The genetic abnormality in the beta cell determines the response to an oral glucose load

Stride, Amanda; Vaxillaire, Martine; Tuomi, Tiinamaija; Barbetti, Fabrizio; Njolstad, PR; Hansen, Torben; Costa, Andréa Miúra da; Conget, Ignacio; Pedersen, Oluf; Søvik, Oddmund; Lorini, Renata; Groop, Leif; Froguel, Philippe; Hattersley, Andrew T.

doi:10.1007/s00125-001-0770-9

Cited by 237 publications

(261 citation statements)

References 17 publications

Supporting

Mentioning

238

Contrasting

Unclassified

Order By: Relevance

“…In summary, these data indicate that the OGTT profile can vary within a MODY2 family, with some members having a typical profile [9] and others having a profile very similar to (at 2 h) or even higher (at 1 and 1.5 h) than those observed in the HNF4A/MODY1 or HNF1A/MODY3 subjects with similarly elevated fasting plasma glucose concentrations. Although the characteristic low OGTT profile is a good predictor of MODY2 [9], a higher profile in any individual subject may not predict the underlying genetic cause of MODY (MODY2 vs MODY1 or MODY3). However, a family history of the diabetic phenotype, including OGTT profiles and the nature of complications, can be useful in predicting the type of MODY before genetic testing.…”

mentioning

confidence: 64%

“…1), i.e. a rapid decline in plasma glucose from peak levels to near-fasting levels at 2 h, although a few subjects had considerably higher plasma glucose levels during the OGTT [9]. The other three members of the G family (ages 14, 49 and 72 years) had OGTT profiles that were considerably higher, particularly at the 1.5 and 2 h times of the test (MODY2 group 2; Fig.…”

mentioning

confidence: 93%

“…The hyperglycaemia of HNF4A/MODY1 and HNF1A/MODY3 is progressive in severity over years and decades, while MODY2 shows very little progression over decades [9,10]. The natural history of MODY1 and MODY3 may vary in different subjects: some are able to be treated with oral agents for many decades, but approximately 35% become insulinrequiring for the control of hyperglycaemia.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Fajans

Bell

2006

Diabetologia

View full text Add to dashboard Cite

Contrary to currently held views [1], different mutations within the same MODY gene may be associated with differences in phenotype in diabetic as well as non-diabetic carrier subjects. This is illustrated by studies of apolipoproteins in different MODY1 pedigrees with various mutations of the gene encoding hepatocyte nuclear factor 4α (HNF4A). The mean plasma triglyceride concentration was significantly lower in 18 subjects (mean BMI 24.0) of the Michigan RW pedigree with the Q268X mutation (mean 0.80 mmol/l) [2] and in six subjects (mean BMI 24.0) from a Swedish family with the K99fsdelAA mutation (mean 0.64 mmol/l) [3] compared with 1.39 and 1.36 mmol/l, respectively, in control groups matched for BMI. The 18 RW subjects also had significantly lower lipoprotein(a) concentrations (mean 0.31 mmol/l) compared with the 24 control subjects (1.16 mmol/l). However, there were no significant differences in triglyceride or lipoprotein(a) concentrations between carriers and controls in 42 subjects (mean BMI 25.3) from 11 families with a variety of HNF4A mutations in a large European collection [4], although six subjects (mean BMI 25.2) with the R154X mutations in another study had elevated lipoprotein(a) levels [5]. Various other apolipoprotein fractions (AI, AII, CIII, total HDL-cholesterol) have been reported to be significantly lower in subjects with various HNF4A mutations [2,4].Different mutations in the gene encoding glucokinase (GCK/MODY2) have also been associated with differences in apolipoprotein levels. In 15 German MODY2 carriers (A232D mutation, 12 subjects; V154fsdelTG mutation, three subjects) (mean BMI 24.4), the mean triglyceride concentration was 0.84 mmol/l [6]. Two non-carrier subjects of the A232D pedigree had triglyceride levels of 1.17 and 1.25 mmol/l, suggesting that triglyceride levels may be lower in subjects with these two GCK mutations. The triglyceride level (mean 0.84 mmol/l) in the 15 MODY2 carriers is similar to that observed in 18 carriers of the RW/MODY1 pedigree (mean 0.80 mmol/l) [2]. In contrast, the triglyceride concentrations were normal in a very large series of primarily French MODY2 patients (mean BMI 22.0) [7]. We have recently studied a fourgeneration family (G pedigree) with a new GCK mutation, Leu 184 Pro (L184P). This pedigree includes affected individuals in three generations (ages 5-72 years). All are lean (mean BMI 21.3). In these six members, the mean triglyceride concentration was 0.68 mmol/l and the mean lipoprotein(a) concentration was 0.13 mmol/l, values that are lower than those in the RW/MODY1 pedigree. While the number of affected members in these various pedigrees is small, the results highlight the heterogeneity in apolipoprotein phenotypes seen in subjects with various HNF4A and GCK mutations. The variability could be due, at least in part, to different effects of the various mutations in each of these MODY genes on lipoprotein synthesis and metabolism but also to other genetic and environmental factors. Studies of larger numbers of pedigrees may determine if...

show abstract

mentioning

confidence: 64%

mentioning

confidence: 93%

mentioning

confidence: 99%

See 1 more Smart Citation

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Fajans

Bell

2006

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Owing to variability in measuring FBG, B2% of patients with GCK MODY have a FBG o5.5 mmol/l but on repeat testing it will be 45.5 mmol/l. 31 The diabetes in HNF1A and HNF4A MODY is progressive and the penetrance increases with age; for HNF1A mutations, it is approximately 63% by age 25 years, 93.6% by age 50 years and 98.7% by age 75 years. 32 Patients can therefore have the mutation but be clinically unaffected at a young age, or have biochemical evidence of abnormal glucose homeostasis but be clinically asymptomatic.…”

Section: Clinical Specificity (Proportion Of Negative Tests If the DImentioning

confidence: 99%

“…Patients with HNF1A and HNF4A mutations can have FBG within the non-diabetic range, but have oral glucose tolerance test results diagnostic for diabetes. 31 Diabetic family members of a proband with MODY may not inherit the familial mutation, and their diabetes is likely to have a different aetiology (typically type 1 or type 2 diabetes).…”

Section: Clinical Specificity (Proportion Of Negative Tests If the DImentioning

confidence: 99%

Clinical utility gene card for: Maturity-onset diabetes of the young

et al. 2014

View full text Add to dashboard Cite

Prevalence of Vascular Complications Among Patients With Glucokinase Mutations and Prolonged, Mild Hyperglycemia

Steele

Shields

Wensley

et al. 2014

JAMA

266

208

View full text Add to dashboard Cite

The genetic abnormality in the beta cell determines the response to an oral glucose load

Cited by 237 publications

References 17 publications

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Clinical utility gene card for: Maturity-onset diabetes of the young

Prevalence of Vascular Complications Among Patients With Glucokinase Mutations and Prolonged, Mild Hyperglycemia

Contact Info

Product

Resources

About