Alan R. Sinaiko

Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

BACKGROUND Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system. METHODS We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. RESULTS A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo. CONCLUSIONS Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)

Relation of weight and rate of increase in weight during childhood and adolescence to body size, blood pressure, fasting insulin, and lipids in young adults : The Minneapolis children's blood pressure study

BACKGROUND Weight gain is of concern during early development because adult obesity and its cardiovascular consequences appear to have their origins during childhood. Insulin resistance is known to be related to obesity. Thus, weight gain beginning in childhood may influence the development of insulin-induced cardiovascular risk during adulthood. METHODS AND RESULTS We monitored 679 individuals from 7.7+/-0.1 years of age with repeated measures of height, weight, and systolic blood pressure (SBP) until 23.6+/-0.2 years of age, when blood samples were obtained for measurements of insulin and lipids. Initial childhood weight, body mass index (BMI), and height were significantly correlated with young adult weight, BMI, and height and with fasting insulin, lipids, and SBP. The increases in weight and BMI but not height during childhood were significantly related to the young adult levels of insulin, lipids, and SBP. CONCLUSIONS These data suggest that weight gain in excess of normal growth during childhood is a determinant of adult cardiovascular risk. The finding in multiple linear regression analysis that weight gain during childhood rather than the childhood weight at 7.7 years of age is significantly related to young adult risk factors suggests that a reduction in weight gain could reduce subsequent levels of cardiovascular risk.

Insulin resistance in children: Consensus, perspective, and future directions

OBJECTIVE Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. PARTICIPANTS The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. EVIDENCE An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. CONSENSUS PROCESS The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. CONCLUSIONS Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.

Relation of Body Mass Index and Insulin Resistance to Cardiovascular Risk Factors, Inflammatory Factors, and Oxidative Stress During Adolescence

Background—This study assessed the relation of fatness and insulin resistance and their interaction with cardiovascular risk factors, inflammatory factors, and oxidative stress in thin and heavy adolescents. Methods and Results—Euglycemic insulin clamp studies were performed on 295 (169 male, 126 female) adolescents (mean±SE age, 15±0.1 years). Comparisons were made between (1) heavy and thin adolescents; (2) insulin-sensitive and insulin-resistant adolescents; and (3) thin insulin-sensitive (T-IS), thin insulin-resistant (T-IR), heavy insulin-sensitive (H-IS), and heavy insulin-resistant (H-IR) adolescents. Summed z scores were used to determine clustering of risk factors (fasting insulin, triglycerides, HDL-C, and systolic blood pressure [SBP]) among the groups. SBP, triglycerides, and fasting insulin were significantly higher and HDL-C significantly lower in the heavy adolescents. Fasting insulin and triglycerides were significantly higher and HDL-C significantly lower in the insulin-resistant adolescents. Among the 4 groups, the risk factors and cluster score followed a pattern of risk as follows: T-IS<T-IR<H-IS<H-IR, with H-IR significantly greater than the other groups and showing an interaction between fatness and insulin resistance. Conclusions—These results show the significant association of both fatness and insulin resistance and their significant interaction with cardiovascular risk factors in adolescence. The finding that insulin resistance may be acting interactively with fatness suggests that interventions directed at insulin resistance in addition to weight loss may be required to alter early development of cardiovascular risk.

Association of physical activity with insulin sensitivity in children

BACKGROUND: Physical activity (PA) has been shown to improve insulin resistance and other cardiovascular disease risk factors in normal and diabetic adults and in obese youth, but not in non-diabetic, normal-weight children.METHODS: Data from 357 non-diabetic children (10–16 y) were used to examine cross-sectional associations with PA. Insulin sensitivity was assessed with a euglycemic hyperinsulinemic clamp and expressed as Mffm (glucose utilization/kg of fat-free mass/min).RESULTS: Correlations were adjusted for age, sex, race and Tanner stage. PA was significantly correlated with fasting insulin and insulin sensitivity (r=−0.12, P=0.03 and r=0.13, P=0.001, respectively), more strongly in children with above-median systolic blood pressure (r=−0.17, P=0.03 and r=0.35, P=0.0001, respectively). Further adjustment for body mass index, body fat percentage, waist circumference or lipids did not alter these observations.CONCLUSIONS: Physical activity is correlated with lower fasting insulin and greater insulin sensitivity in childhood. These results are consistent with the hypothesis that increasing physical activity among youth may reduce the incidence of type 2 diabetes in children and adolescents.

Comparison of body fatness measurements by BMI and skinfolds vs dual energy X-ray absorptiometry and their relation to cardiovascular risk factors in adolescents.

OBJECTIVE:To compare estimates of adiposity by dual emission X-ray absorptiometry (DXA), skinfolds and body mass index (BMI); and to evaluate the relation of these measures to cardiovascular risk in adolescents.DESIGN:In a cohort of adolescents participating in a longitudinal study of insulin resistance, Slaughter formulas were used to estimate adiposity from skinfolds and DXA was used to estimate adiposity as % body fat (%BF) and fat mass (FBM). BMI, blood pressure, lipids and insulin resistance were measured.SUBJECTS:Male and female, 11–17 y old (n=130).MEASUREMENTS:To compare DXA with two office-based methods of assessing fatness and cardiovascular risk.RESULTS:Slaughter estimates were highly correlated with DXA (%BF r=0.92, P=0.0001; FBM r=0.96, P=0.0001). Correlations were similar in heavy and thin children. BMI was also highly correlated with DXA (%BF r=0.85, P=0.0001; FBM r=0.95, P=0.0001), and these relations were stronger in heavy than thin children. BMI and the Slaughter formulas were similar to DXA in their relations to cardiovascular risk factors.CONCLUSIONS:Adiposity by BMI and Slaughter formulas are highly correlated with DXA and similarly related to cardiovascular risk factors. BMI is easy to obtain and is an acceptable method for initial office estimation of body fatness. BMI and skinfolds compare well with DXA in predicting adverse cardiovascular risk profile.

