Non-diabetic First-degree Relatives Of Patients Research Articles

Progression from optimal blood glucose and pre-diabetes to type 2 diabetes in a high risk population with or without hypertension in Isfahan, Iran

AimTo estimate the progression rates from normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), isolated impaired fasting glucose (IFG) and combined IFG/IGT to type 2 diabetes (T2D) in a high risk population with and without hypertension (HTN) in Isfahan, Iran. MethodsDuring a mean (SD) follow-up period of 6.8 (1.7) years, 1489 non-diabetic first-degree relatives of patients with T2D with or without HTN were followed for the occurrence of T2D. At baseline and through follow-ups, participants underwent a standard 75g 2-h oral glucose tolerance test. Blood pressure was measured by standardised protocols and HTN was defined according to the criteria of the JNC7. ResultsThe progression rate (95% confidence interval) from NGT, isolated IFG, isolated IGT, and combined IFG/IGT to T2D was 10.0 (4.3, 19.6), 21.7 (9.5, 42.3), 28.2 (12.3, 54.7) and 64.7 (41.0, 96.4) per 1000 person-years in participants with HTN and 3.1 (1.5, 4.7), 16.3 (10.3, 24.2), 25.9 (17.0, 37.7) and 57.9 (46.1, 71.7) per 1000 person-years in participants without HTN based on 10,134 person-years of follow-up. Compared with individuals with NGT and without HTN, individuals with NGT and HTN, isolated IFG, isolated IGT, and combined IFG/IGT with or without HTN at baseline were more likely to progress to T2D. Compared with participants without HTN, individuals with concomitant HTN were not significantly more likely to progress to T2D. ConclusionsCompared with individuals without HTN, the presence of NGT, isolated IFG, isolated IGT, and combined IFG/IGT with concomitant HTN was not associated with higher likelihood of progression to T2D in high-risk individuals in Iran.

Soluble interleukin-2 receptor alpha in preclinical type 1 diabetes

To the Editor of ‘‘Acta Diabetologica’’. The interleukin-2 receptor alpha (IL-2RA or CD25) plays an essential role in IL-2 signaling and regulation of immune responses [1]. Soluble IL-2RA (sIL-2RA) is produced by proteolytic cleavage of membrane-bound IL-2RA after the induction of cell division and can inhibit IL-2 signaling, but paradoxically enhance T cell proliferation [2]. Serum sIL-2RA concentration is therefore considered a biomarker for T cell activation and can be increased in the context of autoimmune disease, inflammation, or infection [3]. Serum sIL-2RA concentration is also influenced by age and single nucleotide polymorphisms (SNPs) in the IL2RA gene region that are associated with susceptibility for type 1 diabetes and other autoimmune diseases [3, 4]. We here report sIL-2RA concentration in nondiabetic islet autoantibody-positive subjects at risk for type 1 diabetes. We conducted a case–control study using sera from 634 nondiabetic first-degree relatives of patients with type 1 diabetes who participated in prospective cohort studies at our institute [5]. Cases included 317 relatives (158 female) with persistent islet autoantibodies to insulin, GAD, insulinoma-associated antigen-2, and/or zinc transporter 8 [138 with one, 179 with at least two autoantibodies; median age 11.2 years; interquartile range (IQR) 7.3–16.0 years]. Controls were 317 islet autoantibody-negative relatives (169 female) who were matched for age (median age 11.2 years; IQR 7.3–16.0 years). sIL-2RA concentration was measured in a serum sample prior to type 1 diabetes onset or the last available follow-up sample for cases who had not progressed to diabetes, and the respective sample of controls. Sera were stored at -20 C prior to testing. All measurements of sIL-2RA were carried out using the same batch of a commercial ELISA kit (Opt EIA Human IL2sRa [sCD25]; BD Biosciences, San Diego, CA, USA). If DNA was available, IL2RA genotyping was obtained at SNP rs11594656 (n = 413, 247 cases) using the MassARRAY system with iPLEX chemistry (Sequenom, San Diego, CA, USA), and at rs2104286 (n = 383; 233 cases) and rs12722495 (n = 382; 236 cases) using the TaqMan 50 nuclease assay (Applied Biosystems, Warrington, UK). The study was approved by the ethics committees of Bavaria, Germany, and Ludwig-Maximilian University, Munich, Germany. All study participants gave informed consent, and investigations were carried out in accordance with the Declaration of Helsinki. sIL-2RA serum concentrations were minimally increased in islet autoantibody-positive cases (mean ± SD, Communicated by Massimo Porta.

