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A shortage of alanine for gluconeogenesis is believed responsible for various forms of hypoglycemia and in particular ketotic hypoglycemia (KH). We examined the glucose-alanine relationship in two groups of fasting children, 18 with KH and 44 controls. Glucose levels declined in both groups but significantly more in KH; to 1.98 +/- 0.20 versus 3.26 +/-0.13 mM (mean +/- SEM; P less than 0.001). Alanine also fell in both groups, the concentrations correlating significantly with the concomitant glucose levels (KH: r = 0.64, P less than 0.001, and controls: r = 0.50, P less than 0.001). The relationship of alanine to glucose gave virtually identical regression equations, y = 0.054x + 0.063 for KH and y = 0.054x + 0.050 for controls. The differences in alanine levels between the two groups were too small to account for the greater decline in glucose in KH. The results indicate that hypoalaninemia rather than causing hypoglycemia results from it. [ABSTRACT FROM AUTHOR]

Objectives: To quantify urinary citrate and calcium excretion and systemic acid-base status in patients with type 1a glycogen storage disease (GSD1a) and to investigate their relationship to renal complications., Study Design: Fifteen patients (7 male and 8 female; age range, 3--28 years) were studied during annual evaluations of metabolic control. All were treated with intermittent doses of uncooked cornstarch. Hourly blood sampling and a 24-hour urine collection were obtained while subjects followed their usual home dietary regimen., Results: All but the youngest subject had low levels of citrate excretion (mean 2.4 +/- 1.8 mg/kg/d; 129 +/- 21 mg citrate/g creatinine). Normally, urinary citrate excretion increases with age; however, in patients with GSD1a, a strong inverse exponential relationship was found between age and citrate excretion (r = -0.84, P <.0001). Urinary citrate excretion was unrelated to markers of metabolic control. Hypercalciuria occurred in 9 of 15 patients (mean urinary calcium/creatinine ratio, 0.27 +/- 0.15) and was also inversely correlated with age (r = -0.62, P =.001)., Conclusions: Hypocitraturia that worsens with age occurs in metabolically compensated patients with GSD1a. The combination of low citrate excretion and hypercalciuria appears to be important in the pathogenesis of nephrocalcinosis and nephrolithiasis. Citrate supplementation may be beneficial in preventing or ameliorating nephrocalcinosis and the development of urinary calculi in GSD1a.

The purpose of this study was to investigate the usefulness of urinary lactate measurements to assess the adequacy of dietary treatment in patients with type I glycogen storage disease (GSD-I). We determined the correlation of urine and blood lactate concentrations in 21 GSD-I patients during 24-h admissions to the General Clinical Research Center (GCRC) during which hourly blood samples and aliquots of every void were obtained. In all but 1 patient, we found a good correlation between blood lactate concentrations and urinary lactate excretion. One patient did not excrete lactate in significant amounts despite elevated blood lactate concentrations. In 17 patients, the highest blood lactate concentrations occurred during the night. Markedly elevated nighttime average blood lactate concentrations above 3.5 mmol/l resulted in a urinary lactate concentration above the normal limit of 0.067 mmol/mmol creatinine in the first morning urine specimen. Mildly elevated nighttime blood lactate concentrations (between 2.2 and 3.5 mmol/l) led to urinary lactate concentrations that were either normal or moderately elevated. All patients with normal blood lactate concentrations during the night also had normal first morning urinary lactate concentrations. The degree of urinary lactate excretion in relation to blood lactate concentrations varied by individual. Urinary filter paper specimens, collected at home during the night and in the morning and mailed to the laboratory, were used to monitor the dietary compliance of 5 GSD-I patients at home over a period of 6 to 9 weeks prior to their GCRC admissions. These data suggested variable degrees of dietary control. In conclusion, the urinary lactate concentration is a useful parameter to monitor therapy of GSD-I patients at home. To be interpretable, the baseline urinary lactate concentration in relation to the blood lactate concentration has to be determined., (Copyright 2000 Academic Press.)

The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.

Objectives: To study the social and family characteristics of patients with insulin-dependent diabetes mellitus with irregular versus continuous clinical follow-up and to study the medical outcomes of patients with these follow-up patterns., Methods: An onset cohort of 61 children and adolescents with insulin-dependent diabetes mellitus and their parents were studied. Aspects of their social and family environment were assessed at study inception and examined in relation to frequency of follow-up early in the course of the illness. Follow-up was dichotomized so that patients with continuous follow-up were compared with patients with irregular follow-up, who were defined as those missing 1 full year of planned medical appointments during the second through fourth years after diagnosis. Patients with irregular and continuous follow-up were compared in terms of acute metabolic complications, glycemic control, and retinopathy status during a 10-year period., Results: Compared with individuals with continuous follow-up, patients with irregular clinical visits were more likely to be from families of lower socioeconomic class levels, have a parental history of separation and divorce, and were members of families that reported being least openly expressive of positive emotions. Poor glycemic control in year 1 was associated with irregular follow-up in years 2 through 4. Patients with irregular follow-up continued to have worse glycemic control in years 2 through 4 than patients with continuous follow-up. However, in years 7 and 10 their glycemic control no longer differed from patients with continuous follow-up. More episodes of diabetic ketoacidosis occurred in the irregular follow-up group. Finally, retinopathy occurred more frequently among those in the irregular follow-up group., Conclusion: Early irregular clinical follow-up should be considered a risk factor for complications of insulin-dependent diabetes mellitus.

