Clinical Diagnosis Of Maturity-onset Diabetes Of The Young Research Articles

Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. The presence of clinical features of MODY and negative results for three autoantibody markers of type 1 diabetes mellitus (T1DM) in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative T1DM. Twelve variants were classified as pathogenic/likely pathogenic (P/LP) while 12 were interpreted as variant of unknown significance. Nine of the P/LP variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All but one of the variants exhibited heterozygotic inheritance. The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes.

Evaluation of variants in maturity onset of diabetes young related genes in Balıkesir region

Aims: Maturity-onset diabetes of the young (MODY) is an early-onset, monogenic diabetes with an autosomal dominant inheritance pattern. Single gene mutations that cause dysfunction in pancreatic beta cells are responsible for MODY etiology. In this study, we investigated the genetic variants involved in the etiopathogenesis of MODY in our region.
 Methods: Between May 2018 and April 2023, 40 pediatric patients (n=25 females, n=15 males) with a clinical diagnosis of MODY were evaluated by targeted genome sequencing.
 Results: Among the 40 pediatric patients included in this study, variants in MODY-associated genes were detected in 21 patients (52.5%), eight (38.09%), of which were pathogenic (38.09%), five (23.8%) were probable pathogenic, and eight (38.09%), were of uncertain significance.
 Conclusion: In this study, genetic diagnostic yield (including pathogenic and likely pathogenic variants) was detected in 32.5% (13/40) patients with MODY using targeted genome sequencing analysis. This rate is consistent with other studies. However, unlike other similar studies, the MODY12 subtype was the second most frequent in our study. In addition, nine novel variants were reported, including ABCC8 (n=3), CEL (n=2), KLF11 (n=1), GCK (n=1), HNF1A (n=1), and HNF1B (n=1) genes. We have presented clinical findings to improve genotype-phenotype correlation in the literature for novel variants.

Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.

Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well-established. Participants were from the UK Biobank with whole-exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high-penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT-O (p < .05) and (2) lower than the maximum credible frequency in the general population. Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as 'consistent', 'inconclusive' and 'inconsistent' for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the 'consistent' genes had clinical presentations that were most consistent with MODY. In contrast, the 'inconclusive' and 'inconsistent' genes did not differ clinically from non-carriers in diabetes-related characteristics. Data from a large population-based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.

Метод секвенирования нового поколения в дифференциальной диагностике сахарного диабета у детей

In addition to type 1 and 2 diabetes mellitus (DM), endocrine disorders in children include hereditary forms of diabetes, such as maturity onset diabetes of the young (MODY). Since pathogenic mechanisms of chronic hyperglycemia in MODY are different from those in DM1 and DM2, it requires other therapeutic approaches. The diagnosis of MODY is confirmed by expensive molecular testing, such as next generation sequencing (NGS). Therefore, the strategy of choosing candidates for NGS is very important. Objective. To optimize the algorithm of choosing patients for NGS testing for DM type verification. Patients and methods. This study included 97 patients aged 1–18 years suspected of having MODY. We used NGS to confirm the diagnosis and identify polymorphisms in MODY-associated genes. Results. Fifty-three patients were found to have polymorphisms in MODY-associated genes, including GCK gene (MODY2) (n = 44), NHF1A gene (MODY3) (n = 8), and PAX4 gene (MODY9) (n = 1). Comparison of family histories of patients with MODY-associated polymorphisms and those in whom clinical diagnosis of MODY was not confirmed by NGS demonstrated significant differences: children with verified MODY were more likely to have first-degree relatives with some carbohydrate metabolism disorder (CMDs). Clinical, laboratory, and anthropometric parameters, as well as levels of insulin secretion and carbohydrate metabolism were similar in both groups. However, patients with non-confirmed MODY received insulin therapy more frequently than those with verified MODY as the majority of them were on a diet. Conclusion. NGS confirms the diagnosis of MODY in patients with different CMDs. A tailored approach should be used to choose patients for NGS to confirm MODY. Key words: monogenic diabetes mellitus in children, diabetes mellitus, next generation sequencing, GCK, HNF1A, MODY

Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY).

Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

MODY in Siberia – molecular genetics and clinical characteristics

The diagnosis of maturity onset diabetes of the young (MODY) has high clinical significance in young patients (no absolute need for exogenous insulin; normoglycaemia in most patients achieved by dieting or taking oral hypoglycaemic agents) and their relatives (high probability of first-degree relatives being carriers of mutations, which requires a thorough collection of family history and determination of the parameters of carbohydrate metabolism).&#x0D; Aim. This study aimed was to determine the clinical characteristics of different subtypes of MODY in a Siberian region.&#x0D; Materials and Methods. We performed an examination, biochemical and hormonal blood tests, ultrasound and molecular genetic testing of 20 patients with a clinical diagnosis of MODY.&#x0D; Results. Four subtypes of MODY were verified: MODY2 in 11 patients, MODY3 in two, MODY8 in one and MODY12 in two. Eleven patients (69%) exhibited no clinical manifestations of carbohydrate metabolism disorders, and one patient showed weight loss during early stage of the disease. Comorbidities included dyslipidemia, thyroid gland disorders and arterial hypertension. One patient (6%) exhibited diabetic nephropathy; two (13%), diabetic retinopathy and three (19%), peripheral neuropathy of lower legs. All patients achieved the target carbohydrate metabolism; the level of C-peptide was within the reference range.&#x0D; Conclusion. Four different subtypes of MODY (2, 3, 8, 12) were diagnosed in the present study, which differed in their clinical characteristics, presence of complications and treatment strategies. Our knowledge of monogenic forms of diabetes is expanding with the development in molecular genetics, but several aspects related to them require further study.

Diabetic vascular disease and maturity-onset diabetes of the young

Objectives: Vascular disease such as cardiovascular and cerebrovascular diseases, or retinopathy, nephropathy and neuropathy are common in diabetes. Maturity-onset diabetes of the young (MODY) describes a clinically heterogeneous group of familial diabetes characterized by monogenic, autosomal dominant inheritance that generally results from beta cell dysfunction. This study aims to assess the presence of vascular complications on Portuguese patients with a clinical diagnosis of MODY.

Studies of genetic variability of the hepatocyte nuclear factor-1α gene in an Indian maturity-onset diabetes of the young family.

Maturity-onset diabetes of the young (MODY), one of the specific types of diabetes mellitus, is a monogenetic disorder characterized by an autosomal dominant (AD) inheritance and β-cell dysfunction. To study an Indian family with clinical diagnosis of MODY and detect the genetic mutations in the aspect of molecular mechanism, seven blood samples were obtained from the diabetic patients of this pedigree and genomic DNA was extracted from peripheral leukocytes. The exon1, exon2 and exon4 of hepatocyte nuclear factor-1α (HNF-1α) gene were amplified by polymerase chain reaction. Then the products were sequenced and compared with standard sequences on gene bank. As a result, two mutations were detected in exon1. That was CTC → CTG (Leu → Leu) in codon17 and ATC → CTC (Ile → Leu) in codon27. I27L was speculated to have a close relationship with the glycometabolism and the pathogenesis of diabetes mellitus together with the putative novel mutation existed in this Indian pedigree. Meanwhile, one mutation of GGG → GGC (Gly → Gly) in codon288 of exon4 was detected in the proband. No mutations were found in exon2 but a G → T base substitution in the intron4 region among all seven samples was detected. It may have some potential effects on the onset of diabetes in this family, but we do not have any evidence right now. Although it requires further investigation on the function of mutations found in the intron region, our research may provide some clue for this issue and it deserves more attention.

Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.

