Nondiabetic Family Members Research Articles

Prevalence of overweight and obesity amongst patients with diabetes and their non-diabetic family members in Senwabarwana, Limpopo province, South Africa.

BackgroundDiabetes remains a public health concern and the second cause of mortality in South Africa. Family history of diabetes increases risk of developing diabetes. Obesity amongst patients is associated with comorbidity, whilst amongst non-diabetic family members it is associated with developing diabetes. This study aimed at determining prevalence of overweight and obesity amongst patients with diabetes and non-diabetic family members.MethodsA quantitative, cross-sectional descriptive study was conducted on 200 patients and 200 non-diabetic family members were selected using systematic random sampling from rural clinics of Senwabarwana. Data were collected using close-ended questionnaires and anthropometric measurements. Body mass index (BMI) and waist circumference were measured and interpreted according to World Health Organization guidelines. Data were analysed using Statistical Package for Social Sciences, using both descriptive and inferential statistics. Chi-square test was used to calculate associations at 95% confidence interval where a p-value of < 0.05 was considered statistically significant.ResultsMost patients (75.5%) had comorbidities and hypertension was most prevalent (89.0%). Over half of the patients (57.0%) and 38.0% of family members were obese. Most patients (75.0%) and 58.0% of family members had abdominal obesity.ConclusionPatients with diabetes suffer from comorbidities are overweight and obese whilst evidence from various studies suggest that non-diabetic family members are at added risk of developing diabetes because of higher BMI and abdominal obesity. There is an urgent need to create a conducive environment that discourages sedentary behaviours through lifestyle modifications using the family centred approach, and involve family members in the care of patients.

Association of insulin gene VNTR INS -23/Hph1 A>T (rs689) polymorphism with type 1 diabetes mellitus in Egyptian children

BackgroundType1 diabetes mellitus (T1DM) has a multi-factorial pathogenesis; the interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for the disease. Apart from HLA, more than 50 genetic variants are associated with T1DM. INS -23/Hph1 A>T (rs689) is one of the effective loci with inconsistent reports in the literature. Accordingly, this study was designed to define the frequencies of INS -23/Hph1 A>T polymorphism and its association with T1DM in Egyptian diabetic children and their non-diabetic family members as compared to healthy controls.MethodsUsing polymerase chain reaction-restriction fragment length polymorphism methodology, analysis of insulin gene VNTR polymorphism was performed for 496 samples (91 patients, 179 parents, 130 siblings, and 96 controls); parents and siblings were apparently healthy.ResultsINS genotypes and allele frequencies were comparable between patients, non-diabetic siblings, and parents (p = 0.97 and 0.77, respectively). However, the TT/AT genotype and T allele were over-presented in the three family groups compared to controls (p = 0.0015 and 0.0029, respectively).Comparing patients to controls, the T allele is considered a risk factor for the development of TIDM (OR 2.56, 95% CI 1.42–4.62, p = 0.0017).INS -23/Hph1 A>T polymorphism showed concordance between patients and their mothers (Kappa = 0.446, p = 0.000) but not with their fathers (Kappa = 0.031, p = 0.765).ConclusionsINS -23/Hph1 A>T gene polymorphism was shown to be a risk factor for the development of TIDM. This is in agreement with some and in disagreement with other reports. Studies of risk susceptibility factors have to be carried out locally in each community; results cannot be extrapolated from one ethnic group to another.

A Missense (c.T1424C:p.L475P) Mutation of ZYG11A Causes Maturity-Onset Diabetes of the Young

