Non-diabetic Offspring Of Type Research Articles

Serum IgG2 levels are specifically associated with whole-body insulin-mediated glucose disposal in non-diabetic offspring of type 2 diabetic individuals: a cross-sectional study

Preclinical studies suggested that IgG2c isotype may specifically impair skeletal muscle insulin sensitivity in mice. In this study we investigated the association between serum levels of the four IgG subclasses and insulin sensitivity in non-diabetic individuals. Total IgG, IgG1, IgG2, IgG3 and IgG4 levels were measured in 262 subjects. Whole-body insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. IgG2 levels were positively correlated with BMI, waist circumference, 2-h post-load glucose levels and complement C3. Serum IgG2, but not IgG1, IgG3 and IgG4 levels were negatively correlated with whole-body insulin sensitivity (r = −0.17; P = 0.003) and muscle insulin sensitivity index (r = −0.16; P = 0.03) after adjustment for age and gender. No significant correlation was found between IgG2 levels and hepatic insulin resistance assessed by HOMA-IR and liver IR index. In a multivariable regression analysis including variables known to affect insulin sensitivity such as age, gender, BMI, smoking, lipids, inflammatory markers, fasting and 2-h post-load glucose levels, IgG2 levels were independently associated with insulin-stimulated glucose disposal (β = −0.115, 95% CI: −0.541 to −0.024; P = 0.03). These data demonstrate the independent association between higher levels of IgG2 and decreased whole-body insulin sensitivity, thus confirming in humans the animal-based evidence indicating the pathogenic role of IgG2 in insulin resistance.

Assessment of Nerve conduction in non-diabetic offspring of type 2 diabetic parents - a pilot study

Assessment of Nerve conduction in non-diabetic offspring of type 2 diabetic parents - a pilot study

A study of heart rate variability among non-diabetic offspring of type 2 diabetic parents

Background: Type 2 diabetes mellitus is an inheritable condition that runs in families as a disorder of impaired glycemic control and its complications. Among the complications of diabetes, autonomic neuropathy contributes to the development of cardiovascular disease states besides diabetic vascular complications. Sympathovagal imbalance is reported to be observed among the non-diabetic first-degree relatives of diabetic population. Aims and Objectives: To assess the heart rate variability (HRV) parameters in non-diabetic normotensive offspring of diabetic parents and infer the impairment in sympathovagal balance in them by comparing with the HRV findings of non-diabetic offspring of non-diabetic parents. Materials and Methods: This cross-sectional observational study was conducted on 30 healthy non-diabetic, normotensive volunteers with parental history of Type 2 diabetes and 30 non-diabetic normotensive volunteers without parental history of diabetes. The volunteers were between the age of 17 and 25 years with normal body mass index and no health condition that could influence the cardiovascular health. The basal cardiovascular parameters and a 5 min lead II electrocardiogram for short-term HRV analysis were recorded to assess the sympathovagal balance. Results: The HRV analysis reveals a statistically significant increase in the sympathetic components and decreased parasympathetic components in the nondiabetic offspring of diabetic parents when compared to the non-diabetic offspring of non-diabetic parents. Conclusion: From our study, it could be observed that the non-diabetic offspring of diabetic parents have enhanced sympathetic activity and attenuated vagal activity even in their non-diabetic state, thus inferring an early onset of sympathovagal imbalance that could predispose them to hypertension and its sequel.

Association between hemoglobin glycation index with insulin resistance and carotid atherosclerosis in non-diabetic individuals.