Effect of family history of type-2 diabetes on coronary flow reserve and it’s relationship with insulin resistance: an observational study

Coronary microvascular function among offspring of patients with diabetes mellitus might be compromised when compared to persons with no first-degree relative with diabetes mellitus. The aim of the study was to evaluate effect of family history of type-2 diabetes on coronary flow reserve. In this observational study, we evaluated coronary flow reserve (CFR) via echocardiography of 95 subjects having a biological parent with type-2 diabetes and 34 healthy volunteers without any biological parent with type-2 diabetes. We have analyzed possible association with CFR and homeostasis model assessment - insulin resistance (HOMA-IR). Comparison analyses were made using independent samples t test, Chi-square test and one-way ANOVA. Association of independent variables with CFR was obtained by correlation analysis and stepwise linear regression model including potential confounders. CFR was significantly lower in the positive family history group than in the controls. Moreover, when compared with controls, the subgroup of insulin-sensitive subjects in the positive family history group also had significantly reduced CFR (2.67±0.28 vs. 2.83±0.19; p=0.01). Correlation analysis revealed that CFR was inversely correlated with HOMA-IR, (r=-0.433), fasting glucose (r=-0.331), fasting insulin (r=-0.396), and hemoglobin (Hb)A1c (r=-0.405). When the positive family history group was divided into tertiles of insulin resistance (HOMA-IR <1.3, 1.3-2.6, and >2.6; Groups 1-2, and 3), there was a significant difference in CFR between Groups 1 and 2 and between Groups 1 and 3 (p<0.05 for all). Though statistically not significant, there was also a difference in CFR between Groups 2 and 3. In a linear regression model, only fasting glucose level was independent predictor of CFR (β=-677; p value =0.001, 95% CI: -0.061 and -0.019). Nondiabetic first-degree relatives of patients with type-2 diabetes are at increased risk of developing coronary microvascular dysfunction.

P2-125 Incidence of type 2 diabetes by HbA1c and OGTT: the Isfahan diabetes prevention study

AimsThe aim of this study was to estimate the incidence of type 2 diabetes using newly proposed haemoglobin A1C (HbA1c) and current oral glucose tolerance test (OGTT) definition in an...

Insulin resistance emerges prior to β-cell function deficiency in non-diabetic first-degree relatives of patients with type 2 diabetes mellitus

Objective To investigate the insulin resistance and β-cell function in non-diabetic first-degree relatives (FDR) of patients with type 2 diabetes.Methods Of the first-degree relatives of type 2 diabetic patients,10 subjects with normal glucose tolerance(NGT) and 13 with impaired glucose tolerance(IGT) were included.The other 9 healthy subjects without family history of diabetes served as the controls.Insulin resistance was measured by hyperinsulin-euglycemic clamp,and islet β-cell function by intravenous glucose tolerance test (IVGTY).Results NC group(7.04±0.62 and 6.16±0.73 vs 10.22±0.93,both P＜0.05).There was no difference in GIR between the former two groups.The first phase insulin secretion (natural logarithm transformed data) of the NGT group was higher than that of IGT group(3.87±0.24 vs 3.03±0.28,P＜0.05),but not significant with that of NC group (3.37±0.30).The results of the disposition index (DI,natural logarithm transformed data)in NGT group (1.43 ±0.22) and NC group(1.18±0.41) were greater than that in IGT group (0.32±0.20,P＜0.01 or P＜0.05).No difference existed between IGT and NC groups.Conclusions Insulin resistance emerges in non-diabetic firstdegree relatives of patients with type 2 diabetes while glucose tolerance remains normal.Blood glucose rises only when β-cell function fails to compensate. Key words: Diabetes mellitus，type 2; First-degree relatives; Insulin resistance; Islet β-cell function; Glucose clamp technique