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes inherited in an autosomal dominant mode. Approximately, 80% of Thai MODY families did not carry mutations of known MODY genes. This study aims, therefore, to identify an unknown causative gene of MODY in Thais. Exome sequencing was performed in DNA samples of two diabetic and one nondiabetic members of a MODY family with unknown genetic etiology. Only heterozygous non-synonymous variants with minor allele frequencies &amp;lt;0.01%, which were shared between the two diabetic but not existed in nondiabetic family members, were selected for segregation analysis. Among these, a missense mutation (NM_001004339, c.T1424C:p.L475P) in a gene encoding zyg-11 family member A (ZYG11A) showed complete segregation with diabetes in three generations. This mutation is not present in any database and not detected in nondiabetic controls (n = 400) as well as other MODY-X probands (n = 90). The amino acid residue L475 of ZYG11A is evolutionally conserved among many species. Several prediction software tools suggested a deleterious effect of the L475P mutation. ZYG11A acts as a target recruitment subunit of an E3 ubiquitin ligase complex, which plays an important role in degradation of cyclinB1- a regulatory protein involved in mitosis. Suppression of ZYG11A in 1.1B4 β-cell line by specific small interfering RNA (siRNA) significantly reduced cell proliferation (p = 0.001) while increased cyclinB1 protein levels (p = 0.001). Moreover, 1.1B4 cells overexpressing ZYG11A showed a significant increase in proliferation as compared to the control cells (p = 0.019) whereas this effect was not observed in the cells overexpressing the mutant ZYG11A (p = 0.659). Taken together, this finding demonstrates the crucial role of ZYG11A in β-cell cycle regulation. It also suggests heterozygous ZYG11A-L475P mutation as a cause of MODY in the Thai family studied. Disclosure C. Charoensuk: None. P. Jungtrakoon: None. W. Tangjittipokin: None. J. Sujjitjoon: None. N. Plengvidhya: None. P. Yenchitsomanus: None.

Barriers to diabetes awareness and self-help are influenced by people's demographics: perspectives of South Asians with type 2 diabetes

ABSTRACT Aim: To determine whether barriers to diabetes awareness and self-help differ in South Asian participants of different demographic characteristics (age, gender, and literacy) with type 2 diabetes living in the United Kingdom. Methods: Six focus group discussions (FGDs) were carried out in patients who were categorized according to age (30–60 years, ≥60 years), gender (male, female) and literacy status (literate, illiterate). Data were analysed following the iterative process of thematic analysis techniques. Results: Barriers were demographic-specific. The illiterate groups reported language as the major barrier to improved diabetes awareness and self-help. The literate groups reported that information provided by healthcare providers was general, and not specific to their diet/culture. Major barriers to adherence to the recommended diet for diabetes included: insufficient knowledge/awareness about nutritional content of food (all groups); lack of self-will to resist eating sweets, especially during weddings/festivals (literate older groups/literate younger females/illiterate older males); difficulty cooking separate meals for diabetic and non-diabetic family members (illiterate/literate older females). Other barriers to seeking advice/help ranged from not wanting to disclose their diabetes as it may affect employment/work (literate groups) to fear of being singled out at social gatherings (illiterate groups). General lack of motivation to exercise was reported by all groups. Time constraints and not knowing what/how to exercise was reported by literate younger groups whilst the illiterate older groups reported to not having suitable exercising facilities at local communities. Different barriers were also reported when accessing healthcare; language barriers (illiterate groups), restricted access to doctors’ appointments/difficulty attending specific appointment slots offered by General Practitioners (literate females). Conclusion: Different barriers exist to improved awareness about diabetes and self-help in different patient demographics. Lack of culturally appropriate diabetes educational/awareness programs in the community appeared to be a major barrier in most older and illiterate participants while younger participants reported time constraint.

Fungi and diabetes

Fungi and diabetes

A three-step programmed method for the identification of causative gene mutations of maturity onset diabetes of the young (MODY)

To establish a three-step programmed method to find gene mutations related to maturity onset diabetes of the young (MODY). Target region capture and next-generation sequencing (NGS) were performed using customized oligonucleotide probes designed to capture suspected genes for MODY in 11 probands with clinically diagnosed MODY. The suspected associations of certain genes with MODY were then confirmed by Sanger sequencing in the probands and their family members. Finally, to validate variants of one of the genes of interest (glucokinase, GCK) as pathogenic mutations, protein function editing by the variant genes was assessed. In the target region capture and NGS phase, a total of nine variants of seven genes (GCK, WFS1, SLC19A2, SH2B1, SERPINB4, RFX6, and GATA6) were identified in eight probands. Two heterozygous GCK mutations located on the same allele (p.Leu77Arg and p.Val101Met) were identified in a MODY family. Sanger sequencing was used to confirm the variants identified by NGS to be present in probands and their diabetic family members, but not in non-diabetic family members. Finally, enzyme kinetic and thermal stability analyses revealed that the p.Leu77Arg mutation or the p.Leu77Arg mutation in combination with the p.Val101Met mutation inactivates GCK function and stability, while mutation of p.Val101Met alone does not. The p.Leu77Arg but not p.Val101Met GCK mutation is therefore considered a pathogenic mutation associated with MODY. Genetic screening coupled with gene-editing protein function testing is an effective and reliable method by which causative gene mutations of MODY can be identified.

