Early presentation of type 2 diabetes in Mexican-American youth.

OBJECTIVE: To describe features of pediatric-onset type 2 diabetes in the Hispanic population. RESEARCH DESIGN AND METHODS: The medical records of 55 Hispanic subjects with diabetes who were treated from 1990 to 1994 in a pediatric clinic serving lower income Mexican-Americans were reviewed to assess the frequency and clinical features of type 2 diabetes. Additionally, nondiabetic siblings of several patients underwent oral glucose tolerance testing, and a survey of six high schools in the same county was performed. RESULTS: Seventeen of 55 (31%) of the diabetic children and adolescents had type 2 diabetes. An additional 4 Hispanic children with type 2 diabetes treated in other clinics were also identified, yielding a total of 21 subjects who were used to describe the characteristics of childhood type 2 diabetes. At presentation, all were obese (mean BMI 32.9 +/- 6.2 kg/m2), 62% had no ketonuria, and fasting C-peptide levels were elevated (4.28 +/- 3.43 ng/ml). Diabetes was easily controlled with diet, sulfonylureas, or low-dose insulin. No autoantibodies were present in those tested, and family histories were positive for type 2 diabetes. Compliance was poor, and 3 subjects developed diabetic complications. Of the tested siblings, 2 of 8 had impaired glucose tolerance and 5 of 8 had stimulated hyperinsulinemia, correlated with BMI (r = 0.80, P < 0.05). The school survey identified 28 diabetic adolescents, 75% more than expected (P < 0.01). The Hispanic enrollment at each school was highly correlated with the number of diabetic students (r = 0.87, P = 0.011). CONCLUSIONS: Genetic susceptibility to type 2 diabetes, when coupled with obesity, can produce type 2 diabetes in Mexican-American children. This diagnosis should be considered in young Hispanic patients, who might otherwise be assumed to have type 1 diabetes, and also when caring for overweight Hispanic youth with a family history of type 2 diabetes, in whom intervention may prevent or delay diabetes onset.

Hypothalamic-pituitary-adrenal axis function in very low birth weight infants treated with dexamethasone.

The effect of dexamethasone therapy on hypothalamic-pituitary-adrenal axis function was prospectively investigated in very low birth weight infants with bronchopulmonary dysplasia. Ten infants (mean +/- SD birth weight 825 +/- 265 g, gestation 25.8 +/- 1.9 weeks, postnatal age 33.1 +/- 17.7 days) initially received intravenous dexamethasone, 0.5 mg/kg per day for 3 days, and then were weaned over a period of 45 +/- 19.0 days to a replacement dose, followed by a metyrapone test. Morning plasma cortisol and 11-deoxycortisol levels were measured before and after an oral metyrapone dose given at midnight. Five infants (group A: birth weight 876 +/- 313 g, gestation 26.2 +/- 1.3 weeks, age of entry 31.8 +/- 22.8 days) had normal metyrapone test results, and five infants (group B: 778 +/- 234 g, 25.4 +/- 2.5 weeks, 34.4 +/- 13.4 days) had suppressed test results. Group A infants, in comparison with group B infants, had higher basal cortisol plasma levels (14.52 +/- 12.53 and 3.00 +/- 1.38 micrograms/dL, P = .047), higher postmetyrapone 11-deoxycortisol plasma levels (3.11 +/- 3.93 and 0.55 +/- 0.51 micrograms/dL, P = .028), larger differences between basal and postmetyrapone cortisol levels (7.10 +/- 4.67 and 2.12 +/- 1.31 micrograms/dL, P = .047), and larger differences between basal and postmetyrapone 11-deoxycortisol levels (2.99 +/- 3.93 and 0.29 +/- 0.25 micrograms/dL, P = .009). The hypothalamic-pituitary-adrenal axis function in group B infants eventually returned to normal when they continued to receive low-dose dexamethasone therapy after a period of 36.8 +/- 16.6 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen consumption and guanosine diphosphate binding by fetal brown adipose tissue in diabetic pregnancy.

