First-degree Family History Of Type Research Articles

Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial

Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was -0·95 mmol/L (SD 2·78) in the placebo group and -1·70 mmol/L (SD 2·47) in the testosterone group (mean difference -0·75 mmol/L, -1·10 to -0·40; p<0·0001). The treatment effect was independent of baseline serum testosterone. A safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants in the placebo group and 106 (22%) of 491 participants in the testosterone group, and a trigger for an increase of 0·75 μg/mL or more in prostate-specific antigen occurred in 87 (19%) of 468 participants in the placebo group and 109 (23%) of 480 participants in the testosterone group. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the placebo group and 55 (10·9%, 8·5 to 13·9) of 504 patients in the testosterone group. There were two deaths in each group. Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families.

The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.

Screening for Type 1 Diabetes Risk in Newborns: The Freder1k Pilot Study in Saxony.

An increased risk for type 1 diabetes can be identified using genetic and immune markers. The Freder1k study introduces genetic testing for type 1 diabetes risk within the context of the newborn screening in order to identify newborns with a high risk to develop type 1 diabetes for follow-up testing of early stage type 1 diabetes and for primary prevention trials. Consent for research-based genetic testing of type 1 diabetes risk is obtained with newborn screening. Increased risk is assessed using three single nucleotide polymorphisms for HLA DRB1*03 (DR3), HLA DRB1*04 (DR4), HLA DQB1*0302 (DQ8) alleles, and defined as 1. an HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype or 2. an HLA DR4-DQ8 haplotype and a first-degree family history of type 1 diabetes. Families of infants with increased risk are asked to participate in follow-up visits at infant age 6 months, 2 years, and 4 years for autoantibody testing and early diagnosis of type 1 diabetes. After 8 months, the screening rate has reached 181 per week, with 63% coverage of newborns within Freder1k-clinics and 24% of all registered births in Saxony. Of 4178 screened, 2.6% were identified to have an increased risk, and around 80% of eligible infants were recruited to follow-up. Psychological assessment of eligible families is ongoing with none of 31 families demonstrating signs of excessive burden associated with knowledge of type 1 diabetes risk. This pilot study has shown that it is feasible to perform genetic risk testing for childhood disease within the context of newborn screening programs.

Primary prevention of beta-cell autoimmunity and type 1 diabetes - The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives.

ObjectiveType 1 diabetes can be identified by the presence of beta-cell autoantibodies that often arise in the first few years of life. The purpose of this perspective is to present the case for primary prevention of beta-cell autoimmunity and to provide a study design for its implementation in Europe.MethodsWe examined and summarized recruitment strategies, enrollment rates, and outcomes in published TRIGR, FINDIA and BABYDIET primary prevention trials, and the TEDDY intensive observational study. A proposal for a recruitment and implementation strategy to perform a phase II/III primary prevention randomized controlled trial in infants with genetic risk for developing beta-cell autoimmunity is outlined.ResultsInfants with a family history of type 1 diabetes (TRIGR, BABYDIET, TEDDY) and infants younger than age 3 months from the general population (FINDIA, TEDDY) were enrolled into these studies. All studies used HLA genotyping as part of their eligibility criteria. Predicted beta-cell autoimmunity risk in the eligible infants ranged from 3% (FINDIA, TEDDY general population) up to 12% (TRIGR, BABYDIET). Amongst eligible infants, participation was between 38% (TEDDY general population) and 97% (FINDIA). Outcomes, defined as multiple beta-cell autoantibodies, were consistent with predicted risks. We subsequently modeled recruitment into a randomized controlled trial (RCT) that could assess the efficacy of oral insulin treatment as adapted from the Pre-POINT pilot trial. The RCT would recruit infants with and without a first-degree family history of type 1 diabetes and be based on general population genetic risk testing. HLA genotyping and, for the general population, genotyping at additional type 1 diabetes susceptibility SNPs would be used to identify children with around 10% risk of beta-cell autoimmunity. The proposed RCT would have 80% power to detect a 50% reduction in multiple beta-cell autoantibodies by age 4 years at a two-tailed alpha of 0.05, and would randomize around 1160 infants to oral insulin or placebo arms in order to fulfill this. It is estimated that recruitment would require testing of between 400,000 and 500,000 newborns or infants.ConclusionIt is timely and feasible to establish a platform for primary prevention trials for type 1 diabetes in Europe. This multi-site European infrastructure would perform RCTs, supply data coordination and biorepository, provide cohorts for mechanistic and observational studies, and increase awareness for autoimmune diabetes.