Discriminative Ability of Plasma Branched-Chain Amino Acid Levels for Glucose Intolerance in Families At Risk for Type 2 Diabetes.

Insulin resistance and glucose intolerance have been associated with increased plasma levels of branched-chain amino acids (BCAA). BCAA levels do not predict T2DM in the population. We determined the discriminative ability of fasting BCAA levels for glucose intolerance in nondiabetic relatives of patients with T2DM of two different ethnicities. Based on oral glucose tolerance test (OGTT), first-degree relatives of patients with T2DM were categorized as normal glucose tolerance, prediabetes, or T2DM. Included were 34, 12, and 18 Caucasian and 22, 12, and 23 Asian Indian participants, respectively. BCAA levels were measured in fasting plasma together with alanine, phenylalanine, and tyrosine. Insulin sensitivity and beta-cell function were assessed by indices derived from an extended OGTT and their relationship with plasma BCAA levels was assessed in multivariate regression analysis. The value of the amino acids for discriminating prediabetes among nondiabetic family members was determined with the area under the curve of receiver-operated characteristics (c-index). BCAA levels were higher in diabetic than in normoglycemic family members in the Caucasians (P = 0.001) but not in the Asian Indians. In both groups, BCAA levels were associated with waist-hip ratio (β = 0.31; P = 0.03 and β = 0.42; P = 0.001, respectively) but not with indices of insulin sensitivity or beta-cell function. The c-index of BCAA for discriminating prediabetes among nondiabetic participants was 0.83 and 0.74 in Caucasians and Asian Indians, respectively, which increased to 0.84 and 0.79 by also including the other amino acids. The c-index of fasting glucose for discriminating prediabetes increased from 0.91 to 0.92 in Caucasians and 0.85 to 0.97 (P = 0.04) in Asian Indians by inclusion of BCAA+alanine, phenylalanine, and tyrosine. Adding fasting plasma BCAA levels, combined with phenylalanine, tyrosine and alanine to fasting glucose improved discriminative ability for the prediabetic state within Asian Indian families at risk for T2DM. BCAA levels may serve as biomarkers for early development of glucose intolerance in these families.

High heritability and genetic correlation of intravenous glucose- and tolbutamide-induced insulin secretion among non-diabetic family members of type 2 diabetic patients

The aim of this study was to estimate the heritability of quantitative measures of glucose regulation obtained from a tolbutamide-modified frequently sampled IVGTT (t-FSIGT) and to correlate the heritability of the glucose-stimulated beta cell response to the tolbutamide-induced beta cell response. In addition, single nucleotide polymorphisms (SNPs) having an exclusive effect on either glucose- or tolbutamide-stimulated insulin release were identified. Two hundred and eighty-four non-diabetic family members of patients with type 2 diabetes underwent a t-FSIGT with intravenous injection of glucose at t = 0 min and tolbutamide at t = 20 min. Measurements of plasma glucose, serum insulin and serum C-peptide were taken at 33 time points from fasting to 180 min. Insulin secretion rate, acute insulin response (AIR), disposition index (DI) after glucose and disposition index after tolbutamide (DIT), insulin sensitivity (SI), glucose effectiveness (SG) and beta cell responsiveness to glucose were calculated. A polygenic variance component model was used to estimate heritability, genetic correlations and associations. We found high heritabilities for acute insulin secretion subsequent to glucose stimulation (AIRglucose h (2) ± SE: 0.88 ± 0.14), but these were slightly lower after tolbutamide (AIRtolbutamide h (2) ± SE: 0.69 ± 0.14). We also estimated the heritabilities for SI (h (2) ± SE: 0.26 ± 0.12), SG (h (2) ± SE: 0.47 ± 0.13), DI (h (2) ± SE: 0.56 ± 0.14), DIT (h (2) ± SE: 0.49 ± 0.14) and beta cell responsiveness to glucose (h (2) ± SE: 0.66 ± 0.12). Additionally, strong genetic correlations were found between measures of beta cell response after glucose and tolbutamide stimulation, with correlation coefficients ranging from 0.77 to 0.88. Furthermore, we identified five SNPs with an exclusive effect on either glucose-stimulated (rs5215, rs1111875, rs11920090) or tolbutamide-stimulated (rs10946398, rs864745) insulin secretion. Our data demonstrate that both glucose- and tolbutamide-induced insulin secretions are highly heritable traits, which are largely under the control of the same genes.