Oxygen consumption and 3H-guanosine diphosphate (GDP) binding were determined in brown adipocytes and mitochondria from 28-day gestation fetuses of alloxan-diabetic rabbit does and saline-injected controls. Maternal diabetes was classified as severe or mild determined by whether maternal blood glucose values were greater or less than 200 mg/dL, respectively, at death. Basal oxygen consumption and adipocyte diameters did not vary among groups. A significant reduction in maximal norepinephrine (NE) stimulated O2 consumption by fetal brown adipose tissue (BAT) cells was seen in offspring of severely diabetic pregnancies when compared with control values (248 +/- 53 +/- v482 +/- 32 microL O2/10(6) cells/h; P less than .005). In contrast, a significant increase in maximal NE-stimulated O2 consumption by fetal BAT cells occurred in offspring of mild diabetic pregnancies (807 +/- 60, P less than .001 v controls). A highly significant inverse correlation between serum glucose levels and maximal O2 consumption by fetal BAT was observed in fetuses from mild and severe diabetic pregnancies (r = -.98, P less than .005), and there was no correlation between these two parameters in offspring of normal pregnancies. A significant inverse correlation was observed between maximal O2 consumption by fetal BAT cells and serum insulin levels in offspring of both control and diabetic pregnancy (r = -.74; P less than .02). Tissue cytochrome oxidase activity was lower in offspring of severely affected diabetic does, indicating a reduction in BAT mitochondrial content compared with controls. BAT mitochondria from fetuses of severely diabetic does exhibited reduced 3H-GDP capacity, which was 2.5-fold lower than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of glyburide in type II diabetes mellitus. Studies of monocyte membrane fluidity, lipid composition, and insulin binding.

Monocyte membrane lipid composition, fluidity, and insulin binding were studied in 10 previously untreated obese type II (non-insulin-dependent) diabetic subjects before and 2-7 days, 1 mo, and 3 mo after glyburide therapy. A significant reduction in fasting blood glucose levels occurred within 1 wk after initiation of therapy in all subjects. Serum insulin levels did not change significantly. After a transient increase at 2-7 days, insulin binding and receptor number decreased to less than pretreatment levels after 3 mo of therapy despite continued improved glycemic control. Molar cholesterol-phospholipid ratios increased significantly at 2-7 days and then reverted to pretreatment levels. A significant positive correlation between insulin binding and cholesterol-phospholipid ratios was seen at all durations of treatment. Membrane microviscosity as measured by fluorescence polarization of the probe diphenylhexatriene was significantly decreased after 3 mo of therapy. The results indicate that the glycemic effect of glyburide represents enhancement of insulin action and occurs independently of membrane insulin receptors.

Neonatal hypoglycemia associated with umbilical artery catheter positioned at the eighth to ninth thoracic vertebrae.

Previous reports of neonatal hypoglycemia have been associated with malpositioned umbilical cord artery catheters. Neonatal hypoglycemia in association with normally positioned umbilical artery catheter and responsive to catheter repositioning is reported for the first time.

Insulin-receptor development in normal and diabetic pregnancies. Role of membrane fluidity.

In the hyperinsulinemic offspring of the diabetic mother, both significant macrosomia and postnatal hypoglycemia are thought to be due to increased insulin sensitivity. The purpose of this study is to characterize changes in insulin-receptor development in fetal offspring of an experimental model of diabetic pregnancy. Two groups of Sprague-Dawley female rats were studied after timed mating. Both groups received injections of either vehicle (controls) or streptozocin (diabetic), 40 mg/100 g body wt, on day 7 of pregnancy and were killed at either 17, 20, or 21 days of gestation. Maternal and fetal blood were assayed for glucose and insulin, and fetal liver membranes were prepared for 125I-labeled insulin binding, lipid composition, and fluorescence polarization studies with the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Maternal and pooled fetal glucose levels were elevated in streptozocin-treated rats; however, pooled fetal insulin values were not elevated in the offspring of diabetic animals compared with controls (33 +/- 1 vs. 50 +/- 5 microU/ml). 125I-insulin binding was greater in fetal offspring of diabetic (FD) rat membranes at each gestational age studied [P less than .001 by analysis of variance (ANOVA)] due to significantly greater numbers of both high- and low-affinity receptors. The highest insulin-binding capacity was seen on membranes obtained from FD rats at day 21 (9.92 M X L-1 X 100 micrograms membranes-1 vs. 6.38 M X L-1 X 100 micrograms protein-1 in fetal control (FC) rats. At each gestational age, membranes from FDs had lower values for fluorescence polarization (using the probe DPH) than did gestational-age--matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of caloric restriction and exercise on insulin receptors in obesity: association with changes in membrane lipids.

