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Prescription opioid and heroin abuse have been increasing steadily year after year, and continue to be a serious national problem. A sequela of the increase in opioid abuse has been an increase in the number of infants born with opioid dependence. These infants often require costly, prolonged stays in the neonatal intensive care unit (NICU) for drug withdrawal treatment. The authors studied a population of infants from a large Medicaid health plan who were born with neonatal abstinence syndrome (NAS) secondary to in utero opioid exposure to assess the average length of stay in the NICU, and to determine the variables that may account for differences in interinstitutional lengths of stay. The overall average length of stay for NAS was 21.1 days for the 139 infants included in the study. Analysis of the medication used for treatment revealed that infants who were treated with a combined inpatient/outpatient regimen with methadone had an average length of stay of 11.4 days versus 25.1 days for infants who were treated entirely as inpatients (P

The fetal programming theory that birth weight contributes to blood pressure or body size in later life is examined in this study. A prospective longitudinal study was conducted on subjects who were examined as newborns and prospectively interviewed and re-examined at 11 to 14 years old. Low birth weight (r =0.19, P

Objective: Recent retrospective studies of older adults have demonstrated a correlation between lower birth weight and hypertension and insulin resistance. We tested this finding in our sample of urban African Americans with prospective data on growth and blood pressure and also tested other variables (in addition to birth weight) for their relationship to adult cardiovascular risk. Study design: A prospective study of birth weight, growth, and blood pressure (Philadelphia Perinatal Collaborative Project) followed a sample of 137 African Americans, with nine examinations from birth through 28.0 ± 2.7 years. Metabolic measurements (oral glucose tolerance testing, euglycemic hyperinsulinemic clamp, and plasma lipid concentration) were performed on the subjects as adults. Bivariate correlations among parameters were computed using the Pearson r . The chi-squared statistic was used to determine associations of outcomes with birth weight. Stepwise multiple linear regressions were computed using newborn, early childhood, adolescent, and young adult parameters to predict adult outcomes. Results: Birth weight and blood pressure at age 28 years are not correlated (Pearson r = 0.06). Birth weight is also unrelated to adult obesity. However, weight at 0.3 years and after and body mass index at 7 years and after are correlated with adult weight. Furthermore, weight at age 14 years is significantly negatively correlated with measures of insulin-stimulated glucose use, indicating that obese adolescents may be at greater risk than nonobese adolescents for development of non-insulin dependent diabetes in adulthood. Conclusions: We found no relationship between birth weight and adult outcomes pertaining to cardiovascular risk in this sample of adult African Americans. However, we did find evidence that somatic growth (body weight and body mass index) is significantly related to obesity and attenuated insulin-stimulated glucose utilization in adulthood. These findings indicate that the origins of adult cardiovascular disease are related to somatic growth, but not intrauterine growth, and are evident during childhood. (J Pediatr 1998;132:90-7)

We have previously shown that juvenile Sprague-Dawley rats, fed a diet in which complex carbohydrates are replaced by sucrose, develop insulin resistance and hypertension. These conditions develop despite the absence of genetic predisposition to either. When studied with the euglycemic hyperinsulinemic clamp technique, these rats have reduced insulin-stimulated glucose utilization, but normal suppression of hepatic glucose output. In the young sucrose-fed rats, it was noted that the degree of blood pressure elevation was greater in males than in females. The purpose of this study was to test the hypothesis that estrogen withdrawal increases insulin resistance and hypertension. Female rats were randomized at weaning (3 weeks of life) to receive control diet or sucrose diet. Animals were assessed with weekly weight and indirect tail-cuff blood pressure. At 8 weeks of life, the sucrose-fed rats were randomized to receive bilateral oophorectomy or sham surgery (anesthesia and uterine horn exposure without removal of the ovaries). At 13 to 14 weeks of life, all animals were fasted overnight, and had an oral glucose tolerance test while conscious. Weight and weight gain were not different among the groups over the 11 week study period. Animals fed the sucrose diet developed significantly higher blood pressure than animals fed the control diet; oophorectomized animals had higher blood pressure than sham-operated animals (P