Effect of 12 Weeks of Periodized Resistance Training Upon Total Plasma Adiponectin Concentration in Healthy Young Men.

The effects of resistance training on adiponectin have thus far yielded equivocal results. However, the effect of periodized resistance training on plasma adiponectin in offspring of type 2 diabetic and nondiabetic (ND) parents (first-degree family history) has yet to be determined. Untrained healthy young men with and without a first-degree family history of type 2 diabetes were assigned to an exercise intervention group (E) or an active control group (C). The E group performed a 12-week periodized resistance training program, whereas the C group did not participate in any structured exercise program. Fasting plasma samples were obtained pre- and posttraining. Total plasma adiponectin changed significantly in the E group (33.7 ± 14.7%, p = 0.025) but not in the C group (10.8 ± 19.2%). Offspring of type 2 diabetic parents subjects had significantly greater improvements in plasma adiponectin (69.3 ± 34.8%) compared with ND subjects (-3.2 ± 29.9%, p = 0.046). Regular aerobic exercise was significantly correlated with average plasma adiponectin (r = 0.32), whereas first-degree family history of type 2 diabetes (r = -0.58) and decreases in body fat percentage (r = -0.77) were inversely correlated with average plasma adiponectin. Periodized high-intensity resistance training seems to increase plasma adiponectin, particularly in individuals with a first-degree family history of type 2 diabetes or those who experience a significant loss of fat mass. The direct correlation between regular aerobic exercise and adiponectin further suggests that a combination of aerobic and resistance training yields greater improvements in plasma adiponectin compared with resistance training alone.

Sulfonylurea: Personalized Medicine for Type 2 Diabetes

Recently, new drugs targeting different glucose-regulating mechanisms have been brought to market and the pharmacological treatment of type 2 diabetes has become complex and more controversial. Clinicians can be confused about how to manage their patients optimally. Consequently, the American Diabetes Association and European Association for the Study of Diabetes published a consensus algorithm for managing type 2 diabetes patients. This position statement is an evidence-based recommendation that recommends choosing a specific anti-hyperglycemic agent based on several considerations: (1) glycemic effectiveness; (2) effects on long-term complications; (3) safety profile; and (4) patient preference [1]. Sulfonylureas have long been used for the treatment of type 2 diabetes and were the first oral anti-hyperglycemic agents to be introduced into clinical practice. They are still widely used and are first- or second-line drugs if the hemoglobin A1c (HbA1c) target is not achieved after metformin monotherapy [1,2]. Sulfonylureas stimulate insulin secretion by inhibiting the potassium flux through ATP-dependent potassium channels (KATP) in pancreatic β-cells and are most effective in patients who have had diabetes for less than 5 years, and who have residual endogenous insulin production [3]. These drugs have potent and rapid hypoglycemic effects; however, these effects are short-lived and HbA1c eventually increases over time [4]. In addition, there are some safety issues, including hypoglycemia, weight gain, and possibly risk of cardiovascular disease [5]. In this issue, Min et al. [6] investigated the clinical characteristics of patients who are dependent on sulfonylurea treatment for adequate glycemic control. The authors retrospectively selected 19 patients whose HbA1c was maintained below 7.5% with a small dose of sulfonylurea (glimepiride ≤2 mg/day or equivalent dose). The HbA1c level increased after discontinuing the sulfonylurea, but fell again after resuming treatment. The average age of the patients was 67±11 years and there was no gender difference. The mean body mass index was 25.1±3.1 kg/m2 and 73% of the patients had a first-degree family history of type 2 diabetes. In addition, although the patients had relatively long durations of diabetes (18±10 years), β-cell function was preserved; fasting C-peptide level was 3.9±2.6 ng/mL. To date, there has been much effort to determine who best will respond to a specific anti-hyperglycemic agent and which drug is the best option for certain type 2 diabetes patients for optimal glycemic control. Despite these efforts, selecting the best anti-hyperglycemic agent for an individual with type 2 diabetes is still complicated. Furthermore, there is no way to determine who will show good glycemic control after discontinuing sulfonylureas. Although Min et al. [6] did not report the proportion of sulfonylurea-dependent patients among all patients receiving sulfonylurea treatment, and did not compare clinical characteristics between sulfonylurea-dependent patients and sulfonylurea-independent patients, there is arguably a population of type 2 diabetics who can best benefit from sulfonylurea treatment for optimal glycemic control. Future studies need to characterize patients with type 2 diabetes who show a good response to sulfonylureas and are dependent on sulfonylurea treatment for adequate glycemic control.