Non HLA genetic markers association with type-1 diabetes mellitus

The currently available data identified IDDM1 and IDDM2 as 2 susceptibility loci for type 1 diabetes (T1D). The major histocompatibility complex (MHC)/HLA region referred to as IDDM1 contains several 100 genes known to have a great influence on T1D risk. Within IDDM2, a minisatellite variable number of tandem repeats (VNTR) locus in the insulin gene (INS) promoter region is likely to represent the etiologic polymorphism. The aim of the present work was to study the association between genotypes and susceptibility to T1D among Egyptian diabetic children and their family members. Twenty-five nuclear Egyptian families with 27 children having T1D, aged 3–14 years, their non-diabetic 44 sibs, aged 3–15 years and their parents were included in our study. All studied children were subjected to: detailed history and family pedigree. Thorough clinical examination and anthropometric measurements. Laboratory work up of diabetes including random blood sugar (RBS) and HbA 1C. Molecular genetics of INS was studied in four steps; nucleic acid purification, amplification, sequencing and haplotyping using flanking single nucleotide polymorphisms (SNPs) as surrogate markers for minisatellite alleles identification. Analysis of variant repeat distribution among Egyptian families combined with flanking haplotypes revealed that all our diabetic children had class I alleles of INS; 9 had class IC+, 9 had class ID+ and 9 had class ID−, while all non-diabetic family members had class III alleles of INS. Therefore the three class I alleles were considered to be equally predisposing to T1D, while class III alleles are dominantly protective. There was significant positive correlations between body mass index (BMI) and both HbA 1C and AST liver enzyme among diabetic children with class IC+ but not other alleles; indicating that they need close monitoring of their diabetic control and liver functions beside following specific dietary regimens. It can be concluded that all class I alleles (IC+, ID+ and ID−) are equally important susceptibility factors for T1D among Egyptian children, while class III alleles (IIIA and IIIB) are dominantly protective. It is concluded also that our diabetic children with class IC+ are an especially endangered subgroup of diabetics. Genotyping for INS-VNTR alleles is recommended for diabetic children as an important step of diagnostic and follow up regimens and for their non-diabetic family members for family counseling and early identification of potential diabetics. Further studies of INS-VNTR alleles and HLA haplotypes all over Egypt are recommended to define the Egyptian susceptibility loci for T1D and their relations to the clinical and laboratory findings as an important national programs.

Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60

We studied the genetic and clinical features of diabetic subjects in a 5-generation Michigan-Kentucky pedigree ascertained through a proband with pancreatic agenesis and homozygous for the IPF1 mutation Pro63fsx60. Diabetic and nondiabetic family members were genotyped and phenotyped. We also carried out genetic studies to determine the history of the IPF1 mutation in the Michigan-Kentucky family and a Virginia family with the same mutation. We identified 110 individuals; 34 are currently being treated for diabetes and 10 of these are Pro63fsX60 carriers (ie, MODY4). Subjects with MODY as well as those with type 2 diabetes are characterized by obesity and hyperinsulinemia. Genetic studies suggest that the IPF1 mutation was inherited from an ancestor common to both the Michigan-Kentucky and Virginia families. MODY4 and type 2 diabetes in the Michigan-Kentucky pedigree are associated with obesity and hyperinsulinemia. Obesity and hyperinsulinemia have been observed occasionally in other subtypes of MODY, which suggests that hyperinsulinemia may be a general phenomenon when obesity occurs in MODY subjects. Hypoinsulinemia in nonobese MODY subjects seems to be caused by a functional defect in the beta cell. Genetic testing should be considered in multigenerational obese diabetic subjects, particularly when such families contain young diabetic members.

Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15

Objective Individual propensity to chronic, low-grade inflammation—a determinant of atherosclerosis-is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10 cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2547 relative pairs). Methods and results In a variance component analysis, heritability of CRP values was significant ( h 2 = 0.39, p < 0.0001). This effect was independent of BMI and was present in both diabetic ( h 2 = 0.42, p = 0.003) and non-diabetic ( h 2 = 0.34, p = 0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD = 3.41, genome-wide p = 0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD = 1.35) and 17p11 (LOD = 1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD = 2.17) was evident at 3p21. Conclusions A major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.

T-786C Polymorphism of the Endothelial Nitric Oxide Synthase Gene Is Associated with Albuminuria in the Diabetes Heart Study

Albuminuria demonstrates significant heritability in multiply affected hypertensive and diabetic families. The role of endothelial nitric oxide synthase (eNOS) gene variants as risk factors for albuminuria was investigated in 590 European American siblings from 230 families in the Diabetes Heart Study. Two polymorphisms in the eNOS gene (T-786C in the promoter region and Glu298Asp in exon 7) were genotyped. Albuminuria was defined as an albumin:creatinine ratio (ACR) >/=17 mg/g in men and >/=25 mg/g in women. Tests of association were based on generalized estimating equations, and tests of linkage disequilibrium were based on the quantitative pedigree disequilibrium test. A total of 83% of participants had type 2 diabetes. The median ACR was 10.7 mg/g (interquartile range, 5.1 to 32.8), and 34% (202 of 590) of participants had an elevated ACR. The eNOS -786C allele but not the Glu298Asp was associated with increased ACR (31% increase in absolute level of ACR for each additional copy of the -786C allele; P < 0.0001) and a higher risk for albuminuria (odds ratio, 1.55 for each additional copy of the -786C allele; P = 0.0005). Adjustment for the nongenetic determinants of ACR had no significant effect on the results; neither did stratification by gender, presence of diabetes, and the Glu298Asp genotype. Results were confirmed by quantitative pedigree disequilibrium test analysis and were consistent with haplotype analysis. The -786C eNOS variant was positively correlated with a higher prevalence and a greater degree of albuminuria in European American families in both diabetic and nondiabetic family members.

Does the aspartic acid to asparagine substitution at position 76 in the pancreas duodenum homeobox gene (PDX1) cause late-onset type 2 diabetes?

Considerable data support an inherited defect in insulin secretion as one component of type 2 diabetes. Coding variants of the pancreas duodenum homeobox gene (PDX1) were proposed to predispose late-onset type 2 diabetes and to decrease transactivation in vitro. We tested the hypothesis that the Asp76Asn (D76N) variant that was identified in several populations predisposed type 2 diabetes and reduced insulin secretion. We performed a case-control study in 191 control subjects and 190 individuals with type 2 diabetes, all of European descent, then characterized the D76N variant in 704 members of 68 families. We compared the phenotypic characteristics of those with and without the variant by diagnostic status and determined the insulin secretory response to intravenous glucose and tolbutamide among nondiabetic family members. D76N was not associated with type 2 diabetes, either in our population or when all reported studies in Caucasians were combined. D76N did not segregate with diabetes among the families examined. Among D76N carriers, nondiabetic individuals had a lower waist-to-hip ratio and a trend to lower BMI than their diabetic counterparts. Diabetic carriers of D76N were significantly leaner by BMI (P = 0.012) and tended to be younger than diabetic individuals with the D/D genotype. However, insulin secretion in response to oral and intravenous glucose challenge and to intravenous tolbutamide was not reduced in D76N carriers. The D76N variant of PDX1 does not significantly alter insulin secretion or act as a high-risk susceptibility allele for late-onset type 2 diabetes as proposed previously, although we cannot exclude a minor role in increasing risk of diabetes.

Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians.