To test the hypothesis that atrial natriuretic peptide (ANP) concentration in the newborn is negatively related to plasma renin concentration (PRC), as it is in the adult, we measured the concentration of both substances in the same plasma sample. We studied 24 well term newborns and 20 samples of umbilical venous blood from normal deliveries. Both ANP and PRC are elevated in newborn plasma, but not in umbilical venous plasma. ANP levels on the second day of life are greater than either day 1 or day 3. Linear regression of ANP and PRC demonstrates a highly significant negative correlation [r = -0.65, p less than 0.001], which suggests that the suppression of the renin-angiotensin system by ANP seen in the adult may be intact in the newborn. ANP may act to blunt the effects of the augmented renin-angiotensin system of the newborn and promote normal neonatal diuresis.

To determine experimentally if insulin resistance is associated with spontaneously occurring hypertension, insulin-stimulated glucose metabolism was studied in an animal model of genetic hypertension. The spontaneously hypertensive rat (SHR) and its genetic control, the Wistar-Kyoto strain (WKY) were studied with the euglycemic hyperinsulinemic clamp technique. Clamp studies demonstrated reduced insulin-stimulated glucose uptake in SHR (P less than .001). These data indicate that SHR is insulin-resistant when compared with WKY. A reduction of insulin-stimulated glucose metabolism occurred in older animals of both strains, providing evidence of an aging effect on insulin-stimulated glucose metabolism. However, the reduction of insulin-stimulated glucose metabolism was more pronounced in the hypertensive animals. This study demonstrates the presence of peripheral (skeletal muscle) insulin resistance in the SHR.

Abstract— In older white American adults, recent retrospective studies have demonstrated a relationship between lower birth weight and hypertension. Black Americans have a higher occurrence of both lower birth weight and hypertension than do white Americans. To test the low birth weight–high blood pressure hypothesis, data from a prospective study (Perinatal Collaborative Project) were examined. The study followed a sample of 137 black Americans, with nine examinations. Data on birth weight, growth, and blood pressure from birth through 28.0±2.7 years were obtained longitudinally. Bivariate correlations among parameters were computed with the Pearson r . Birth weight and blood pressure at age 28 years are not correlated (Pearson r =.06). However, systolic blood pressures measured at 0.3 years and thereafter are correlated with adult systolic blood pressure. Also, weight at 0.3 years and body mass index at 7 years and thereafter are correlated with adult weight. Our data did not confirm the birth weight–blood pressure hypothesis. Rather, we detected significant correlations between preadult measurements of blood pressure and weight with adult measurements. These results indicate that in black Americans, childhood growth is a stronger determinant than intrauterine growth of adult blood pressure.

The purpose of this study was to determine whether there are gender differences in plasma insulin levels or insulin resistance in young adult African-Americans. Male (n = 53) and female (n = 45) subjects (age 23 to 28 years) included normotensives (N, blood pressure [BP]135/85 mm Hg) and borderline hypertensives (BH, BP135/85 mm Hg). Plasma insulin concentration was measured during an oral glucose tolerance test (OGTT) in all subjects. In 50 cases, insulin clamps were performed. Plasma estradiol and free testosterone were analyzed in a subsample (n = 15) of women. Data were analyzed for BP and gender groups by two-way ANOVA. Compared to men, women in each BP group had higher plasma insulin: glucose ratios (P.01) and sums of insulin on OGTT (P.02). The insulin clamp data also demonstrated significantly lower insulin-stimulated glucose utilization (M) in women compared to men in each BP group (N males 7.28 +/- 0.72 v N females 4.94 +/- 1.2 mg/kg-min; BH males 5.28 +/- .56 v BH females 2.59 +/- 0.50 mg/kg-min; P.004 for gender differences). Analysis of the sex hormone data found a significant correlation in the ratio of free testosterone/estradiol (T/E) with plasma glucose, insulin, insulin/glucose, and systolic BP (P.05), and no correlation of T/E with body mass index or triceps skinfold thickness. These data indicate that there are significant gender differences in plasma insulin levels and in insulin sensitivity in African-Americans. The relationship of plasma insulin to sex hormones suggests that in females, hyperinsulinemia cosegregates with increased androgenicity.