Prevalence of diabetes and impaired glucose metabolism in younger ‘at risk’ UK adults: insights from the STAND programme of research

Rising rates of obesity have led to an increasing prevalence of Type 2 diabetes mellitus in young people. Uncertainty exists over the utility of screening younger adults for Type 2 diabetes, as existing data sets have focused on mature (> 40 years) cohorts. The aim of this study was to determine the prevalence of impaired glucose metabolism in higher risk younger adults. Overweight (with an additional risk factor) or obese adults (18-40 years) were recruited for the Sedentary Time And Diabetes (STAND) randomized controlled trial. Measures included an oral glucose tolerance test, HbA1c , biochemical and anthropometric data. One hundred and ninety-three individuals (68% female; median age 33.8 years; median BMI 33.9 kg/m²) were recruited. Forty-three per cent had a first-degree family history of Type 2 diabetes. Previously undiagnosed Type 2 diabetes was present in 4.7% (n = 9). Of participants, 18.1% (n = 35) had impaired glucose metabolism: 4.7% (n = 9) HbA1c ≥ 48 mmol/mol (6.5%); 9.3% (n = 18) HbA1c 42-46 mmol/mol (6.0-6.4%); 3.1% (n = 6) Type 2 diabetes on oral glucose tolerance test; 6.2% (n = 12) isolated impaired glucose tolerance; 2.1% (n = 4) isolated impaired fasting glucose; 1% (n = 2) both impaired fasting glucose and impaired glucose tolerance. Of participants, 58.5% (n = 113) had dyslipidaemia, 28.0% (n = 54) had hypertension, 31.1% (n = 60) were vitamin D deficient and 7.3% (n = 14) had abnormal liver function. This study identified a high prevalence of Type 2 diabetes and impaired glucose regulation in overweight and obese younger adults. These findings require confirmation in a larger, representative, population.

Markedly reduced rate of diabetic ketoacidosis at onset of type 1 diabetes in relatives screened for islet autoantibodies

To determine whether screening for islet autoantibodies in children prevents ketoacidosis and other metabolic complications at diabetes onset and improves the clinical course after diagnosis. The German BABYDIAB and the Munich Family Study follow children with a first-degree family history of type 1 diabetes for the development of islet autoantibodies and type 1 diabetes. The Diabetes Prospective Documentation (DPV) Initiative registers and collects information on pediatric patients with type 1 diabetes throughout Germany. Here, clinical characteristics at diabetes onset [ketoacidosis, mean hemoglobin A1c (HbA1c), and length of hospitalization] and the 5-yr clinical course (HbA1c and insulin dose) of screened and followed islet autoantibody-positive children (n = 101) and 49 883 non-screened children within the DPV registry were compared. At diabetes onset, children who were followed after screening and were positive for islet autoantibodies had lower HbA1c (8.6 vs. 11%, p < 0.001) and a lower prevalence of diabetic ketoacidosis (3.3 vs. 29.1%, p < 0.001). Screened children also had a shorter hospitalization period at onset (11.4 vs. 14.9 d, p = 0.005). Similar results were observed when the analysis was restricted to 759 non-screened DPV children with a first-degree family history of type 1 diabetes. No differences between screened and non-screened children were observed with respect to HbA1c and insulin dose during the first 5 yr after diagnosis. Screening for islet autoantibodies in children likely leads to earlier diabetes diagnosis resulting in less complications at diagnosis. However, no substantial benefit in the clinical outcome during the first 5 yr after diagnosis was observed.

Primary Dietary Intervention Study to Reduce the Risk of Islet Autoimmunity in Children at Increased Risk for Type 1 Diabetes