Hemoglobin glycation index (HGI), defined as the difference between the observed HbA1c value and the value of HbA1c predicted from plasma glucose levels, represents a measure of the degree of non-enzymatic glycation of hemoglobin and it has been found to be positively associated with micro- and macro-vascular complications in subjects with type 2 diabetes. To investigate the pathophysiological abnormalities responsible for the increased cardiovascular risk of patients with higher HGI, we evaluated the association of HGI with cardio-metabolic characteristics in nondiabetic offspring of type 2 diabetic individuals. Insulin sensitivity, measured by a hyperinsulinemic-euglycemic clamp, cardio-metabolic risk factors including lipid profile, uric acid and inflammatory factors, and ultrasound measurement of carotid intima–media thickness (IMT) were assessed in 387 nondiabetic individuals. Participants were stratified in tertiles according to HGI (high, moderate and low). As compared with subjects with low HGI, those with high HGI displayed an unfavorable cardio-metabolic risk profile having significantly higher values of BMI, waist circumference, triglycerides, uric acid, fasting insulin, inflammatory markers, such as high sensitivity C reactive protein, erythrocytes sedimentation rate, complement C3, fibrinogen, and white blood cell count, and carotid IMT, and lower HDL and insulin-stimulated glucose disposal. In a linear regression analysis model including several atherosclerotic risk factors such as gender, age, BMI, inflammatory factors, lipid profile, insulin-stimulated glucose disposal, fasting insulin, uric acid, and blood pressure, HGI was the major predictor of IMT (β = 0.35; P = 0.001). In a logistic regression analysis adjusted for confounders, individuals with high HGI showed a 2.7-fold increased risk of vascular atherosclerosis (OR 2.72, 95%CI 1.01–7.37) as compared with subjects with low HGI. The present findings support the notion that HGI may be a useful tool to identify a subset of nondiabetic individuals conceivably harboring a higher risk of cardiovascular disease.

A Possible Early Alteration of Autonomic Activity Assessed by Heart Rate Variability in Saudi Offspring of Type 2 Diabetic Patients

Background and Objectives: To evaluate cardiac autonomic function in non-diabetic offspring of Type 2 diabetes mellitus patients through assessment of heart rate variability. Autonomic dysfunction was reported in glucose tolerant on insulin-resistant offspring of Type 2 diabetes mellitus subjects. No data is available on cardiac autonomic dysfunction in Saudi offspring of Type 2 diabetes mellitus.
 Subject and Methods: Ninety-seven subjects with family history and 30 subjects with no family history of diabetes mellitus as a control group were studied. Anthropometric and biochemical characteristics (fasting blood glucose, lipids, and insulin resistance) were measured. Heart rate variability parameters were recorded.
 Results: No significant differences in the anthropometric, biochemical or heart rate variability parameters between the group with positive family history of diabetes mellitus and the control group. Subjects with positive family history of diabetes mellitus were split into 2 groups as per the presence or absence of insulin resistance. Insignificantly, an increased sympathetic tone was seen in Type 2 diabetes mellitus offspring with insulin resistance as compared to those without it. Body mass index, waist circumference, waist to hip ratio, total cholesterol, triglyceride, and fasting insulin and fasting blood glucose were also significantly higher in the insulin resistance group.
 Conclusion: There was a high prevalence of insulin resistance among the young subjects with positive family history of diabetes. Thus, had an increased sympathetic activity compared to those who were insulin sensitive. This study confirms the early autonomic dysfunction in offspring of Type 2 diabetes mellitus subjects previously reported in other non-Saudi populations.

A Possible Early Alteration of Autonomic Activity Assessed by Heart Rate Variability in Saudi Offspring of Type 2 Diabetic Patients