The purpose of this investigation was to determine whether there is a relation between impaired insulin-stimulated glucose utilization, or insulin resistance, and blood pressure (BP) in a young adult black population. Clinically well, young black men and women, including normotensive (BP < 135/85 mm Hg, n = 23) and borderline hypertensive (BP > or = 135/85 mm Hg, n = 27) individuals, were studied. Each subject had an oral glucose tolerance test (OGTT) and underwent a euglycemic hyperinsulinemic clamp procedure. A two-way analysis of variance demonstrated a significantly greater fasting insulin plasma concentration (P < .02) and sum of insulin levels during the OGTT (P = .04) in the borderline hypertensive compared with normotensive subjects. In both BP groups, women had significantly higher fasting plasma insulin levels than men (P < .02 and P = .009). Body mass index was a significantly covariate of the plasma insulin concentration. Data obtained from the clamp demonstrated significant insulin resistance in borderline hypertensive compared with normotensive subjects (4.69 +/- 0.50 versus 6.57 +/- 0.63 mg/kg per minute, P = .002). A stepwise multiple linear regression analysis demonstrated that there are significant multiple correlations of insulin resistance with body mass index, clamped insulin level, BP group, and systolic BP (multiple R = .7862, P < .001). Application of this analysis to the nonobese sample (n = 33) found significant correlations of insulin resistance with sex, BP group, and systolic BP (multiple R = .6817, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance, independent of obesity or non-insulin-dependent diabetes mellitus, has been demonstrated to be associated with high blood pressure. To determine if insulin resistance could be an antecedent to hypertension in a high-risk population, we studied normotensive (112 +/- 12/70 +/- 10 mm Hg) and borderline hypertensive (135 +/- 8/85 +/- 5 mm Hg) lean young black men (22-26 years old) with the euglycemic hyperinsulinemic clamp technique. All subjects had clinically normal oral glucose tolerance. Body mass index and percent adipose mass were the same in both groups. Fasting plasma insulin concentration was significantly higher in the borderline hypertensive group (p less than 0.01). Insulin-directed exogenous glucose metabolism at the same degree of steady-state hyperinsulinemia was significantly lower in the borderline hypertensive group (5.98 +/- 2.22 versus 8.22 +/- 1.96 mg/kg/min; p less than 0.01). For the total population, a significant inverse correlation existed between the glucose infusion rate and systolic blood pressure (p less than 0.01). These data indicate that there is a relation between insulin-mediated glucose uptake and blood pressure. Furthermore, in this high-risk population insulin resistance may precede the onset of established essential hypertension.

