Clinical and Etiologic Heterogeneity of Idiopathic Diabetes Mellitus

Fajans, Stefan S.; Cloutier, M. C.; Crowther, R.

doi:10.2337/diab.27.11.1112

Cited by 149 publications

(78 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Almost 30 years ago Burkeholder et al (12) described significant nonfasting OGTT abnormalities in 25 children after testing 138 asymptomatic siblings of type 1 diabetic patients, of whom only 2 subsequently developed overt diabetes. Fajans et al (13,14) mentioned that some patients manifest diabetes only by their postprandial glucose value. Several authors noted that abnormalities in postprandial glucose tolerance (chemical diabetes) were often associated with normal or elevated insulin values.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Manifested Solely by 2-h Oral Glucose Tolerance Test Criteria

Greenbaum

Cuthbertson²,

Krischer³

2001

Diabetes

View full text Add to dashboard Cite

The clinical presentation of type 1 diabetes usually involves symptoms such as polyuria and polydipsia. However, investigators in the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) have detected a group of subjects with type 1 diabetes who have a different phenotype. These subjects are asymptomatic, have normal (<6.1 mmol/l) (group A) or impaired (6.1-<7.0 mmol/l) (group B) fasting glucose, but have 2-h glucose values >11.1 mmol/l on their oral glucose tolerance tests (OGTT). Of the 585 OGTTs performed on islet cell antibody (ICA)-positive relatives with insulin autoantibodies (IAA) or low first-phase insulin response (FPIR), normal glucose tolerance (NGT) was found in 427 subjects; impaired glucose tolerance (IGT) was found in 87 subjects, and diabetes was found by 2-h OGTT criteria alone in 61 subjects. Despite marked differences in 2-h glucose values (NGT 5.8 ± 1.1 mmol/l, IGT 8.9 ± 0.9 mmol/l, and group A 13.5 ± 2.5 mmol/l), there were no significant differences in fasting glucose values among NGT (4.8 ± 0.5 mmol/l), IGT (5.03 ± 0.5 mmol/l), and group A (4.99 ± 0.7 mmol/l) categories. Mean FPIR was higher in subjects with NGT compared with subjects with IGT and subjects diagnosed by 2-h OGTT criteria alone. However, the correlation between FPIR and 2-h glucose value was low (r 2 = 0.14). Multivariate analysis demonstrated that additional independent variables provide smaller contributions to the 2-h glucose value. In conclusion, there are asymptomatic type 1 diabetic subjects whose diabetes was diagnosed by the 2-h criteria on OGTT alone. Despite the importance of ␤-cell dysfunction in the pathogenesis of type 1 diabetes, factors other than impaired FPIR must also contribute to postprandial glucose tolerance in these subjects. Diabetes 50:470-476, 2001

show abstract

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Manifested Solely by 2-h Oral Glucose Tolerance Test Criteria

Greenbaum

Cuthbertson²,

Krischer³

2001

Diabetes

View full text Add to dashboard Cite

show abstract

“…Our aim was to compare the findings in the European cohort with the prevalence of macrosomia and neonatal hypoglycaemia in a single, large six-generation MODY1 pedigree with a Q268X mutation: the RW pedigree from Michigan. This pedigree has been followed prospectively by one of us (S. S. Fajans) since 1958 [3][4][5][6][7].…”

mentioning

confidence: 99%

Macrosomia and neonatal hypoglycaemia in RW pedigree subjects with a mutation (Q268X) in the gene encoding hepatocyte nuclear factor 4α (HNF4A)