We have studied the effects of supervised caloric restriction and exercise on mononuclear leukocyte lipid composition, membrane fluidity, and insulin receptors in ten nondiabetic obese adults, (175 +/- 9.3% of ideal body weight) and ten normal adult subjects. In a second study, we examined the effects of caloric restriction alone using a very low calorie liquid diet in the treatment of another ten obese adults. In both groups of obese adults, fasting insulin levels were elevated and fell to normal levels following treatment. Insulin binding to monocytes, which was reduced in obese subjects, increased toward normal after short-term treatment; this was due to the restoration of total insulin binding capacity to levels one half of that seen in the normal adult group. Obese subjects undergoing either treatment had elevated membrane cholesterol/phospholipid ratios prior to treatment (0.499 +/- 0.050 and 0.446 +/- 0.011 v 0.400 +/- 0.025 mol/mol in normal adults P less than 0.005 by ANOVA). Prior to treatment, for all subjects there was a significant inverse correlation between insulin tracer binding and membrane cholesterol/phospholipid ratios (r = .484, n = 34, P less than 0.005). This relationship did not change significantly in obese subjects in either treatment group. Cell membrane microviscosity was determined by fluorescence polarization (FP) using DPH (2 X 10(-6) mol/L). Prior to weight loss, obese subjects had significantly higher FP values than controls (0.304 +/- 0.006 and 0.319 v 0.259 +/- 0.009, P less than 0.005, by ANOVA) indicating greater microviscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial excitation-contraction coupling in the fetus of alloxan-diabetic rabbit.

This study was conducted to investigate myocardial excitation-contraction coupling in the fetus of the diabetic rabbit (FDM). On day 14 of gestation, diabetes was induced in pregnant rabbits by alloxan injection. On day 28 of gestation, mechanical function of the fetal myocardium was determined in the isolated arterially perfused heart preparation. At 1.5 mM [Ca2+]o (control), the force of myocardial contraction in FDM was not significantly different from that in the control fetus. At higher [Ca2+]o, developed tension and maximal rate of tension development [+dT/dt (max)] in FDM were significantly greater than in the control fetus. High [Ca2+]o caused significant increases in resting tension and half-relaxation time (toxic effects) in the control fetus, but not in FDM. Perfusion with lanthanum (known to displace sarcolemma-bound Ca2+ and block sarcolemmal Na-Ca exchange) decreased developed tension and +dT/dt (max) and increased resting tension and these effects in FDM were significantly less than in the control fetus. Perfusion with manganese (known to displace Ca2+ from intracellular sites) also decreased developed tension and +dT/dt (max) and increased resting tension, and these effects were similar in the two groups. The myofibrillar ATPase activities at various calcium concentrations were not different between the two groups. The rates of Ca2+ uptake by mitochondria and sarcoplasmic reticulum were similar in the two groups. These data suggest that in FDM the inotropic effect of Ca2+ is greater and the toxic effect of Ca2+ is less than in the control fetus.(ABSTRACT TRUNCATED AT 250 WORDS)

Membrane fluid properties of cord blood mononuclear leucocytes: association with increased insulin receptors.