Mitochondrial tRNALeu(UUR) gene mutation and maternally inherited diabetes mellitus in Pakistani population

Background and objectivesMaternally Inherited Diabetes Mellitus and Deafness (MIDD) occurs due to the mutations in mitochondrial DNA (mtDNA). The most common heteroplasmic point mutation reported, is in the tRNALeu(UUR) gene, i.e., A3243G, accompanied with deafness. The objectives of the present study were to determine whether the cause of MIDD in selected Pakistani population, is also the mutation of A3243G in mitochondrial tRNALeu(UUR) gene or not, and is there any genotype–phenotype correlation for the MIDD in this population. Subjects and methodsThe present study was conducted in the Department of Biochemistry and Molecular Biology, Army Medical College, Rawalpindi, Pakistan, during the period November 2005 to November 2007. The patients and control subjects were randomly selected from the two cities; Rawalpindi and Multan (both rural and urban areas) and were divided into three groups. (1) Fifty patients with T2DM and maternal history with feature(s) of MIDD. (2) Fifty non-diabetic first-degree relatives of patients with T2DM. (3) Fifty non-diabetic controls with no maternal history of T2DM. The patients and control subjects were scanned for the detection of potential mutations in mitochondrial DNA tRNALeu(UUR) gene (np 3035–3456, 422 bp fragment). ResultsOn the basis of a polymerase chain reaction, electrophoresis and mtDNA sequencing along with insulin dependence, degree of deafness in patients and subjects, it is proved that there is no A-to-G mutation at np 3243 of mitochondrial leucine tRNA gene in any of the groups studied. ConclusionIt is concluded that in the Pakistani population, selected for the present study, the MIDD is not due to A3243G mutation in mitochondrial tRNALeu(UUR) gene.

Coronary Vasomotor Function Is Abnormal in First-Degree Relatives of Patients With Type 2 Diabetes

Nondiabetic first-degree relatives of patients with type 2 diabetes are at increased risk of developing diabetes (1) and cardiovascular disease (CVD) (2). Endothelial dysfunction is regarded as an early step in the development of atherosclerosis (3). Abnormal peripheral endothelial dysfunction detected by flow-mediated, endothelium-dependent, forearm-mediated dilatation (FMD) has been reported in first-degree relatives (4,5). The abnormal FMD could not be explained by confounding variables including age, sex, ethnicity, obesity, lipids, blood pressure, glycemia, or insulin resistance (5). However, endothelial dysfunction detected in brachial arteries may not reflect the condition of the coronary vasculature, as brachial and coronary circulations differ in terms of the microvascular architecture, pattern of blood flow, their metabolic regulation, and the pathways that are activated to induce hyperemia (6). Coronary flow reserve measurement has been considered to be a useful physiologic index for coronary circulation (6). In this study, we report for the first time impaired coronary flow reserve in young nonobese normoglycemic first-degree relatives compared with healthy control subjects. The study subjects were healthy volunteers recruited by advertisements for the University of Malaya. All gave written informed consent to participate in the study, which was approved by the local ethics committee. To be eligible as a first-degree relative, subjects had to have one or more parent with type 2 diabetes. To avoid any confounding influence on endothelial function, subjects were excluded if they had a history of smoking, manifest type 2 diabetes, hypertension, hypercholesterolemia (serum cholesterol ≥6.5 mmol/l), and concurrent CVD, including current or previous history of myocardial infarction and angina. None were on regular medication. At the screening visit, …

Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus

The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines. Forty-two non-diabetic first-degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA-2 antibody). Follow-up for 9-11 years confirmed high vs. moderate diabetes risk in islet autoantibody-positive vs. -negative relatives. Cytokines and chemokines were determined by enzyme-linked immunosorbent assay (ELISA). Serum concentrations of classic Th1-associated cytokines (IFN-gamma, IL-12, IL-18) or Th2/Treg-associated cytokines (IL-5, IL-10, IL-13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody-positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody-negative group. Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.