OBJECTIVETo determine whether delaying the introduction of gluten in infants with a genetic risk of islet autoimmunity is feasible, safe, and may reduce the risk of type 1 diabetes–associated islet autoimmunity.RESEARCH DESIGN AND METHODSA total of 150 infants with a first-degree family history of type 1 diabetes and a risk HLA genotype were randomly assigned to a first gluten exposure at age 6 months (control group) or 12 months (late-exposure group) and were followed 3 monthly until the age of 3 years and yearly thereafter for safety (for growth and autoantibodies to transglutaminase C [TGCAs]), islet autoantibodies to insulin, GAD, insulinoma-associated protein 2, and type 1 diabetes.RESULTSAdherence to the dietary-intervention protocol was reported from 70% of families. During the first 3 years, weight and height were similar in children in the control and late-exposure groups, as was the probability of developing TGCAs (14 vs. 4%; P = 0.1). Eleven children in the control group and 13 children in the late-exposure group developed islet autoantibodies (3-year risk: 12 vs. 13%; P = 0.6). Seven children developed diabetes, including four in the late-exposure group. No significant differences were observed when children were analyzed as per protocol on the basis of the reported first gluten exposure of the children.CONCLUSIONSDelaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children.

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk

Our aim was to determine the relationships between autoantibodies to zinc transporter 8 (ZnT8), genotypes of the ZnT8-encoding gene SLC30A8 and type 1 diabetes risk. ZnT8 autoantibodies (ZnT8A) were measured in sera of 1,633 children with a first-degree family history of type 1 diabetes and who were prospectively followed from birth. Antibodies were measured by Protein A-based radiobinding assays and COOH-terminal (R325, W325 or Q325 variants) or NH(2)-terminal constructs of human ZnT8. SLC30A8 genotyping at single-nucleotide polymorphism (SNP) rs13266634 was performed on 1,170 children. Antibodies against COOH-terminal ZnT8 constructs (ZnT8A-COOH) developed in 58 children as early as 9 months of age (median 3 years). They were detected in 55 of 128 (43%) children with autoantibodies to insulin, GAD and/or insulinoma-associated protein 2 and 34 of 42 (81%) who progressed to diabetes. The additional presence of ZnT8A-COOH stratified diabetes risk in islet autoantibody-positive children (p < 0.0001). SLC30A8 genotype strongly influenced ZnT8A type and diabetes risk in ZnT8A-COOH-positive children. Antibody binding against the ZnT8 R325 variant was strictly correlated with the number of the corresponding SLC30A8 R325-encoding alleles, whereas binding against the W325 variant was highest in children who had SLC30A8 W325-encoding alleles (p = 0.001). Moreover, ZnT8A-COOH-positive children who carried homozygous SLC30A8 SNP rs13266634 genotypes progressed faster to diabetes than those who were heterozygous (59% [95% CI 42.3-75.7%] vs 22% [95% CI 0-44.3%] within 5 years; p = 0.01). Autoimmunity against the COOH-terminal region of ZnT8 is a highly relevant prognostic feature in childhood type 1 diabetes. Risk stratification in ZnT8A-COOH-positive children is further improved by SLC30A8 genotyping.

Endocrine autoimmunity in families with type 1 diabetes: frequent appearance of thyroid autoimmunity during late childhood and adolescence

Thyroid autoimmunity clusters with other endocrine and non-endocrine forms of autoimmunity. The aim of this study was to determine the chronological appearance of thyroid autoantibodies in relation to other forms of autoimmunity in at-risk children. The BABYDIAB study follows children of parents with type 1 diabetes. Children born in Germany between 1989 and 2000 were recruited at birth and followed up at 9 months and at 2, 5, 8, 11, 14 and 17 years. Antibodies to thyroid peroxidase were measured in samples taken at the last study visit in 1,489 children and in all previous samples in children who tested positive. Islet antibodies and antibodies to 21-hydroxylase and transglutaminase were also measured in all children. Median follow-up was 8 years. The cumulative risk for developing antibodies to thyroid peroxidase was 20.3% (95% CI 12.3-28.3) by age 14 years. The risk was increased in girls (adjusted HR 2.0; 95% CI 1.2-3.4; p = 0.008), in children who had multiple first-degree family history of type 1 diabetes (adjusted HR 3.3; 95% CI 1.4-8.0; p = 0.006) and in children who also had antibodies to GAD (adjusted HR 3.0; 95% CI 1.5-5.9; p = 0.001). Thyroid peroxidase antibody appearance was most common from age 8 years and was often the last autoantibody to develop in children with other autoantibodies. Among children of patients with type 1 diabetes, the appearance of thyroid autoantibodies is frequent, is not synchronous to the appearance of other autoantibodies and is most common in late childhood and adolescence.