Insulin receptors are present on fetal and newborn tissues in significantly greater numbers than on adult tissues. Recent studies have suggested that membrane fluidity, which is dependent upon lipid constituents, is important in regulating the appearance and behavior of insulin receptors. We have compared the lipid composition and fluidity as well as insulin receptor binding to monocytes from normal adults and full term normal infants. Newborn infants had significantly higher insulin levels than did fasting adults (17.4 +/- 2.4 versus 9.8 +/- 0.6 microU/ml; P less than 0.001); despite this, cord blood monocytes showed significantly higher 125I-insulin tracer binding than did those of adults (9.5 +/- 0.51 versus 7.6 +/- 0.45%/10(7) cells; P less than 0.02). From Scatchard analysis, it was evident that cord monocytes had greater numbers of both high (2.94 versus 1.25 X 10(-10) M-1) and low affinity (13.1 versus 8.57 X 10(-10) M-1) receptors than adult monocytes. Cord mononuclear cells had significantly lower phospholipid concentrations than adult cells (0.085 +/- 0.012 versus 129 +/- 0.012 mg/mg of protein; P less than 0.025) and significant elevations of cholesterol/phospholipid ratios (0.520 +/- 0.045 versus 0.354 +/- 0.009; P less than 0.005). Microviscosity determinations were performed using the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene. Cord cells had significantly greater microviscosity values (fluorescence polarization) (0.339 +/- 0.030 versus 0.186 +/- 0.019; P less than 0.005), compared to adult cells. For all subjects, a highly significant correlation was noted between cell microviscosity measurements (fluorescence polarization) and 125I-insulin tracer binding to mononuclear cells (r = 0.72, n = 15, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased fetal insulin receptors and changes in membrane fluidity and lipid composition.

Fetal tissues exposed to hyperinsulinemia in utero have significantly greater numbers of insulin receptors than do those of controls. We have studied this upregulation phenomenon using crude microsomal membranes from fetal rabbit litters exposed to varying degrees of hyperinsulinemia in diabetic pregnant rabbits. We have observed that insulin binding capacity of membranes increased directly with the severity of maternal diabetes, ranging from 8.5 ng in controls to 44.6 ng insulin/mg membrane protein in offspring of severely diabetic animals and related directly with increasing fetal insulin levels (r = 0.77, P less than 0.005). Lipid analyses of fetal lung membranes showed that reduction of phospholipid to protein ratios occurred in the presence of maternal diabetes. Membrane cholesterol-to-phospholipid ratios were also altered in the presence of maternal diabetes. Significantly, increases in plasma membrane microviscosity were noted in the membranes from diabetic offspring. The data suggest that reduction of membrane fluidity is associated with increases in fetal membrane insulin receptors in severely diabetic pregnancies.

Monocyte insulin receptors in infants of strictly controlled diabetic mothers.

Infants of diabetic mothers have hyperinsulinism at birth, presumably resulting from maternal hyperglycemia or some other derangement of maternal metabolism, and are extremely sensitive to insulin. Such infants have significantly greater numbers of insulin receptors on cord blood monocytes compared to normal infants. To assess the role of maternal diabetic control, nine infants of insulin-dependent diabetic mothers, who were intensively treated during pregnancy, were studied. Maternal blood glucose values were measured during weekly out-patient visits throughout pregnancy, and insulin therapy was given to maintain fasting blood glucose values below 100mg/dl. When necessary, the patients were hospitalized early in pregnancy in order to achieve glucose control, and all patients were hospitalized for up to 2 weeks before delivery for strict glucose control. The mean birth weight (+/- SD) of these infants (3.23 +/- 0.23 kg) was lower than that of nine infants of mothers with gestational diabetes not receiving insulin or intensive efforts at maintenance of normoglycemia (3.99 +/- 0.12; P less than 0.01) and was not significantly different from that of normal infants (3.51 +/- 0.37 kg). Mean cord blood C-peptide levels (+/- SD), determined by RIA, were 1.6 +/- 0.78 ng/ml for infants of these strictly controlled diabetic mothers and 1.4 0.1 ng/ml for normal infants. Scatchard analysis of [125]insulin binding to cord blood monocytes yielded mean receptor numbers for infants of diabetic mothers of 22,500 vs. 105,000 sites/cell for infants of diabetic mothers (P less than 0.001) and 26,600 sites/cell for normal infants. We conclude that the strict control of maternal diabetes during the last trimester of pregnancy prevents fetal hyperinsulinemia and is associated with the development of normal numbers of insulin receptors on the infants' monocytes.