Secular trends of blood pressure and body size in a multi-ethnic adolescent population: 1986 to 1996.

OBJECTIVES To determine the levels and time trends of blood pressure and body size in a healthy population of youth. STUDY DESIGN Minneapolis, Minnesota, fifth through eighth grade public school children (aged 10 to 14 years) were surveyed in 1986 and 1996. Blood pressure, height, and weight were measured by technicians trained to the same rigorous protocol at each time period, and comparisons were made between the 2 groups (1986 and 1996). RESULTS In 1986 and 1996, 8222 and 10,241 children, respectively, were measured with participation rates of over 93%. African American, Hispanic, Native American, Asian, and non-Hispanic white groups were all represented. Systolic blood pressure was significantly higher and diastolic blood pressure lower in 1996 than in 1986 in all ethnic and gender groups. Weight and body mass index (wt/ht2) were significantly higher in all groups in 1996. Adjustment for body size largely eliminated the systolic blood pressure differences but had no effect on measured diastolic blood pressure. CONCLUSIONS Body size and systolic blood pressure are rising among school children. Weight and body mass index show substantial increases over 10 years (1986-1996). Diastolic blood pressure fell for unclear reasons. These changes may have future health implications for cardiovascular disease, as these youth move into adulthood.

Changes in Insulin Resistance and Cardiovascular Risk During Adolescence Establishment of Differential Risk in Males and Females

Background— Developmental changes in insulin resistance and cardiovascular risk were studied in youths 11 to 19 years of age. Methods and Results— A cohort was randomly selected after blood pressure screening of Minneapolis, Minn, school children. Studies were done 3 times on this cohort and once on their siblings (996 observations on 507 individuals from 363 families). Insulin sensitivity was determined by euglycemic clamp. Body mass index and waist circumference increased similarly in both sexes from ages 11 to 19 years. Body fat decreased in males and increased in females (P<0.001). Lean body mass increased at a steeper rate in males (P<0.0001). Insulin resistance was lower in males at 11 years but increased steadily to 19 years (P=0.003); in contrast, it did not increase in females. Thus, despite being less insulin resistant at 11 years and decreasing in fatness during puberty, males became more insulin resistant than females by 19 years of age. Triglycerides increased in males and high-density lipoprotein cholesterol decreased, whereas the opposite pattern was seen in females, which resulted in higher triglycerides and lower high-density lipoprotein cholesterol in males at 19 years. No gender difference in low-density lipoprotein or total cholesterol was seen. Systolic blood pressure increased in both sexes but at a greater rate in boys (P=0.03). Conclusions— During the transition from late childhood through adolescence, insulin resistance in males increased in association with increased triglycerides and decreased high-density lipoprotein cholesterol, despite a concurrent reduction in body fatness, whereas the opposite occurred in females. These gender-related developmental changes in insulin resistance, which were independent from changes in fatness, total cholesterol, and low-density lipoprotein cholesterol, are consistent with an early role for insulin resistance in the increased cardiovascular risk found in males.

Measurement of insulin sensitivity in children: comparison between the euglycemic-hyperinsulinemic clamp and surrogate measures.

OBJECTIVE—In this study we compared fasting insulin and measures of insulin sensitivity (M) based on fasting insulin and glucose (i.e., homeostasis model assessment [HOMA], quantitative insulin sensitivity check index [QUICKI], and fasting glucose–to–insulin ratio [FGIR]) or triglycerides to the insulin clamp in a cohort of children/adolescents. RESEARCH DESIGN AND METHODS—The subjects were Minneapolis fifth- to eighth-grade students. Euglycemic-hyperinsulinemic clamps were performed on 323 adolescents at mean age 13 and were repeated on 300 of these subjects at mean age 15. Insulin sensitivity was determined by glucose uptake (milligrams per kilogram per minute) adjusted for lean body mass (MLBM) and steady-state insulin (MLBM/ln SSI). Comparisons were made for the whole cohort and by body size (BMI <85th percentile vs. BMI ≥85th percentile). Receiver operating characteristic (ROC) curves were used to test whether specific fasting insulin cut points separated true-positive from false-positive approximations of insulin resistance. RESULTS—Fasting insulin was significantly correlated with HOMA (r = 0.99), QUICKI (r = 0.79), FGIR (r = −0.62), and (ln fasting insulin + ln triglycerides) (r = 0.88). Correlations of the surrogates with MLBM were significantly lower than those with M for the total cohort and ≥85th percentile group. In general, correlations in the ≥85th percentile group were higher than those in the <85th percentile group. Correlations with MLBM and MLBM/ln SSI decreased in the total cohort and ≥85th percentile group from age 13 to 15. ROC curves showed only a modest capability to separate true- from false-positive values. CONCLUSIONS—Surrogate measures are only modestly correlated with the clamp measures of insulin sensitivity and do not offer any advantage over fasting insulin. In general, lower correlations are seen with MLBM than with M and with thinner than with heavier individuals.

Antineutrophil cytoplasmic autoantibody-positive crescentic glomerulonephritis as a complication of treatment with propylthiouracil in children

Propylthiouracil, which is commonly used in the treatment of hyperthyroidism, has been associated in adults with antineutrophil cytoplasmic autoantibody, a serologic marker of vasculitis. Severe renal disease has not been reported as a complication of therapy with this drug. We report severe antineutrophil cytoplasmic autoantibody-positive vasculitis in children receiving propylthiouracil, as well as rapidly progressive crescentic glomerulonephritis after administration of this drug.