: Monogenic Diabetes Pregnancymentioning

confidence: 99%

Management of sulfonylurea‐treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer

et al. 2017

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“…This was especially dramatic for the severe neurological symptoms often associated with the disease. Patients with MODY3 (HNF-1 mutations) are supersensitive to treatment with sulfonylureas whereas they respond poorly to treatment with metformin (68). It has also recently been shown that individuals with the TCF7L2 risk genotype respond poorly to treatment with sulfonylureas, eventually as a consequence of their more severe impairment in beta-cell function (69).…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

122

114

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Compared to the successful probing of genetic causes of monogenic disorders, dissecting the genetics of complex polygenic diseases has until recently been a fairly slow and cumbersome process. With the introduction of whole genome wide association studies (WGAS) the situation dramatically changed in 2007. The results from several recent WGAS on type 2 diabetes (T2D) and obesity have identified at least eighteen genes consistently associated with T2D. Many of the genes implicate pancreatic beta-cell function in the pathogenesis of T2D whereas only one clearly associate with insulin resistance. The identified genes most likely merely represent the tip of the iceberg in the explanation behind T2D. Refined tools will have to provide a more complete picture of the genetic complexity of T2D over the next few years. In addition to common variants increasing susceptibility for the disease, rare variants with stronger effects, copy number variations, and epigenetic effects like DNA methylation and histone acetylation will become important. Nevertheless, today we are able for the first time to anticipate that the genetics of a complex disease like T2D really can be dissected. Key wordsgenetics, complex disease, monogenic, polygenic, linkage study, genome wide scan, association study, single nucleotide polymorphism, epigenetic, type 2 diabetes, obesity. Evidence that type 2 diabetes is inheritedThere is ample evidence that T2D has a strong genetic component. The concordance of T2D in monozygotic twins is approximately 70% compared with 20-30% in dizygotic twins (1,2). Given the age-dependent penetrance of the disease, it is clear that the longer the follow-up, the higher the concordance rate (2). T2D clusters in families. The life-time risk of developing the disease is about 40% in offspring of one parent with T2D (3), greater if the mother is affected (4), the risk approaching 70% if both parents have diabetes. Translated into a s-value, the recurrence risk for a sibling of an affected person divided by the risk for the general population, this means that a first-degree relative of a patient with type 2 diabetes has a 3-fold increased risk of developing the disease (5). Large ethnic differences in the prevalence of T2D have also been ascribed to a genetic component (6,7). The change in the environment towards a more affluent Western life style plays a key role in the epidemic increase in the prevalence of T2Dworldwide. This change has occurred during the last 50 years. Clearly, our genes have not changed during this period but this does not exclude an important role for genes in the rapid increase in T2D, since genes or gene variants explain how we respond to the environment. Page 4 of 25A c c e p t e d M a n u s c r i p t 4 Thrifty genotypes or phenotypes?A plausible explanation for the interaction between genes and environment comes from the thrifty gene hypothesis. Neel (8) proposed that individuals living in an environment with unstable food supply (as for hunters and nomads) would maximize their probabilit...

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“…Diagnosis may have implications for treatment such as the preferred use of sulphonylurea derivatives in HNF1A MODY or stopping insulin treatment in GCK MODY. 6 The diagnosis of GCK MODY is considered important in relation to pregnancy as it helps to understand the presence or absence of macrosomia and may direct therapeutic decisions. 5,7 A correct genetic diagnosis also has implications for anticipation of complications, as microvascular complications are much rarer in GCK than in HNF1A and HNF4A MODY.…”

Section: Introductionmentioning

confidence: 99%

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands

et al. 2014

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Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

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Genetic cause of hyperglycaemia and response to treatment in diabetes

Cited by 523 publications

References 31 publications

Management of sulfonylurea‐treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer

Management of sulfonylurea‐treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer

Genetic dissection of type 2 diabetes

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands

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