Background and Objectives: To evaluate cardiac autonomic function in non-diabetic offspring of Type 2 diabetes mellitus patients through assessment of heart rate variability. Autonomic dysfunction was reported in glucose tolerant on insulin-resistant offspring of Type 2 diabetes mellitus subjects. No data is available on cardiac autonomic dysfunction in Saudi offspring of Type 2 diabetes mellitus.
 Subject and Methods: Ninety-seven subjects with family history and 30 subjects with no family history of diabetes mellitus as a control group were studied. Anthropometric and biochemical characteristics (fasting blood glucose, lipids, and insulin resistance) were measured. Heart rate variability parameters were recorded.
 Results: No significant differences in the anthropometric, biochemical or heart rate variability parameters between the group with positive family history of diabetes mellitus and the control group. Subjects with positive family history of diabetes mellitus were split into 2 groups as per the presence or absence of insulin resistance. Insignificantly, an increased sympathetic tone was seen in Type 2 diabetes mellitus offspring with insulin resistance as compared to those without it. Body mass index, waist circumference, waist to hip ratio, total cholesterol, triglyceride, and fasting insulin and fasting blood glucose were also significantly higher in the insulin resistance group.
 Conclusion: There was a high prevalence of insulin resistance among the young subjects with positive family history of diabetes. Thus, had an increased sympathetic activity compared to those who were insulin sensitive. This study confirms the early autonomic dysfunction in offspring of Type 2 diabetes mellitus subjects previously reported in other non-Saudi populations.

Variant near ADAMTS9 Known to Associate with Type 2 Diabetes Is Related to Insulin Resistance in Offspring of Type 2 Diabetes Patients—EUGENE2 Study

BackroundA meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity.Methodology/ResultsOral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2nd phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits.ConclusionThe present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.

Cardiovascular Autonomic Dysfunction as a Link Between Insulin Resistance and Nocturnal Blood Pressure Elevation

HomeHypertensionVol. 51, No. 4Cardiovascular Autonomic Dysfunction as a Link Between Insulin Resistance and Nocturnal Blood Pressure Elevation Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCardiovascular Autonomic Dysfunction as a Link Between Insulin Resistance and Nocturnal Blood Pressure Elevation Antonio Perciaccante Antonio PerciaccanteAntonio Perciaccante Internal Medicine, “San Giovanni Decollato-Andosilla” Hospital, Civita Castellana, Italy Search for more papers by this author Originally published3 Mar 2008https://doi.org/10.1161/HYPERTENSIONAHA.108.110361Hypertension. 2008;51:e30Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 3, 2008: Previous Version 1 To the Editor:I read with interest the article by Lurbe et al1 on the relationship between insulin resistance and the ambulatory blood pressure components in obese children and adolescents. The authors have observed that nocturnal systolic blood pressure and heart rate were significantly higher in subjects in the highest homeostasis model assessment index tertile. They conclude that the increased nocturnal blood pressure and heart rate associated with hyperinsulinemia may contribute to heightened cardiovascular risk associated with this condition. I agree with the authors, and I want suggest cardiovascular autonomic function as a possible link between insulin resistance and increased nocturnal blood pressure.This hypothesis is supported by several pieces of evidence. Scherrer and Sartori2 have observed that hyperinsulinemia activates the central sympathetic drive. Several studies performed by spectral analysis of heart rate variability have shown sympathetic hyperactivity in insulin-resistant subjects with normoglycemia.3,4 In a previous study performed in adult subjects, Perciaccante et al5 have reported a relationship between insulin resistance and cardiovascular autonomic dysfunction, characterized by an impaired circadian rhythm of heart rate variability with a sympathetic hyperactivity at nighttime. Moreover, the authors have reported that this hyperactivity of sympathetic component at nighttime (evaluated by heart rate variability analysis in the frequency domain as low frequency expressed in normalized units and the low frequency:high frequency ratio) is correlated with the highest homeostasis model assessment index.I conclude that insulin resistance has an impact on nocturnal blood pressure and heart rate, and this may be because of the effect of the insulin resistance on the cardiovascular autonomic activity.DisclosuresNone.1 Lurbe E, Torro I, Aguilar F, Alvarez J, Alcon J, Pascual MJ, Redon J. Added impact of obesity and insulin resistance in nocturnal blood pressure elevation in children and adolescent. Hypertension. 2008; 51: 635–641.LinkGoogle Scholar2 Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone. Implications for blood pressure regulation, insulin sensitivity and cardiovascular morbidity. Circulation. 1997; 96: 4104–4114.CrossrefMedlineGoogle Scholar3 Laitinen T, Vauhkonen IK, Niskanen LK, Hartikainen JE, Lansimies EA, Uusitupa MI, Laakso M. Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects. Diabetes. 1999; 48: 1295–1299.CrossrefMedlineGoogle Scholar4 Pikkujamsa SM, Huikuri HV, Airaksinen KE, Rantala AO, Kauma H, Lilja M, Savolainen MJ, Kesaniemi YA. Heart rate variability and baroreflex sensitivity in hypertensive subjects with and without metabolic features of insulin resistance syndrome. Am J Hypertens. 1998; 11: 523–531.CrossrefMedlineGoogle Scholar5 Perciaccante A, Fiorentini A, Paris A, Serra P, Tubani L. Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus. BMC Cardiovasc Disord. 2006; 2: 6: 19–28.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByLurbe E (2008) Response to Cardiovascular Autonomic Dysfunction as a Link Between Insulin Resistance and Nocturnal Blood Pressure Elevation, Hypertension, 51:4, (e31-e31), Online publication date: 1-Apr-2008. April 2008Vol 51, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.108.110361PMID: 18316649 Originally publishedMarch 3, 2008 PDF download Advertisement SubjectsObesity

