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At least 19 recordsLinked to original sources
PubMed1989

Maturity-onset diabetes of the young (MODY).

This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes.

Adolescent↗
PubMed1985

Heterogeneity within type II and MODY diabetes.

The heterogeneity within Type II diabetes (NIDDM) and within Maturity-Onset type Diabetes of Young people (MODY), a subset of NIDDM which is inherited in an autosomal dominant fashion, is discussed. Aspects of the definition and phenotypic expression of MODY are reviewed. Within NIDDM there are differences in patterns of inheritance between subgroups. HLA antigen associations are not found in most NIDDM populations but exist in three specific population groups with Type II diabetes. Within NIDDM and within MODY there are differences in the magnitude of insulin responses to glucose, differences in target tissue responsiveness to insulin in vivo, and differences in receptor and post-receptor effects of insulin. Structurally abnormal variant and biologically defective insulin molecules have been found in some Type II diabetic patients and in members of certain MODY families. The presence or absence of obesity may mark heterogeneous groups of Type II diabetic patients, in addition to the importance of obesity in uncovering an insulin secretory defect by causing insulin resistance. There is heterogeneity in susceptibility to vascular disease within NIDDM and MODY. The natural history of carbohydrate metabolism and of insulin secretory responses to glucose in early Type I diabetes and in MODY with low insulin secretory responses are illustrated and similarities and dissimilarities compared and contrasted. Failure to recognize young patients with MODY may contribute to incorrect diagnosis, management, and assignment of prognosis of this form of diabetes in the young by many practicing physicians. The recognition that Type I or insulin-dependent diabetes (IDDM) and Type II or noninsulin-dependent (NIDDM) differ from each other not only phenotypically but also in etiology and pathogenesis led the National Diabetes Data Group (NDDG) to devise the present nomenclature and classification of diabetes mellitus. These were adopted by the World Health Organization. As suggested by the NDDG report, the classification should be reexamined periodically to reflect improved understanding of the disease, to stimulate further research, and to be of help to practicing physicians.

Adult↗
PubMed1990

Scope and heterogeneous nature of MODY.

This review summarizes aspects of the phenotypic expression, natural history, recognition, pathogenesis, and heterogeneous nature of maturity-onset diabetes of the young (MODY), which is inherited in an autosomal-dominant pattern. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among White pedigrees. In MODY patients with low insulin responses, there are delayed and decreased insulin and C-peptide secretory responses to glucose from childhood or adolescence even before glucose intolerance appears, which may represent the basic genetic defect. When followed for decades, nondiabetic siblings have normal insulin responses. The fasting hyperglycemia of some MODY patients has been treated successfully with sulfonylureas for up to 30 yr. In a few patients, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they resemble those of early insulin-dependent diabetes mellitus. The progression of the insulin secretory defect over time distinguishes between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose, despite glucose intolerance and fasting hyperglycemia similar to that seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta-cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, a structurally abnormal mutant insulin molecule that is biologically ineffective is secreted. No associations have been found between specific HLA antigens and MODY in White, Black, and Asian pedigrees. Linkage studies of the insulin gene, insulin-receptor gene, erythrocyte/HepG2 glucose-transporter locus, and apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional non-insulin-dependent diabetes mellitus. Because of autosomal-dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in non-insulin-dependent diabetes mellitus, including the use of genetic linkage strategies to identify diabetogenic genes.

Adult↗
PubMed1992

Linkage analysis of maturity-onset diabetes of the young (MODY): genetic heterogeneity and nonpenetrance.

We have analyzed the inheritance of maturity-onset diabetes of the young (MODY) on chromosome 20 in a large multigeneration family, the R.-W. family, and in two other MODY families. Of the four branches of the R.-W. pedigree which have been studied, two have documented early onset of non-insulin-dependent diabetes mellitus (NIDDM), while there is no evidence of early onset in the other two branches. The early-onset branches have apparently inherited the same D20S16 allele from the affected parent, while another D20S16 allele was inherited in the two branches without evidence of early onset. A test for homogeneity, the M-test, using the results of two-point linkage analysis with D20S16 indicates heterogeneity between early- and late-onset branches of the R.-W. family (P less than or equal to .014). In addition, analysis strongly suggests that MODY as expressed in the EDI and WIS families is unlinked to loci on chromosome 20 (P less than or equal to .018-.004). Comparable results are seen when the data are analyzed by the HOMOG program. Three polymorphic loci-D20S16, D20S17, and ADA--show no recombination with the MODY locus when two-point linkage analysis is used in the early-onset branches of the family. The multipoint lod score in the early-onset branches of the R.-W. family is 10.16, with the most likely location being between D20S4 and D20S17. Multipoint linkage analysis using the CHROMPICS option of the program CRI-MAP has been used to follow inheritance of the MODY disease locus. This analysis has identified two cases of possible nonpenetrance in the early-onset branches of the family (odds of at least 156:1), as determined by the appearance of apparent isolated double crossovers at the MODY locus in these unaffected individuals.