Our study aims were to determine the frequency of MODY mutations (HNF1A, HNF4A, glucokinase) in a diverse population of youth with diabetes and to assess how well clinical features identify youth with maturity-onset diabetes of the young (MODY). The SEARCH for Diabetes in Youth study is a US multicenter, population-based study of youth with diabetes diagnosed at age younger than 20 years. We sequenced genomic DNA for mutations in the HNF1A, HNF4A, and glucokinase genes in 586 participants enrolled in SEARCH between 2001 and 2006. Selection criteria included diabetes autoantibody negativity and fasting C-peptide levels of 0.8 ng/mL or greater. We identified a mutation in one of three MODY genes in 47 participants, or 8.0% of the tested sample, for a prevalence of at least 1.2% in the pediatric diabetes population. Of these, only 3 had a clinical diagnosis of MODY, and the majority was treated with insulin. Compared with the MODY-negative group, MODY-positive participants had lower FCP levels (2.2 ± 1.4 vs 3.2 ± 2.1 ng/mL, P < .01) and fewer type 2 diabetes-like metabolic features. Parental history of diabetes did not significantly differ between the 2 groups. In this systematic study of MODY in a large pediatric US diabetes cohort, unselected by referral pattern or family history, MODY was usually misdiagnosed and incorrectly treated with insulin. Although many type 2 diabetes-like metabolic features were less common in the mutation-positive group, no single characteristic identified all patients with mutations. Clinicians should be alert to the possibility of MODY diagnosis, particularly in antibody-negative youth with diabetes.

Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young

Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem; there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR); single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.

Identification of HNF1A-MODY and HNF4A-MODY in Irish families: Phenotypic characteristics and therapeutic implications

Aim The prevalence of hepatocyte nuclear factor ( HNF)- 1A and HNF4A mutations, and the clinical implications following the genetic diagnosis of maturity-onset diabetes of the young (MODY) in the Irish population, remain unknown. The aim of this study was to establish the occurrence of HNF1A and HNF4A mutations in subjects classified clinically as MODY to identify novel mutations, and to determine the phenotypic features and response to therapy. Methods A total of 36 unrelated index cases with a clinical diagnosis of MODY were analyzed for HNF1A/HNF4A mutations. OGTT was performed to determine the degree of glucose tolerance and insulin secretory response. Also, 38 relatives underwent OGTT and were tested for the relevant known mutations. HNF1A-/HNF4A-MODY subjects were compared with nine HNF1A mutation-negative relatives and 20 type 2 diabetic (T2DM) patients. Results Seven different HNF1A mutations were identified in 11/36 (30.5%) index cases, two of which were novel (S352fsdelG and F426X), as well as two novel HNF4A mutations (M1? and R290C; 6%). Family screening revealed 20 subjects with HNF1A and seven with HNF4A mutations. Only 51.6% of HNF1A mutation carriers were diagnosed with diabetes by age 25 years; 11 of the mutation carriers were overweight and four were obese. Insulin secretory response to glucose was significantly lower in HNF1A-MODY subjects than in T2DM patients and HNF1A mutation-negative relatives ( P = 0.01). Therapeutic changes occurred in 48% of mutation carriers following genetic diagnosis. Conclusion There was an HNF1A-MODY pick-up rate of 30.5% and an HNF4A-MODY pick-up rate of 6% in Irish MODY families. Genetically confirmed MODY has significant therapeutic implications.

Identification of Novel Variants in the Hepatocyte Nuclear Factor-1α Gene in South Indian Patients with Maturity Onset Diabetes of Young

Mutations in the HNF 1A gene are the most common cause of maturity-onset diabetes of the young (MODY) in most populations. India currently has the largest number of people with diabetes in the world, and onset of type 2 diabetes occurs at a younger age with possible overlap with MODY. There are very few data on MODY mutations from India. The objective was to screen coding and promoter regions of HNF1A gene for mutations in unrelated South Indian subjects in whom a clinical diagnosis of MODY was made. This was an observational cross-sectional study. The study was conducted at a diabetes specialties centre in Chennai in southern India. Ninety-six unrelated south Indian subjects in whom clinical diagnosis of MODY was made were included in the study. The control population comprised of 57 unrelated nondiabetic subjects selected from the Chennai Urban Rural Epidemiology Study, a study conducted on a representative population (aged > or =20 yr) of Chennai. We identified nine novel variants comprising seven mutations (one novel mutation -538G>C at promoter region and six novel coding region mutations) and two polymorphisms in the HNF1A gene. Functional studies revealed reduced transcriptional activity of the HNF1A promoter for two promoter variants. We also observed cosegregation with diabetes of the Arg263His coding region mutation in eight members of one MODY family, whereas it was absent in nondiabetic subjects of this family. This study suggests that mutations in the HNF1A gene comprise about 9% of clinically diagnosed MODY subjects in southern India and a novel Arg263His mutation cosegregates with MODY in one family.

Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation inNEUROD1

The aim of the study was to search for mutations in the NEUROD1 and IPF-1 genes in patients with clinical characteristics of maturity-onset diabetes of the young (MODY) but with no mutations in the HNF-4A (MODY1), GCK (MODY2) and TCF1 (MODY3) genes. We studied 30 unrelated Czech probands with a clinical diagnosis of MODY (median age at testing, 18 yr; median age at the recognition of hyperglycaemia, 16 yr). The promoter, exons and exon/intron boundaries of the NEUROD1 and IPF-1 genes were examined by polymerase chain reaction-denaturing high performance liquid chromatography and direct sequencing. While no mutations were found in the IPF-1 gene, a novel H241Q substitution of NEUROD1 gene was identified in two unrelated families. In the first proband, the H241Q mutation led to early diagnosed (20 yr) hyperglycaemia followed by development of diabetic microvascular complications by the age of 32 yr. The second proband suffered from slowly progressing hyperglycaemia detected at the age of 30 yr. Affected members of both families were obese. The overall prevalence of the variant among the general population was 4 of 13 568 chromosomes. We report a novel disease-associated variant in NEUROD1 identified among a set of MODYX families. The variant seems to precipitate type-2-like diabetes in excessively obese individuals.

Mutations in GCK and HNF‐1α explain the majority of cases with clinical diagnosis of MODY in Spain

The aim of this study was to group patients with MODY (maturity-onset diabetes of the young) according to the genetic alterations underlying the disease and to investigate their clinical characteristics. Molecular analysis of GCK (MODY2), HNF-1alpha (MODY3), HNF-4alpha (MODY1) and HNF-1beta (MODY5) genes was performed by DNA sequencing in 95 unrelated index probands (47M/48F; mean age 9.9 +/- 5.2 years) with clinical diagnosis of MODY. After classification into MODY subtypes according to the genetic alterations, clinical characteristics were compared between the groups. Seventy-six families were shown to carry mutations in GCK (34 of them previously unreported), eight families presented HNF-1alpha mutations, and a large genomic rearrangement in HNF-1beta was found in a family. No alteration was found in HNF-4alpha. Thus, relative frequencies in the group studied were 80% MODY2, 8.5% MODY3 and 1% MODY5. Comparison of clinical parameters according to genetic status showed significant differences between MODY2 and MODY3 patients in age at diagnosis (9.4 +/- 5.4 years vs. 12.7 +/- 4.6 years), diagnosis (impaired glucose tolerance vs. diabetes), diagnostic test used (OGTT vs. fasting glucose), treatment (diet and exercise vs. insulin/oral antidiabetic agents) and birth weight (2.96 +/- 0.44 kg vs. 3.40 +/- 0.67 kg). Almost 90% of the MODY cases in the group studied are explained by mutations in the major genes GCK (MODY2) and HNF-1alpha(MODY3), although differences in the relative prevalence of each form could be partly due to patient referral bias (paediatric vs. adult). In general, patients with MODY2 were diagnosed at an earlier age in life than MODY3 patients and had a milder form of diabetes. Moreover, the majority of patients with MODY2 mutations were treated with diet whereas half of MODY3 patients received pharmacological treatment.