Influence of a family history of type II diabetes on fasting leptin and adiponectin plasma levels

Background and aimsFamily history of type II diabetes appears to increase the risk of type II diabetes and of coronary heart disease. The aim of this study was to evaluate the effect of a first-degree family history of type II diabetes on fasting plasma concentrations of leptin and adiponectin in an outpatient clinical setting.Methods and resultsThe study included 46 nondiabetic premenopausal overweight and obese women, aged 22–50 years. A total of 22 subjects had no family history of type II diabetes until the third generation (FH−) and 24 subjects had a family history of type II diabetes (FH+), defined as having one or both parents with type II diabetes. Fasting plasma leptin and adiponectin were measured by radioimmunoassay. Leptin concentrations were significantly higher (p < 0.05) in FH+ than in FH− subjects. Moreover, after multiple regression analyses, both leptin (positively, p < 0.01) and adiponectin (negatively, p < 0.05) maintained a significant association with family history of diabetes, independently of age, body mass index, insulin resistance (estimated by homeostasis model assessment, HOMAIR), glucose, lipids, and blood pressure levels.ConclusionsThis study indicated that a genetic predisposition to type II diabetes is associated with higher leptin concentrations and lower adiponectin levels independently of insulin resistance, blood pressure and metabolic parameters, which thus possibly contribute to the higher risk of type II diabetes and cardiovascular disease in subjects with a family history of type II diabetes.

IDDM1 and Multiple Family History of Type 1 Diabetes Combine to Identify Neonates at High Risk for Type 1 Diabetes

Children of affected probands are at increased risk for type 1 diabetes. The objective of this study was to determine and stratify the risk for islet autoimmunity and childhood diabetes in newborn offspring of affected parents using family history and HLA genetic markers. Antibodies to islet autoantigens were measured at ages 9 months, 2 years, 5 years, and 8 years in 1,610 offspring of parents with type 1 diabetes participating in the German BABYDIAB study. HLA DR and DQ genetic typing was performed. Family history of type 1 diabetes was obtained from questionnaires. Extensive family history of type 1 diabetes and HLA DR/DQ genotyping were associated with islet autoantibody and diabetes risks. Significant contributions to the child's risk for developing islet autoantibodies and type 1 diabetes were conferred by a multiple first-degree family history of type 1 diabetes (two parents or one parent and a sibling; adjusted hazard [HR] ratio, 6.2 for multiple islet autoantibodies and 7.8 for type 1 diabetes), high-risk HLA genotypes (adjusted HR, 11 and 10.9), and moderate-risk HLA genotypes (adjusted HR, 6.3 and 4.3) in a multivariate analysis. Combining these factors stratified the risk for islet autoantibodies from 1 to 46% and for type 1 diabetes from 0 to 19.5% by 5 years of age. Risk of childhood diabetes in affected families can be stratified using a combination of genetic and family history markers very early in life.

European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes

Results of studies in animals and human beings suggest that type 1 diabetes is preventable. Nicotinamide prevents autoimmune diabetes in animal models, possibly through inhibition of the DNA repair enzyme poly-ADP-ribose polymerase and prevention of beta-cell NAD depletion. We aimed to assess whether high dose nicotinamide prevents or delays clinical onset of diabetes in people with a first-degree family history of type 1 diabetes. We did a randomised double-blind placebo-controlled trial of nicotinamide in 552 relatives with confirmed islet cell antibody (ICA) levels of 20 Juvenile Diabetes Federation (JDF) units or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, and were randomly allocated oral modified release nicotinamide (1.2 g/m2) or placebo for 5 years. Random allocation was done with a pseudorandom number generator and we used size balanced blocks of four and stratified by age and national group. Primary outcome was development of diabetes, as defined by WHO criteria. Analysis was done on an intention-to-treat basis. There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1.07 (95% CI 0.78-1.45; p=0.69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1.01 (0.73-1.38; p=0.97). Of 168 (30.4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion. Large-scale controlled trials of interventions designed to prevent the onset of type 1 diabetes are feasible, but nicotinamide was ineffective at the dose we used.

Effect of family history of type 2 diabetes on white blood cell count in adult women.