Adolescent↗
PubMed1988

Pregnancy outcome in maturity onset diabetes at young age (MODY).

Diabetes mellitus is not a single disease, but rather a syndrome comprised of a variety of diseases characterized by hyperglycaemia. Indeed it has a heterogeneous nature. Maturity Onset Diabetes of the Young or MODY is an unusual, mild type of hyperglycaemia, which develops in young women, (below the age of 25), who do not require insulin. This study describes 10 pregnancies in MODY women, who are compared to a group of patients with insulin-dependent diabetes mellitus (IDDM), a group with gestational diabetes, and a control group of normal, healthy pregnant women. Our group of pregnant MODY patients proved to have an intermediate form of diabetes, more severe than gestational diabetes and yet not as severe as insulin-dependent diabetes mellitus. Mean duration of diabetes was shorter and mean daily insulin requirement (during pregnancy) was lower among MODY patients in comparison to IDDM gestants. Moreover the frequency of maternal complications and Caesarean deliveries in MODY patients were lower than in the IDDM group, but higher when compared to the gestational diabetes group.

Adolescent↗
PubMed1989

[MODY type diabetes mellitus in children and adolescents].

Nineteen diabetics aged 9 to 18 years with the MODY type were investigated, incl. their families, by the oGTT. Diabetes in the parents was nine times and in siblings four times more frequent than in families of adolescents with IDDM. In parents the manifest form predominated, in siblings PGT. Vertical transmission of diabetes in three consecutive generations was found only in the MODY type (in 35%). Diabetes with the MODY type and their diabetic siblings did not differ significantly as to their mild glucose intolerance (blood sugar level up to 13 mmol/l), and their mild diabetic phenotypes did not differ either. Similarly diabetics with IDDM and their diabetic siblings did not differ substantially as to their severe glucose intolerance (blood sugar level up to 21 mmol/l), and their severe diabetic phenotypes did not differ either. IRI levels revealed five times a hyperinsulinaemic and three times a normal insulinaemic response. Obese diabetics were treated with a reducing diet and physical activity. To non-obese diabetics, if the above procedure was not sufficiently successful, sulphonylurea preparation were also administered. During check-up examinations fasting values and values three hours after a meal lower than 6.1 mmol/l were required. In the course of a four- to ten-year follow up it did not change. Existence of the MODY type already macroangiopathic complications developed; in one diabetic the glucose tolerance improved, in the remainder it did not change. Existence of the MODY type already in adolescents justifies early detection in families with a cumulated incidence of NIDDM and prophylactic procedures ensuring euglycaemia in confirmed diabetics.

Adolescent↗
PubMed1988

Insulin action and insulin secretion in identical twins with MODY. Evidence for defects in both insulin action and secretion.

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a beta-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMedDate not supplied

High prevalence of maturity-onset diabetes of the young (MODY) among Indians.

This article describes the high prevalence of maturity-onset diabetes in the young (MODY) in an Indian clinic population of diabetic patients. MODY appears to be more common among Indians than among Caucasians. Only 27% of MODY patients had definite autosomal-dominant inheritance. In 73% the mode of inheritance was not definite. Microvascular complications were common and macrovascular complications rare. The high prevalence of MODY in this diabetes clinic might suggest an ethnic variation in diabetes.

Adult↗
PubMed1988

One Japanese MODY family with severe and progressive microangiopathies.

Recently we investigated maturity-onset diabetes of the young (MODY) with severe and progressive microangiopathies in one Japanese family. The proband was a female who was diagnosed as having diabetes when she was 11 years old, and was controlled without insulin for 9 years. She is now 30 years old and has been suffering from proliferative retinopathy since the age of 20. Her maternal grandfather, mother, uncle, and younger sister are also diabetic with severe microangiopathies. MODY is a concept which was first put forward by Tattersall and Fajans in 1975. It was defined as a form of diabetes diagnosed before the age of 25 years, controlled without insulin for more than 2 years and demonstrating dominant heredity over more than three generations. Most Western papers have reported few microangiopathies in the MODY patient, but our findings run counter to this description.

Adult↗
PubMed1989

Proliferative diabetic retinopathy in a patient with maturity-onset diabetes of the young (MODY).

Maturity-onset diabetes of the young (MODY) has been described as being characteristically free from severe complications. This has led to speculation that the type of diabetes may be important in the pathogenesis of complications in diabetes. We report a case of classical MODY in which severe proliferative diabetic retinopathy developed. The retinopathy was detected shortly after the diagnosis of diabetes was made when the patient was 32 years old, and did not progress subsequently. No further complications developed during the subsequent 29 years in which normal postprandial plasma glucose levels were maintained with chlorpropamide therapy (mean 4.7, range 4.1-6.0 mmol I-1). This case demonstrates that severe retinopathy can occur in MODY and we suggest that in this patient there may have been a period of hyperglycaemia prior to diagnosis which was sufficient to lead to the microvascular complication.