Attitudes and barriers to dietary advice aimed at reducing risk of type 2 diabetes in first‐degree relatives of patients with type 2 diabetes

To evaluate the attitudes to and adoption of dietary advice in nondiabetic first-degree relatives of patients with type 2 diabetes and to examine barriers to adherence. One-year controlled intervention study, where treatment group (n=73) received lifestyle education. Attitudes towards dietary advice, change in dietary habits and importance of potential barriers to adherence were evaluated by questionnaires. Nondiabetic relatives (25-55 years; males and females) of individuals with type 2 diabetes were recruited. Education was based on current nutrition recommendations and aimed at improving dietary fat quality, increasing intake of fruit and vegetables, with additional advice to reduce dietary glycaemic index (GI). Attitudes and importance of barriers were classified by the intervened subjects into four categories ranging from 'No problem' to 'Yes, definitely a problem'. Dietary adherence was monitored by food frequency questionnaire at baseline and after 1 year. Participants were generally in favour of advice aimed at improving dietary fat quality. Attitudes towards advice to reduce GI varied widely. Food selection changed in accordance with predefined dietary goals. 'Forgetfulness', 'low availability in lunch restaurant' and 'lack of ideas for cooking' were barriers to adherence. Dietary advice aimed at reducing risk of type 2 diabetes was generally positively received and adopted in subjects with heredity for the disease. The most prevalent barriers reported are potentially modifiable.

Metabolic effects of chronic glipizide gastrointestinal therapeutic system on serum glucose, insulin secretion, insulin sensitivity, and hepatic insulin extraction in glucose-tolerant, first-degree relatives of African American patients with type 2 diabetes: New insights on mechanisms of action

We examined the long-term metabolic effects of a potent sulfonylurea (SU), glipizide gastrointestinal therapeutic system (glipizide GITS) in normal glucose-tolerant (NGT), first-degree relatives of African American patients with type 2 diabetes in a randomized, placebo-controlled, double-blind manner for 24 months and 6 months after discontinuation of glipizide GITS. Fifty NGT African American first-degree relatives (n = 50)) were randomized to receive either glipizide GITS (GITS, 5 mg/d) or identical placebo (PLAC). The NGT consisted of NGT/GITS (n = 16; mean age, 43.1 ± 8.7years; body mass index [BMI], 34.8 ± 10) and NGT/PLAC (n = 34; 45.5 ± 9.7 years; BMI, 31.3 ± 3.1years). Each of the subjects underwent an oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and at yearly intervals for 2 years. Insulin sensitivity (Si) and glucose effectiveness (Sg) were determined by Bergman's minimal model method. Hepatic insulin extraction (HIE) was calculated as the molar ratio of C-peptide and insulin. The mean fasting serum glucose, insulin, and C-peptide levels in the NGT/GITS were not different from that of the NGT/PLAC. After oral glucose challenge, mean serum glucose responses slightly increased (P = not significant [NS]) at 12 and 24 months in the NGT/GITS group when compared with the baseline, 0 month, but remained unchanged in the NGT/PLAC group. In addition, serum insulin and C-peptide responses significantly increased in the NGT/GITS group, but were unchanged in the NGT/PLAC group at 12 and 24 months versus 0 month. The HIE, during OGTT, decreased by 30% from the baseline (0 month) values in the NGT/ GITS, but remained unchanged in the NGT/PLAC group at 12 and 24 months. Mean Si decreased by 30% from the baseline in the NGT/GITS group by 12 and 24 months, but remained unchanged in the NGT/PLAC group. However, the disposition index (DI) remained normal in the NGT/GITS and the NGT/PLAC groups. The DI data in the NGT/GITS group suggested that β cells maintained the ability to compensate for the lower Si during the chronic GITS administration in our high risk African Americans. Chronic GITS was well tolerated without any symptoms of either hypoglycemia or weight gain in the NGT/IGTS group. After discontinuation of GITS, the altered metabolic parameters significantly improved, returning to baseline values in the NGT/IGTS group in 6 months. In summary, chronic glipizide GITS administration (5 mg/d) was associated with increased β-cell secretion, peripheral hyperinsulinemia, reduced Si, and reduced HIE in glucose-tolerant, first-degree relatives of African American patients with type 2 diabetes. These metabolic changes were reversible within 6 months after discontinuation of glipizide GITS. Our study defines a unique mode of action of glipizide GITS in African Americans at high risk for type 2 diabetes. We conclude that the use of glipizide GITS in the primary prevention of type 2 diabetes in nondiabetic first-degree relatives of patients with type 2 diabetes impaired glucose homeostasis. © 2003 Elsevier Inc. All rights reserved.