Changes in Inflammatory Cytokines Are Related to Impaired Glucose Tolerance in Offspring of Type 2 Diabetic Subjects

We sought to determine whether levels of inflammatory markers and different cytokines are abnormal in nondiabetic offspring of type 2 diabetic subjects. Cytokine levels were measured in 19 healthy control subjects and 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance [NGT] and 20 with impaired glucose tolerance [IGT]). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography. Levels of C-reactive protein and inflammatory cytokines were elevated in nondiabetic offspring of type 2 diabetic subjects. Interleukin (IL)-1beta was increased in the NGT group and decreased in the IGT group. In contrast, levels of IL-1 receptor antagonist (IL-1Ra) were increased in both groups. IL-1beta and -Ra levels correlated inversely (P < 0.05) with rates of whole-body glucose uptake and IL-1beta positively with visceral fat mass (P < 0.05) in normoglycemic offspring. Nondiabetic offspring of type 2 diabetic subjects have changes in the levels of inflammatory cytokines. The level of IL-1Ra seems to be the most sensitive marker of cytokine response in the pre-diabetic state.

Familial factors in diabetic nephropathy: an offspring study

Familial clustering of diabetic nephropathy in patients with Type 2 diabetes suggests that inherited factors predispose to diabetic nephropathy, but the nature of these factors is uncertain. The aim of the study was to compare the prevalence of known risk factors for nephropathy in non-diabetic offspring of Type 2 diabetic patients with and without nephropathy and in control subjects. Three groups of patients were recruited with 40 or 41 subjects in each group. These were subjects having one Type 2 diabetic parent with nephropathy (DN); subjects having one parent with Type 2 diabetes without nephropathy (DnoN), and non-diabetic unrelated control subjects with no personal or parental history of diabetes (Control subjects). The median (interquartile range) albumin/creatinine ratio (ACR) was 1.40 (0.96-2.90) mg/mmol in DN; 0.94 (0.50-1.46) mg/mmol in DnoN and 1.22 (0.66-1.83) mg/mmol in Controls (ANOVA: P = 0.03). ACR was higher in group DN than in DnoN (P < 0.006) and in Control subjects (P < 0.03), but there was no difference between DnoN and Control subjects. Twenty-four-hour ambulatory blood pressure monitoring showed mean daytime systolic blood pressure to be significantly higher in group DN than in DnoN (P < 0.02) or Control subjects (P < 0.01) (ANOVA: P = 0.004). Fasting insulin, HOMA-IR, interleukin-6 (IL-6) and C-reactive protein (CRP) were similar in the three groups. Our data provide further evidence that genetic factors are important in determining urinary albumin excretion and renal disease associated with Type 2 diabetes and suggest that genes that affect systemic arterial blood pressure but not those relating to insulin resistance or inflammation are likely to be implicated.

Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: The Bogalusa Heart Study

The occurrence of metabolic abnormalities related to insulin resistance syndrome in nondiabetic offspring of type 2 diabetic parents is known. However, information is lacking on the timing and the course of development of the components of this syndrome from childhood to adulthood in the offspring of parents with diabetes. This aspect was examined in a community-based cohort with (n = 303) and without (n = 1,136) a parental history of type 2 diabetes followed longitudinally since childhood (ages 4 to 17 years; mean follow-up period, 15 years) by repeated surveys. Offspring with parental diabetes versus those without such history had significantly excess generalized and truncal adiposity as measured by body mass index (BMI) and subscapular skinfold beginning in childhood, higher levels of fasting insulin and glucose and homeostasis model assessment index of insulin resistance (HOMA-IR) from adolescence, and higher levels of low-density lipoprotein (LDL) cholesterol and triglycerides and lower levels of high-density lipoprotein (HDL) cholesterol in adulthood. Many of these risk variables changed adversely at an increased rate in offspring of diabetic parents. In a multivariate analysis, parental diabetes was an independent predictor of longitudinal changes in adiposity, glucose, insulin, HOM-IR, systolic and diastolic blood pressure, and LDL cholesterol in the offspring, regardless of race and gender. As young adults, the offspring of diabetic parents had a higher prevalence of generalized (BMI > 30, 36% v 16%, P =.0001) and visceral (waist > 100 cm, 15% v 6%, P =.0001) obesity, hyperinsulinemia indicative of insulin resistance (insulin > 18 μU/mL, 15% v 8%, P =.0001), hyperglycemia (≥110 mg/dL, 2% v 0.5%, P =.02), high LDL cholesterol (≥160 mg/dL, 11% v 7%, P =.02), low HDL cholesterol (<40 mg/dL for males and <50 mg/dL for females, 40% v 31%, P =.004), high triglycerides (≥150 mg/dL, 23% v 15%, P =.0001), and hypertension (>140/90 mm Hg, 11% v 6%, P =.004). Thus, the offspring of diabetic parents displayed excess body fatness beginning in childhood and accelerated progression of adverse risk profile characteristics of insulin resistance syndrome from childhood to young adulthood. These observations have important implications for early prevention and intervention. Copyright 2003 Elsevier, Inc. All rights reserved.

Increased Plasma-Soluble Tumor Necrosis Factor-α Receptor 2 Level in Lean Nondiabetic Offspring of Type 2 Diabetic Subjects

Tumor necrosis factor-alpha (TNF-alpha) is one of the proposed mediators of insulin resistance, upregulated in human obesity. Insulin resistance, however, might precede the development of obesity, especially in subjects with a family history of type 2 diabetes. Therefore, the aim of the present study was to assess plasma levels of TNF-alpha and soluble forms of its receptors (soluble TNF-alpha receptors 1 [sTNFR1] and 2 [sTNFR2]) and to evaluate the relationship of the TNF-alpha system with insulin resistance in lean, nondiabetic offspring of type 2 diabetic patients. We compared 20 lean offspring (BMI <25 kg/m(2), 8 men and 12 women) of type 2 diabetic patients with 20 lean subjects with no family history of diabetes, matched for age, sex, and BMI (control group). Anthropometry and blood biochemical parameters were measured, and insulin sensitivity was evaluated with the euglycemic-hyperinsulinemic clamp technique. Both men and women in the offspring group were markedly more insulin-resistant and had higher plasma levels of sTNFR2 (all P < 0.05). TNF-alpha, sTNFR1, and other examined parameters did not differ between the studied groups. Both TNF-alpha receptors were related to waist-to-hip ratio (WHR), fat-free mass (FFM), plasma total cholesterol, HDL cholesterol, LDL cholesterol, and nonesterified fatty acids (NEFAs). sTNFR2, but not sTNFR1, was also associated with insulin sensitivity (r = -0.49, P = 0.001). This relationship remained significant after adjustment for WHR, FFM, plasma insulin, and NEFA. TNF-alpha system might be involved in modulating insulin action before the onset of obesity in subjects at high risk for type 2 diabetes.