Insulin receptors in cystic fibrosis: increased receptor number and altered affinity.

Patients with cystic fibrosis are known to have pancreatic disorganization with associated pancreatic exocrine insufficiency. Endocrine hormonal secretion is also affected but diminution in insulin secretion is rarely accompanied by overt diabetes. We studied seven patients with cystic fibrosis to determine their carbohydrate tolerance and the status of peripheral monocyte insulin receptors. Oral glucose tolerance tests showed the presence of mild hyperglycemia and diminished insulin secretion. Mean insulin receptor sites per cell were markedly increased above controls, 25,000 vs 13,100 sites per cell while receptor affinity was diminished. The increase in receptor number could be a consequence of the insulinopenia and/or the decreased body weight of the patients and serve as a compensatory mechanism maintaining a degree of relative insulin sensitivity. Ultimate carbohydrate tolerance may be a function of the patient's ability to maintain increased receptor numbers in the face of hypoinsulinemia and impaired receptor affinity.

Inhibition of surfactant production by insulin in fetal rabbit lung slices.

Incorporation of labeled glucose and fatty acid residues into saturated phosphatidylcholine was significantly reduced in lung slices from 27.5 days of gestation fetal rabbits during 90 min incubation in the presence of 100 microU/ml insulin. When 14C-glucose was used as substrate, incorporation into both phosphatidylcholine and saturated phosphatidylcholine was reduced by insulin. This occurred despite an increase in overall glucose utilization by the lung from 11.3 +/- 3.9 to 16.3 +/- 5.2 nmole/g tissue in the presence of insulin (P less than 0.05). A decrease in incorporation of fatty acid residues into saturated phosphatidylcholine was also observed when 14C-palmitate was used as substrate, from 102 +/- 4 to 90 +/- 5 nmole palmitate/g tissue (P less than 0.01). In the presence of insulin, there were significant reductions of both substrates appearing in lysophosphatidylcholine, a precursor of saturated phosphatidylcholine. There was no significant change in incorporation of glucose residues into glycogen or lactate under these conditions.

Increased monocyte receptor binding of [125I]insulin in infants of gestational diabetic mothers.

Monocyte insulin receptor binding has been shown to be inversely correlated with basal insulin concentrations in a variety of clinical conditions and is believed to reflect autoregulation of receptor properties of insulin. We examined the insulin receptor in the infant of the gestational diabetic mother (IGDM) where hyperinsulinism has been implicated in the attendant metabolical abnormalities. Insulin concentrations in plasma of cord blood of IGDM were significantly greater than in normals delivered between 36-38 weeks by elective cesarean section (101.3 +/- 9.8 vs. 59.9 +/- 9.4 microU/ml; P less than 0.005). [125I]Insulin binding to receptors of monocytes obtained from cord blood showed that IGDM had more receptor sites per monocyte than normal adults and normal infants. In normal infants of similar gestational age, a significant correlation was found between birthweight and binding which was not observed in IGDM. Monocytes from both normal infants and IGDM showed greater affinity for insulin than those from adults. At plasma insulin concentrations of 1 and 4 ng/ml, monocytes from IGDM had about 10 times and normal infants had about 4 times as many sites occupied as those from normal adults. Monocytes from IGDM seem to develop increased concentrations of insulin receptors with hyperinsulinemia. Thus, despite increased ambient levels of insulin, monocytes of IGDM seem to develop increased concentrations of insulin receptor as well as increased affinity for the hormone.

Disproportionate growth of the lower extremities. A major determinant of short stature in Turner's syndrome.

The relationships between the height (H), sitting height (SH), and the lower segment (H-SH) were studied in a group of 21 patients with Turner's syndrome. The SH/H ratio was markedly abnormal (0.55), equivalent to that of 6-year-old normal girls. The abnormality in ratio was a result of markedly shortened lower extremities. Further, there was a significant inverse correlation between SH/H-SH ratio and height such that patients with the most shortening of their legs were the shortest. The degree of abnormality in lower segment, therefore, is a major determinant of stature in Turner's syndrome.