CHILDHOOD GROWTH, NOT BIRTH WEIGHT, PREDICTS CARDIOVASCULAR RISK IN AFRICAN AMERICANS. † 549

The effects of euglycemic hyperinsulinemia on hepatic and muscle metabolism were determined in the fasted newborn dog during the first day of life. Hyperinsulinemia was sustained with a primed constant infusion of insulin whereas euglycemia was maintained with an intravenous infusion of 10% glucose using the insulin clamp technique. Euglycemic hyperinsulinemia caused an increase of glucose utilization from 43.9 +/- 3.7 to 66.5 +/- 5.4 mumol/kg/min (p less than 0.001) and reduced endogenous glucose production to 44.4 +/- 5.4% of basal values obtained before the induction of hyperinsulinemia. Hepatic tissue glycogen, triglycerides, or intermediates were not altered by hyperinsulinemia nor was the incorporation of [3H]glucose into glycogen. However, the hepatic cytoplasmic redox state was more oxidized, and the incorporation of [3H]glucose into triglycerides was higher among hyperinsulinemic pups. Pups who demonstrated incomplete suppression of endogenous glucose production had metabolite perturbation suggestive of ongoing gluconeogenesis. Despite very few changes in hepatic tissue metabolite levels, pups subjected to hyperinsulinemia demonstrated a linear uptake of 2-deoxyglucose into hepatic tissue as a function of circulating insulin levels during hyperinsulinemia. Muscle tissue demonstrated no alterations of tissue metabolites, glycogen, or triglycerides levels or precursor incorporation into these storage pools. Nonetheless, 2-deoxyglucose incorporation into neonatal muscle tissue was a significant linear function of plasma insulin concentration. Total tissue 2-deoxyglucose uptake was lower in muscle tissue than in hepatic tissue (245 +/- 19 versus 514 +/- 20 dpm/g/min) (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The developmental response to the euglycemic hyperinsulinemic clamp was assessed among newborn and adult beagles to investigate neonatal insulin resistance. Both neonatal dogs and adults were clamped at euglycemic blood glucose concentrations while receiving insulin at a rate of 3.75, 15, 30, 60, 75 or 100 mU/kg/min to generate a dose-response curve. Blood glucose levels, plasma insulin concentrations and glucose turnover rates during the basal preclamp fasting period were similar in pups and adult dogs. During the clamp period, blood glucose levels were equivalent to the preclamp period whereas plasma insulin concentrations increased. Total glucose utilization increased from 28.7 +/- 18 to a plateau level of 114 +/- 52.3 mumol/kg/min in adult dogs and from 30.9 +/- 10.9 to 53.9 +/- 28.9 mumol/kg/min in newborn dogs. Suppression of endogenous glucose production during euglycemic hyperinsulinemia was close to 100% among adult dogs, whereas in the newborn pups, endogenous glucose production was suppressed 80%. To determine if the newborn was unable to increase glucose uptake because of a saturation effect on glucose utilization independent of insulin, another group of adult and newborn dogs received a hyperglycemic hyperinsulinemic clamp. In response to the hyperglycemic clamp, adults demonstrated an increase of glucose utilization to 261 +/- 83, and newborn dogs increased utilization to 227 +/- 76 mumol/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Made available in DSpace on 2022-04-28T18:53:55Z (GMT). No. of bitstreams: 0 Previous issue date: 1988-01-01 There is a paucity of information on the significance of insulin on neonatal cerebral glucose metabolism. The effect of insulin on neonatal cerebral glucose uptake and cerebral cortical metabolic intermediates was investigated with the euglycemic hyperinsulinemic clamp in unanesthetized beagles during the first day of life. Insulin was infused at various rates to sustain an elevated steady state plasma insulin concentration in individual pups. Furthermore, blood glucose and 2-deoxyglucose levels were also maintained (clamped) in a steady state by infusion of glucose and 2-deoxy-[14C]-gIucose. Mean (± SD) plasma insulin levels were 20 ± 12 and 2971 ± 3386 (33-14330) nU/ml in control and hyperinsulinemic pups. Blood glucose concentration was 4.43 ± 2.64 mM during basal periods and 4.54 ± 2.87 mM during the clamp period in study pups. Basal fasting glucose utilization in study pups was 43.9 ± 24 μmol/kg/min and increased to 60.9 ± 35.2 ^mol/ kg/min (p < 0.001) during hyperinsulinemia. Immediately after the euglycemic hyperinsulinemic clamp or fasting in control pups, the cerebral cortex was frozen to the temperature of liquid nitrogen. No differences were noted for any cerebral cortical intermediate between the two pup groups. In addition, there was no relationship between the cerebral intermediates concentration when analyzed as a function of plasma insulin levels. The uptake of cerebral 2-deoxyglucose was analyzed as a function of plasma insulin concentration (120-6900 μU/ml). Brain tissue demonstrated a positive linear relationship for 2-deoxyglucose uptake as a function of plasma insulin concentration. Although static determination of brain metabolites were not influenced by hyperinsulinemia, there was a positive effect of insulin on cerebral glucose uptake. Either directly or indirectly, insulin may increase brain glucose utilization in the newborn dog. © 1988 International Pediatric Research Foundation, Inc. Department of Pediatrics Case Western Reserve University Rainbow Babies Childrens Hospital, Cleveland, OH, 44106 Department of Pediatrics UNESP, Sao Paulo Department of Pediatrics UNESP, Sao Paulo

Insulin infusion to 3 hr old term dogs (n=6, control=6)lowered blood glucose (1.31±0.17 vs 8.12±0.29 mM p