Fajans

Bell

2007

Diabetologia

View full text Add to dashboard Cite

To the Editor: In a recent publication, Pearson et al. [1] reported on a previously unrecognised feature of the natural history of the type 1 form of maturity onset diabetes of the young (MODY1), which is caused by mutations in the gene encoding hepatocyte nuclear factor 4α (HNF4A). In a comparison of 54 mutation carriers (from 15 European pedigrees and with 12 different mutations) with their unaffected family members, they found a significant increase in median birthweight (790 g) with a 56% prevalence of macrosomia compared with 13% in family members without mutations. Macrosomia was inherited from either mother or father (64 and 46% of total cases, respectively). Transient neonatal hypoglycaemia was reported in eight of 54 neonates, three of whom had documented hyperinsulinaemia as infants. Similar observations were made in a mouse model with a beta cell-specific Hnf4a deletion [1].Since only 50-60% of neonates had macrosomia [1], phenotypic heterogeneity resulting from the study of subjects with 12 different mutations was considered possible, as has been reported for plasma apolipoprotein concentrations in MODY1 pedigrees with different mutations [2]. Our aim was to compare the findings in the European cohort with the prevalence of macrosomia and neonatal hypoglycaemia in a single, large six-generation MODY1 pedigree with a Q268X mutation: the RW pedigree from Michigan. This pedigree has been followed prospectively by one of us (S. S. Fajans) since 1958 [3][4][5][6][7].Birthweight and genotype were available for 34 mutation carriers and 52 family members without the mutation. Birthweight and history of neonatal hypoglycaemia were obtained by parental recall, supported by data in baby books for some. Informed consent was obtained from all participants and the study was approved by the Institutional Review Board of The University of Michigan. Birthweight was increased by a median of 751 g (mean of 704 g) in mutation carriers as compared with family members without the mutation (p<0.0001). As in the report by Pearson et al., macrosomia was defined as a birthweight exceeding 4,000 g, but we used actual birthweights rather than birthweights corrected for sex and gestational age. Among neonates, macrosomia occurred in 59% (20/34) of mutation carriers compared with 8% (4/52) of those without a mutation (p<0.0001). The prevalence of macrosomia was 68% (13/19) if the mutation was inherited from the mother (p=0.0001) and 47% (7/15) if inherited from the father (p<0.01). The high prevalence of macrosomia in the offspring of fathers with the mutation excludes an effect mediated by maternal hypoglycaemia. In the 52 neonates without the mutation, the rates were 9% (3/32) for offspring of an affected mother and 5% (1/20) for an affected father. There was no extreme macrosomia (birthweight exceeding 5,000 g). As several macrosomic neonates were delivered Diabetologia

show abstract

“…For the glyoxalase (GLO) locus there is a slight but nonsignificant increase in the frequency bf the GLO 2 allele, but a significant disturbance in the distribution of the GLO phenotypes for type 2 patients. These results for the GLO alleles may be due to stratification in our series of type 2 patients.…”

mentioning

confidence: 99%

Genetic Susceptibility to Diabetes Mellitus: the Distribution of Properdin Factor B (Bf) and Glyoxalase (GLO) Phenotypes

et al. 1979

View full text Add to dashboard Cite

SUMMARYThe distribution of phenotypes controlled by two loci on chromosome 6 has been studied in a series of 239 patients with type 1 (insulin-dependent) and 297 patients with type 2 (non-insulin-dependent) diabetes mellitus. At the properdin factor B (Bf) locus there is a significant increase in the frequency of the Bf s1 and Bf n alleles for type 1 patients, and the combined increase in frequency of Bf s^ and Bf F1 in those patients is highly significant. The relative risk for F1 is 6.2 and for F1 and S1 combined is 5.3. These results confirm the association with F1 reported recently by Raum and co-workers in Boston. The two rare alleles Bf s1 and Bf F1 are in significant negative disequilibrium with HLA B8.For the glyoxalase (GLO) locus there is a slight but nonsignificant increase in the frequency bf the GLO 2 allele, but a significant disturbance in the distribution of the GLO phenotypes for type 2 patients. These results for the GLO alleles may be due to stratification in our series of type 2 patients. Further studies are in progress to test this hypothesis. DIABETES 28:949-951, October 1979. . R enewed attention has been given recently to the role of genetic factors in susceptibility to diabetes mellitus, 1 " 4 and this has received added impetus from the studies of the distribution of human leucocyte antigens (HLA) in diabetic patients. Several surveys 5 " 9 have shown, a significant increase in some antigens, particularly HLA B8 and BW15 for Caucasian patients with type 1 (juvenile or insulin-dependent) diabetes mellitus,

show abstract

Clinical and Etiologic Heterogeneity of Idiopathic Diabetes Mellitus

Cited by 149 publications

References 16 publications

Type 1 Diabetes Manifested Solely by 2-h Oral Glucose Tolerance Test Criteria

Type 1 Diabetes Manifested Solely by 2-h Oral Glucose Tolerance Test Criteria

Macrosomia and neonatal hypoglycaemia in RW pedigree subjects with a mutation (Q268X) in the gene encoding hepatocyte nuclear factor 4α (HNF4A)

Genetic Susceptibility to Diabetes Mellitus: the Distribution of Properdin Factor B (Bf) and Glyoxalase (GLO) Phenotypes

Contact Info

Product

Resources

About