Optimized autoantibody-based risk assessment in family members. Implications for future intervention trials.

To determine the best autoantibody-based testing strategy for recruiting relatives for future intervention trials and to establish the role of islet cell antibodies (ICAs) within this strategy. ICAs, insulin autoantibodies (IAAs), GAD antibodies, and IA-2 antibodies were determined in serum samples at study entry of 3,655 non-diabetic first-degree relatives of patients with type 1 diabetes who were followed for a median of 5.5 years. The cumulative risk of diabetes associated with single and combined antibody marker levels of > or = 97.5th percentile in schoolchildren was calculated by using life-table analysis. Of the 26 relatives who developed insulin-requiring diabetes during follow-up, 16 were aged < 20 years and 7 were aged 20-39 years at study entry. Of the 23 cases aged < 40 years, 83% had IA-2 and/or GAD antibodies, and 87% had IAA and/or GAD antibodies > or = 97.5th percentile compared with 61% who had ICAs of > or = 5 Juvenile Diabetes Foundation units (JDF U). A two-step strategy with parallel testing for IA-2/GAD antibodies followed by IAA testing identified 50% of cases aged < 20 years and was associated with a 71% risk within 10 years. In subjects aged 20-39 years, this strategy conferred a 51% risk, whereas using ICAs as the second test gave 86% sensitivity and a 74% risk. Primary screening for IA-2 and/or GAD antibodies followed by testing for IAA and/or ICA antibodies achieved the highest sensitivity in both age-groups and conferred a 63% risk. In contrast, ICAs of > or = 20 JDF U (the inclusion criteria for the European Nicotinamide Diabetes Intervention Trial) gave 48% sensitivity and 35% risk. ICA testing can be replaced as a primary screening measure by IA-2/GAD or IAA/GAD antibody testing. The sensitivity of ICAs (used alone or in combination with IAAs) gives them a useful role in second-line testing. Combination testing could reduce the size of screening populations needed for recruitment in future intervention trials by approximately 50% compared with testing based on ICAs alone.

Insulin resistance and abnormal albumin excretion in non-diabetic first-degree relatives of patients with NIDDM

Microalbuminuria has recently been associated with insulin resistance in both insulin-dependent and non-insulin-dependent (NIDDM) diabetes mellitus. To establish whether microalbuminuria in non-diabetic subjects as well is associated with insulin resistance and associated abnormalities in glucose and lipid metabolism, oral glucose tolerance tests were performed with measurement of urinary albumin excretion rate, lipids and lipoproteins in 582 male non-diabetic first-degree relatives of patients with NIDDM. In addition, insulin sensitivity was assessed in 20 of these subjects with the euglycaemic hyperinsulinaemic clamp technique. Abnormal albumin excretion rate (AER), defined as AER 15–200 Μg/min, was associated with higher systolic blood pressure (p<0.05), higher fasting glucose values (p<0.05), lower HDL-cholesterol (p<0.05) and lower apolipoprotein A-I (p<0.05) concentrations than observed in subjects with normal AER. The rate of glucose metabolism was lower in subjects with abnormal compared to subjects with normal albumin excretion rate (38.0±2.8 vs 47.3±2.4 Μmol·kg lean body mass−1. min−1; p=0.028). This difference was almost completely accounted for by a reduction in non-oxidative glucose metabolism (17.7±1.9 vs 27.4±2.7 Μmol·kg lean body mass−1. min−1; p = 0.010), which correlated inversely with the AER (r=−0.543; p=0.013). These results suggest that in non-diabetic individuals genetically predisposed to NIDDM, abnormal AER is associated with insulin resistance and abnormalities in glucose and lipid metabolism.