Half of Clinically Defined Maturity-Onset Diabetes of the Young Patients in Denmark Do Not Have Mutations inHNF4A,GCK, andTCF1

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of diabetes characterized by an autosomal dominant inheritance, an early clinical onset, and a primary defect in beta-cell function. The aims of the present study were to examine the prevalence and nature of mutations in the three common MODY genes, HNF4A, GCK, and TCF1, in Danish patients with a clinical diagnosis of MODY and to describe metabolic differences in probands with and without mutations in HNF4A, GCK, and TCF1. Seventy-eight unrelated subjects of Danish Caucasian origin (29 men, 49 women) and their 351 family members were examined. The promotor and coding regions including intron-exon boundaries of HNF4A, GCK, and TCF1 were examined by denaturing HPLC and/or direct sequencing. We identified 29 different mutations in 38 MODY families. Fifteen of the mutations were novel. The variants segregated with diabetes within the families, and none of the variants were found in 100 normal Danish chromosomes. Our findings suggest a relative prevalence of 3% of MODY1 (two different mutations in two families), 10% of MODY2 (seven in eight), and 36% of MODY3 (21 in 28) among Danish kindred clinically diagnosed as MODY. No significant differences in biochemical and anthropometric measurements were observed at baseline examinations. Forty-nine percent of the families carried mutations in the three examined MODY genes. Our findings highlight that unidentified MODY genes may play a central role for diabetes characterized by autosomal dominant transmission. Furthermore, baseline measurements of various anthropometric and biochemical variables are not appropriate markers of MODYX.

Genetic variation in the hepatocyte nuclear factor-3beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians.

Mutations in genes encoding hepatocyte nuclear factor (HNF) are responsible for three of the five subtypes of maturity-onset diabetes of the young (MODY). This observation and molecular studies indicate that the HNF network is required for normal function of pancreatic beta-cells. This suggests that transcription factors involved in this complex network are candidates for genetic defects in MODY. Because the HNF-3beta gene is implicated in this network, we screened it for mutations in 21 probands of French ancestry with clinical diagnosis of MODY and early-onset type 2 diabetes. All of the five known MODY genes, HNF-4alpha, glucokinase, HNF-1alpha, HNF-1beta, and IPF1, were previously excluded as being the cause of diabetes in these families. By direct sequencing, we identified two transitions, an A-to-G at position -213 and a C-to-T at position -63 in the promoter and exon 1, respectively, of the HNF-3beta gene. A G-to-C transversion at position +32 in the intron 1 and three transitions, C-to-T at position 291, A-to-G at position 837, and G-to-A at position 1188 in the exon 3, resulting in noncoding mutations Ala97Ala, Gly279Gly, and Gln396Gln, respectively, were also identified. The allele frequencies were not significantly different between a control group and MODY probands. Familial segregation studies and linkage analysis showed that genetic variation in the HNF-3beta gene is unlikely to be the cause of early-onset type 2 diabetes in these Caucasian families.

Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.

Maturity-onset diabetes of the young (MODY) can be defined by the clinical characteristics of early-onset Type 2 (non-insulin-dependent) diabetes and autosomal dominant inheritance. Mutations in four genes have been shown to cause MODY: glucokinase, hepatic nuclear factor 1 alpha (HNF1alpha), hepatic nuclear factor 4 alpha (HNF4alpha) and insulin promoter [corrected] factor 1 (IPF1). In white Caucasians it is now possible to define the gene in most patients with a clinical diagnosis of MODY. Each gene involved in MODY has its own specific clinical and physiological characteristics. Patients with mutations of the glucokinase gene have mild fasting hyperglycaemia throughout life, and rarely require medication or develop microvascular complications. The principle pathophysiology is stable beta-cell dysfunction characterized by reduced sensing of glucose by the pancreas. Patients with mutations in HNF1alpha have normal glucose tolerance in early childhood and usually present with symptomatic diabetes in their late teens or early adulthood. They show increasing hyperglycaemia and treatment requirements with frequent microvascular complications. The underlying defect is progressive beta-cell failure, with the early lesion characterized by failure to increase insulin secretion with increasing glucose levels. Patients with HNF4alpha and IPF1 mutations show a similar clinical picture to HNF1alpha although diabetes may be diagnosed later. There are other patients with MODY in whom the genetic defect is still unknown. Molecular genetic testing in patients with diabetes offers the possibility of making a firm diagnosis of MODY and allows prediction of the future clinical course. The role of predictive testing in non-diabetic subjects within families is uncertain at present. Preliminary evidence suggests that maintaining insulin sensitivity by avoiding obesity and regular physical exercise may help delay the onset of diabetes.