Adolescent↗
PubMed2026

Progressive HNF1A-MODY pathophysiology revealed by a translational mouse model.

HNF1A-MODY, the most common monogenic diabetes, exhibits progressive β cell dysfunction, but existing mouse models fail to recapitulate human disease progression, limiting understanding of pathogenic mechanisms. We developed mice with heterozygous deletion of the Hnf1a transactivation domain (Hnf1a+/Δe4-10) to model human HNF1A haploinsufficiency, conducted cross-sectional metabolic characterization, and validated our findings in HNF1A-deficient human islets. Unlike previous models, Hnf1a+/Δe4-10 mice successfully recapitulated temporal HNF1A-MODY progression. Male mice developed sequential pathophysiology: early insulin resistance in young adults (7 weeks), followed by testosterone deficiency and fasting hyperglycemia in adult mice (10 weeks). Glucose intolerance emerged in middle-aged mice (30 weeks), progressing to multi-organ dysfunction in aged mice (44-70 weeks), characterized by elevated hepatic gluconeogenesis, impaired renal glucose handling, and hepatic steatosis/fibrosis. This dual pathophysiology involving β cell dysfunction and peripheral insulin resistance was associated with dysregulated hormone secretion from both α and β cells in aged mice (40-70 weeks). Human islet studies with HNF1A knockdown confirmed translational relevance, demonstrating reduced SGLT2 protein expression and inappropriate glucagon and insulin secretion. This work established a physiologically relevant HNF1A-MODY model, identified early insulin resistance as a key mechanism triggering hormonal dysfunction, and revealed HNF1A's role in multi-organ pathophysiology beyond traditional β cell dysfunction.

Animals↗
PubMedDate not supplied

C-Peptide responses to glucose load in maturity-onset diabetes of the young (MODY).

Pancreatic beta cell responses were measured in obese and nonobese maturity-onset diabetes of the young (MODY) patients by estimating serum immunoreactive insulin (IRI) and C-peptide (CP) during oral glucose tolerance testing (OGTT). The serum CP responses were generally low in MODY patients and more pronounced in obese patients. The IRI responses were heterogenous; some patients had normal and others low responses. It was observed that in several patients there was a relatively higher IRI concentration in comparison with the CP values, as indicated by low CP and normal IRI values. This is suggestive of altered metabolic fates of insulin and CP in the MODY patients.

Adult↗
PubMed1992

A microsatellite polymorphism associated with the PLC1 (phospholipase C) locus: identification, mapping, and linkage to the MODY locus on chromosome 20.

A highly polymorphic (dC-dA)n.(dG-dT)n dinucleotide repeat at the PLC1 locus on human chromosome 20 has been identified. Primers flanking the dinucleotide repeat were used for PCR amplification of the repeat region in 37 informative kindreds from the Centre d'Etude du Polymorphisme Humain. Two-point linkage analysis indicates that PLC1 is closely linked to several chromosome 20 markers, including D20S16 (Zmax = 41.25; theta = 0.07), D20S17 (Zmax = 42.81; theta = 0.09), and ADA (Zmax = 57.24; theta = 0.05). Multipoint linkage analysis places the PLC1 locus between D20S18 and D20S17, 11.2 and 6.6 cM, respectively, from these loci (sex-averaged distances). In addition, the PLC1 gene shows linkage to the maturity-onset diabetes of the young (MODY) locus on chromosome 20 with a lod score of 4.57 at theta = 0.089.

Base Sequence↗
PubMed1989

[Insulin and peptide C secretion after food ingestion and the interaction of insulin with its erythrocyte receptor in a family with MODY type diabetes mellitus].

In 12 members of a family with MODY, insulin and C-peptide release after intake of a test breakfast was measured as well as binding of insulin to its erythrocyte receptor. According to serum glucose concentrations, subjects were classified into: diabetic, carbohydrate intolerant, and normal subjects. The two diabetic patients had an insulin release pattern similar to that of non-insulin dependent diabetics. The two patients with carbohydrate intolerance presented hyperinsulinism either at base state and after stimulation. Of the eight normal subjects, three presented high concentrations of serum insulin either at base level and after stimulation; in the remaining five, base insulinemia was normal and the response after food intake was poor. Insulin binding to the receptor was decreased in diabetic patients and this anomaly was more evident in patients with carbohydrate intolerance. In the three patients with increased serum insulin concentration, no disturbances in insulin-receptor binding were detected; in the remaining five patients, insulin-receptor binding was significantly decreased. Our findings prove that these subjects present a disturbance of insulin release and an impairment of insulin-receptor binding with a predominance of one or the other alteration even before hyperglycemia is evident.

Adolescent↗