Normal blood pressure and preserved diurnal variation in offspring of type 2 diabetic patients characterized by features of the metabolic syndrome: the Fredericia Study.

To examine whether an elevated blood pressure (BP) level and an impaired reduction in nocturnal BP are already present in nondiabetic first-degree relatives of type 2 diabetic patients. We examined 253 offspring of type 2 diabetic patients using ambulatory BP monitoring and compared the BP level and profile with 275 offspring of nondiabetic subjects. Anthropometric measures and cholesterol, fasting blood glucose, and insulin levels were also compared between groups. No significant differences in BP level (P > 0.05) or diurnal BP profile were evident between the nondiabetic glucose-tolerant offspring of type 2 diabetic subjects and the offspring of nondiabetic subjects. BMI (P < 0.05 and P < 0.01, male vs. female), waist-to-hip ratio (P < 0.05), fasting blood glucose (P < 0.01), C-peptide (P < 0.05 and P < 0.01, male vs. female), insulin resistance index (P < 0.05 and P < 0.01, male vs. female), triglycerides (P < 0.05), apolipoprotein B (apoB) (P < 0.01 and P < 0.05, male vs. female), and apoA1/apoB (P < 0.01) were significantly higher in the nondiabetic offspring of type 2 diabetic subjects than in the offspring of nondiabetic subjects. This study shows a preserved diurnal BP profile and a normal BP level in the nondiabetic glucose-tolerant offspring of type 2 diabetic subjects compared with the offspring of nondiabetic subjects, although the offspring of diabetic patients are characterized by features of the metabolic syndrome.

Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects.

Sympathetic activation has been considered as a link between insulin resistance, hyperinsulinemia, and hypertension. However, little is known about the association between insulin sensitivity and autonomic regulation or about the effect of acute hyperinsulinemia on cardiac sympathovagal balance. The aim of this study was to investigate heart rate variability (HRV) during the euglycemic-hyperinsulinemic clamp in nondiabetic offspring of patients with type 2 diabetes. We studied 35 nondiabetic offspring of patients with type 2 diabetes and 19 control subjects. Probands were chosen from a 10-year follow-up study of patients with well-characterized type 2 diabetes according to their fasting C-peptide level (selected from both ends of the distribution) and from control subjects to form three groups: 1) a group including subjects who were offspring of type 2 diabetic patients with low C-peptide levels (deficient insulin secretion group [IS group], n = 17), 2) a group including subjects who were offspring of type 2 diabetic patients with high C-peptide levels (insulin-resistant group [IR group], n = 18), and 3) a control group without a history of type 2 diabetes in first-degree relatives (n = 19). HRV was assessed at baseline and at the steady state during the euglycemic-hyperinsulinemic clamp. Rates of whole-body glucose uptake (M value) were lower in the IR group than in the IS group and the control group (41+/-3 vs. 54+/-2 vs. 60+/-4 micromol x kg(-1) x min(-1), P < 0.01 and P < 0.01, respectively). In all groups, heart rate increased significantly during hyperinsulinemia. In the IR group, insulin infusion increased total power of HRV [from 7.70+/-0.15 to 8.05+/-0.15 ln(ms2), P < 0.01] and the low frequency-to-high frequency ratio (from 0.62+/-0.14 to 1.14+/-0.18, P < 0.01) and decreased power of the high frequency spectral component (from 5.73+/-0.17 to 5.43+/-0.16 ln(ms2), P < 0.05), whereas in other groups, changes in HRV were not significant. We conclude that the HRV response to acute hyperinsulinemia in the offspring of type 2 diabetic probands was likely to be modulated by the type 2 diabetic phenotype of the parent. In insulin-resistant subjects, autonomic dysfunction may be an earlier defect than hitherto acknowledged.