To evaluate the effect of a first-degree family history of type 2 diabetes on white blood cell (WBC) count, a risk factor for atherosclerotic vascular disease, in glucose-tolerant adult women. WBC count was measured in 174 normal weight, overweight, and obese female offspring of type 2 diabetic patients (FH(+)) and 174 age- and BMI-matched female controls with no family history of type 2 diabetes (FH(-)). Other measurements included fat mass (FM), measured by body impedance analysis; central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostatic model assessment for insulin resistance (HOMA(IR)); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. WBC count, waist circumference, systolic blood pressure, and fasting levels of glucose, insulin, and triglycerides were significantly higher in FH(+) than in FH(-) subjects. In FH(+) individuals, WBC count was positively associated with BMI, FM, waist circumference, HOMA(IR), and triglyceride and insulin concentrations, and negatively correlated with age and high-density lipoprotein-cholesterol. In FH(-) subjects, WBC count was directly associated with BMI, FM, waist circumference, and triglyceride and insulin concentrations, and inversely correlated with age and high-density lipoprotein-cholesterol. After multivariate analyses, WBC count maintained a significant association with age, systolic blood pressure, and HOMA(IR) in FH(+) subjects and with age, BMI, FM, and triglycerides in FH(-) individuals. This study indicates that WBC count is increased in adult women with genetic predisposition to type 2 diabetes, and its main correlates are insulin resistance in FH(+) and adiposity in FH(-) individuals.

Effect of family history of type 2 diabetes on the intima-media thickness of the common carotid artery in normal-weight, overweight, and obese glucose-tolerant young adults.

To evaluate the effect of a first-degree family history of type 2 diabetes on the intima-media thickness of the common carotid artery (IMT-CCA), a surrogate marker of coronary atherosclerosis, in glucose-tolerant young adults. IMT-CCA was measured by high-resolution B-mode ultrasound imaging in 401 individuals aged 18-45 years with normal glucose tolerance (NGT). A total of 213 subjects had no family history of type 2 diabetes until the third generation (FH(-)), and 188 subjects had a family history of type 2 diabetes (FH(+)), defined as having one or both parents with type 2 diabetes. Other measurements included: central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostasis model assessment for insulin resistance (HOMA(IR)); systolic and diastolic blood pressure; fasting and postload concentrations of glucose; fasting insulin levels; and lipid profile. IMT-CCA and both 1- and 2-h postchallenge glucose concentrations were significantly higher in FH(+) than in FH(-) subjects. IMT-CCA was positively correlated with age, BMI, waist circumference, triglycerides, systolic and diastolic blood pressure levels, basal glucose concentrations, 1- and 2-h postchallenge glucose concentrations, and HOMA(IR). IMT-CCA was inversely associated with HDL cholesterol. After multivariate analysis, IMT-CCA maintained a significant association with family history of type 2 diabetes, BMI, waist circumference, HDL cholesterol, diastolic blood pressure, and fasting glucose. This study indicates that a genetic predisposition to type 2 diabetes, probably in association with slightly elevated glucose levels, may accelerate the development of atherosclerosis and increase the risk for coronary heart disease in glucose-tolerant individuals.

The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population.

To examine whether a potential marker for type 2 diabetes (family history) is related to CAD in type 1 diabetic subjects. The two major types of primary diabetes, type 1 and type 2, are both associated with an increased risk of developing coronary artery disease (CAD). However, the etiology and associated risk factors may differ by type of diabetes. In type 2 diabetes, CAD is likely to be linked with the insulin resistance associated with the type 2 "process," while CAD in type 1 diabetes has, so far, been more closely linked to renal disease. Because the etiologies of type 1 and type 2 diabetes are different, it is possible that some CAD in type 1 diabetes may be related to the coexistence of type 2 diabetes susceptibility (i.e., insulin resistance). We evaluated the interrelationships between family history of type 2 diabetes (age at onset > 30 years, no insulin for 1st year) and presence of CAD in a cohort of childhood-onset type 1 diabetic subjects using the Pittsburgh Epidemiology of Diabetes Complications study (n = 658). A first-degree family history of type 2 diabetes was reported in 112 subjects, and CAD was present in 119 subjects. Those subjects reporting a family history of type 2 diabetes were significantly older, had a longer duration of type 1 diabetes, had higher triglyceride and LDL cholesterol levels, and had a borderline significantly increased Beck depression inventory. Sex differences in CAD risk factors were also noted. Using logistic regression analysis, the odds ratio (95% CI) for the presence of CAD in association with a family history of NIDDM was 1.89 (1.27-2.84). The odds ratio (95% CI) after adjusting for disease duration, triglycerides, hypertension, Beck depression, and nephropathy status was 1.45 (0.87-2.28). We conclude that a family history of type 2 diabetes is a risk factor for CAD in type 1 diabetic subjects. This supports the concept that insulin resistance may contribute to development of CAD in type 1 diabetes.