Insulin resistance is strongly associated with obesity, but even among obese subjects insulin sensitivity varies widely. Recently, a new adipocyte hormone, resistin, was identified, shown to reduce insulin-mediated glucose uptake, and shown to be increased in obese mice. We used the chromosome 19 draft sequence to determine the genomic structure of human resistin and to screen the exons, introns, and flanking sequences for variation. We screened 44 subjects with type 2 diabetes and 20 nondiabetic family members who were at the extremes of insulin sensitivity. We identified eight noncoding single nucleotide polymorphisms (SNPs) and one GAT microsatellite repeat. Three SNPs, which were in incomplete linkage disequilibrium with each other and had allelic frequencies exceeding 5%, were selected for further study. No SNP was associated with type 2 diabetes, but the SNP in the promoter region was a significant determinant of insulin sensitivity index (P = 0.04) among nondiabetic family members who had undergone iv glucose tolerance tests. The three common SNPs showed statistical significance as determinants of insulin sensitivity index (P < 0.01) in interaction with body mass index. Noncoding SNPs in the resistin gene may influence insulin sensitivity in interaction with obesity, but this finding will need to be confirmed in other populations.

Role of calpain-10 gene variants in familial type 2 diabetes in Caucasians.

The calpain-10 gene (CAPN10) has been implicated in type 2 diabetes (T2DM) susceptibility by both linkage and association in a Hispanic population from Starr County Texas. Common intronic variants seem to alter CAPN10 mRNA levels and were associated with insulin resistance but not diabetes in Pima Indians. The role of these variants in Caucasian populations is less clear. We found some evidence for linkage of T2DM to chromosome 2q approximately 20 cM proximal to the NIDDM1/CAPN10 locus. To test the hypothesis that CAPN10 is a diabetes susceptibility locus in Caucasian families at high risk for T2DM, we examined the influence of the three previously implicated CAPN10 variants on both diabetes risk and measures of insulin sensitivity and glucose homeostasis. We genotyped approximately 700 members of 63 families for 3 variants (SNP-43, SNP-19, and SNP-63). We tested each variant separately and as haplotype combinations for altered transmission from parents to affected children (transmission disequilibrium test), and we tested for an effect of each variant individually on measures of glucose and insulin during a glucose tolerance test in nondiabetic family members. Finally, we looked for an effect of each variant on measures of insulin sensitivity (S(I)) and insulin secretion estimated by frequently sampled iv glucose tolerance test and Minimal Model analysis. We could not confirm an increase in risk for T2DM susceptibility for any variant or for any haplotype combination, although we found marginal evidence for an increased risk of the 111/221 haplotype combination (P = 0.036) after ascertainment correction. However, both SNP-19 and SNP-63 increased fasting and/or postchallenge insulin levels, consistent with reduced insulin sensitivity. Furthermore, SNP-19 had modest effects on insulin sensitivity measured by homeostatic model, and on postchallenge glucose. The reduction in insulin sensitivity was confirmed by analysis of the subset of individuals who underwent iv glucose tolerance tests, where SNP-19 significantly altered the insulin sensitivity index. CAPN10 cannot be considered a major diabetes susceptibility gene in our population and seems unlikely to explain the observed linkage findings. However, CAPN10 influences insulin sensitivity and glucose homeostasis in nondiabetic members of kindreds at high risk for T2DM.

A major gene effect on fasting insulin and insulin sensitivity in familial combined hyperlipidemia.

The most common inherited dyslipidemia, familial combined hyperlipidemia (FCHL), is associated with insulin resistance. Whether insulin sensitivity in these families is inherited is not known. Therefore, we investigated the inheritance of insulin sensitivity in 352 nondiabetic family members from 37 families with FCHL, 105 of whom had undergone testing using the hyperinsulinemic-euglycemic clamp technique for the measurement of insulin sensitivity. First, complex segregation analysis of fasting insulin levels (both unadjusted and age-, age(2)-, and BMI-adjusted) was used for modeling of the variance in fasting insulin levels. In these analyses, Mendelian codominant inheritance (P = 0.320 for unadjusted and P = 0.295 for adjusted insulin values) was not rejected over the most general model and fit the data significantly better than the sporadic model (P < 0.001). Polygenic and environmental models were rejected (P < 0.001). The Mendelian codominant model explained 44 and 45% of the variance in unadjusted and adjusted fasting insulin levels, respectively. The proposed genotypes of this locus, based on segregation analysis, were associated with directly measured insulin sensitivity in 105 FCHL family members who underwent the hyperinsulinemic-euglycemic clamp (P < 0.001). These results provide evidence for a major gene regulating insulin sensitivity in FCHL families. Possible pleiotropic effects of this insulin sensitivity locus on dyslipidemias in FCHL remain to be elucidated.

Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations.

The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes. We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (non-insulin-dependent) diabetes mellitus and in 92 non-diabetic control subjects. Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p < 0.05) and reduced insulin:glucose ratios (p < 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay. Although mutations in the IPF-1 gene are rare in early- (3.5 %) and late-onset (2.7 % ) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.

Cytokine overproduction in healthy first degree relatives of patients with IDDM.

Healthy family members of patients with insulin-dependent diabetes mellitus (IDDM) are known to share a number of immunological abnormalities with their affected relatives. Since monocyte and type 1 T-cell-derived cytokines contribute to the pathogenesis of IDDM, we studied the production of these cytokines in the healthy first degree relatives of 29 children with IDDM. We report that circulating tumour necrosis factor-alpha (TNF-alpha) and soluble interleukin-2 (sIL-2) receptor were present in increased amounts in non-diabetic family members at levels similar to those found in the diabetic children (duration of disease 3 months-5 years). Furthermore, marked hypersecretion of IL-1alpha and TNF-alpha by mitogen-stimulated peripheral blood mononuclear cells was found in both diabetic and healthy family members. Abnormalities of cytokine production in healthy relatives did not correlate with the presence of islet cell antibodies or with HLA DR type. These data indicate that healthy family members of patients with IDDM exhibit overproduction of a number of cytokines that have been implicated in diabetogenesis.

The Emotional, Social, and Behavioral Implications of Insulin-Induced Hypoglycemia.

Hypoglycemic episodes occur commonly in patients with insulin-dependent (Type I) diabetes and are associated with several negative sequelae. These include unpleasant symptoms, deterioration in cognitive-motor functions, embarrassment, accidents, unconsciousness, seizures, and even death. Although hypoglycemic disruptions in cognitive and motor function caused by neuroglycopenia are well-documented, the effects of hypoglycemia on other areas of psychosocial function have received less scientific attention. This paper examines the impact of hypoglycemia on emotional status, social behavior, and relationships. The physical symptoms and cognitive impairment that occur with hypoglycemia are caused primarily by hormonal changes and neuroglycopenia. These physiologic responses also seem to cause negative changes in affect and social behavior. These include changes in acute mood state, such as feelings of tension and anger, as well as negative interpersonal behavior, such as argumentiveness. Patients may also develop significant fear of hypoglycemia (FOH) and engage in behaviors aimed at avoiding low blood glucose levels, which may jeopardize metabolic control. Nondiabetic family members, who witness episodes and often must provide emergency treatment, can experience significant distress. Parents of diabetic children who have experienced unconsciousness exhibit high FOH, as do spouses of diabetic adults who have frequent episodes. Taken together, the research clearly shows that hypoglycemia can have a significant negative impact on psychosocial function and quality of life, which has important clinical and empirical implications.

The GENNID Study. A resource for mapping the genes that cause NIDDM.

To develop a resource, consisting of comprehensive data and lymphoblastoid cell lines, of well-characterized NIDDM families that will be available to the scientific community for genetic studies of NIDDM. Non-Hispanic white, Hispanic, African-American, and Japanese-American multiplex NIDDM families, with a minimum of one affected sib-pair, are being collected by the eight Harold Rifkin Family Acquisition Centers. Detailed family and medical histories are obtained from all participants. Family members with diabetes have fasting blood samples drawn, while nondiabetic family members have an oral glucose tolerance test and, when possible, insulin sensitivity and insulin secretion measurements by frequently sampled intravenous glucose tolerance testing or euglycemic insulin clamp. Lymphoblastoid cell lines are established for all participants. Over 1,400 individuals from approximately 220 families have been studied since the start of the GENNID (Genetics of NIDDM) program in July 1993. The goal is that by July 1997, data from 300 non-Hispanic white families, > 100 Hispanic families, > 100 African-American families, and 15 Japanese-American families will have been collected. The identification of the genes responsible for NIDDM may now be achievable, but only if sound phenotypic data are linked to genetic material from a large number of well-described multiplex families. The GENNID project of the American Diabetes Association is creating a comprehensive resource that will expedite the identification of the genetic basis of NIDDM.