Risk of progression to diabetes of low titer ICA-positive first-degree relatives of type I diabetics in southern Germany

In a prospective study to evaluate the prevalence and predictive potential of circulating cytoplasmatic islet cell antibodies (ICA) and competitive insulin autoantibodies (CIAA), we screened 406 non-diabetic first-degree relatives of patients with Type I diabetes mellitus (n = 154 for CIAA). The prevalence of ICA was 2.5% (10/406) and of CIAA 0.6% (1/154) in ICA- and 10% (1/10) in ICA+ relatives at initial screening. The titer of ICA positivity in all relatives varied between 1:1 and 1:4. Values of elevated CIAA were 256 nU/ml of the CIAA+/ICA+, and 97 nU/ml of the CIAA+/ICA- relatives (normal range less than or equal to 39 nU/ml). Sera for repeat ICA and CIAA determination was obtained, and 70% of relatives were found to be again ICA+ after 1.5 years, 40% after 3 years, and 10% after 5.7 years. Both CIAA+ relatives were found to be again CIAA+ on follow-up. Intravenous glucose tolerance tests (IVGTT) were performed in all antibody-positive relatives. No decrease in first-phase insulin secretion (1 + 3 min) below the 1st percentile was observed in any of the ICA+ relatives during follow-up. No ICA+, but one CIAA+/ICA- relative had developed Type I diabetes after 5.6 years of follow-up. In summary, these results indicate that low titer ICA (less than 40 JDF units) are often transient and relatives with low titer ICA rarely progress to Type I diabetes. Elevated CIAA appear to be constant over time and associated with increased progression to overt diabetes.

Increased Basal Glucose Production and Utilization in Nondiabetic First-Degree Relatives of Patients With NIDDM

To characterize the abnormalities in basal glucose homeostasis in people who are at increased risk for non-insulin-dependent diabetes mellitus (NIDDM), we measured the rates of basal hepatic glucose output (HGO), glucose disappearance, and metabolic clearance of glucose (MCR) in 27 nondiabetic first-degree relatives of NIDDM patients and 16 age-, sex-, and weight-matched healthy control subjects with no family history of NIDDM. Mean fasting plasma glucose was significantly lower (P less than 0.05) in control subjects (mean +/- SE 77 +/- 2 mg/dl) than in relatives (84 +/- 2 mg/dl). Mean basal insulin levels were not significantly different between relatives and control subjects (10.0 +/- 1.5 vs. 7.7 +/- 1.0 microU/ml). Mean basal HGO was significantly lower in control subjects compared with relatives (1.83 +/- 0.07 vs. 2.20 +/- 0.10 mg.kg-1.min-1, P less than 0.05). Mean MCR was similar in relatives (2.58 +/- 0.12 mg.kg-1.min-1) and control subjects (2.35 +/- 0.09 mg.kg-1.min-1). In summary, this study demonstrates that basal hepatic glucose production and glucose utilization are increased in glucose-tolerant first-degree relatives compared with healthy control subjects. We conclude that impaired basal hepatic glucose regulation rather than glucose disposal is present as an early defect in glucose-tolerant first-degree relatives of NIDDM patients.

Increased basal glucose production and utilization in nondiabetic first-degree relatives of patients with NIDDM

Increased basal glucose production and utilization in nondiabetic first-degree relatives of patients with NIDDM