The goal of treatment of type I glycogen storage disease (GSD-I) is to prevent hypoglycemia and its biochemical consequences. In seven patients with GSD-I with a mean age of 19.5 y (range: 18.8-21.7 y), we compared the biochemical effects of isoenergetic amounts of uncooked cornstarch (UCS; 1.76 +/- 0.41 g/kg) given in random order on consecutive nights either as a single dose at 2100 (time 0) or as equally divided doses at 2100 and 0200. Over the 10-h period of observation there were significant regimen-by-time interactions for plasma glucose, serum insulin, and blood lactate concentrations. Mean time-averaged plasma glucose (5.8 +/- 0.5 compared with 4.9 +/- 0.9 mmol/L) and serum insulin (244 +/- 93 compared with 151 +/- 57 pmol/L) concentrations from 0 to 360 min were significantly higher after the single dose; blood lactate and serum fatty acid concentrations were not significantly different. At 360 min, mean plasma glucose (4.8 +/- 1.2 compared with 4.7 +/- 1.6 mmol/L) and serum insulin (138 +/- 76 compared with 136 +/- 116 pmol/L) concentrations were virtually identical. After a single dose, plasma glucose concentrations were > or = 3.9 mmol/L for 7 h in five of seven subjects; three subjects were treated for hypoglycemia after 7-9.5 h. With divided doses, plasma glucose concentrations were > or = 3.9 mmol/L for 9 h in six of seven subjects; hypoglycemia occurred at 6 h in one subject. A single dose (1.76 +/- 0.41 g/kg) of UCS at bedtime maintains plasma glucose concentrations > or = 3.9 mmol/L for > or = 7 h in most young adults with GSD-I.

Past cross-sectional studies have suggested that young adults with insulin-dependent (Type 1) diabetes mellitus (IDDM) may experience problems in their close peer relationships. For 10 years, we have followed an onset cohort of children and adolescents with IDDM (n = 57) and an age-matched group who were originally recruited after an acute illness, accident, or injury (n = 54). Now aged 19-26 years, these two groups were compared in terms of their friendship patterns, dating and love experiences, and sense of loneliness. All subjects in both groups had at least one friend. However, the IDDM group reported fewer friendships overall. The difference was accounted for by the number of less intimate friends. The two groups had similar frequencies of current romantic partners (IDDM = 63%; comparison group = 64%). While dating attitude and dating assertiveness did not differ between groups, some differences were found in terms of experiences of a primary love relationship. IDDM patients experienced less trust and sense of intimate friendship in these love relationships. No differences in loneliness were found. The preponderance of our findings indicate that the two groups had similar patterns and experiences of close peer relationships. Thus, the study does not suggest that IDDM leads to serious problems in forming social relationships for these patients during the transition to young adulthood. On the other hand, the IDDM patients' lower level of trust and intimacy within love relationships are consistent with other findings from this study suggesting specific areas of lowered self-worth that appear in social relationships.

In this paper we determine whether individual and family psychosocial functioning predicts the risk for recurrent acute diabetic complications. An onset-cohort of 61 children and adolescents with Type 1 diabetes received conventional diabetes care. Episodes of ketoacidosis and of severe hypoglycemia were recorded for 8 years, and glycaemic control was measured by glycohaemoglobin. Measures of psychosocial functioning of the patient and parents were obtained during the first year. Over 8 years, 28% of subjects had at least one episode of ketoacidosis, and 21% had at least one episode of hypoglycaemia. The odds of observing recurrent hypoglycaemia versus recurrent ketoacidosis was 14 times greater in boys than in girls (Fisher's exact test p < 0.05). Girls with recurrent ketoacidosis had more behaviour problems and lower social competence, they reported higher levels of family conflict, and their parents reported lower levels of family cohesion, expressiveness and organization in year one. These relationships were independent of any association with poor glycaemic control. Recurrent hypoglycaemia in boys was generally unrelated to individual and family functioning or glycohaemoglobin. Despite our small sample size, our findings are suggestive of relationships that may lead to early identification of patients who are prone to recurrent ketoacidosis, and to the development of early intervention strategies.

Objective: To identify complications amenable to prevention in adults with glycogen storage disease (GSD) types Ia, Ib, and III and to determine the effect of the disease on social factors., Design: Case series and clinical review., Setting: Referral medical centers in the United States and Canada., Patients: All patients with GSD-Ia (37 patients), GSD-Ib (5 patients), and GSD-III (9 patients) who were 18 years of age or older., Measurements: Ultrasound or radiographic studies identified liver adenomas, nephrocalcinosis, or kidney stones. Radiographic studies identified osteopenia. Reports of the clinical examination, serum chemistry results, and social data were obtained., Results: For patients with GSD-Ia, problems included short stature (90%), hepatomegaly (100%), hepatic adenomas (75%), anemia (81%), proteinuria or microalbuminuria (67%), kidney calcifications (65%), osteopenia or fractures or both (27%), increased alkaline phosphatase (61%) and gamma-glutamyltransferase (93%) activities, and increased serum cholesterol (76%) and triglyceride (100%) levels. Hyperuricemia was frequent (89%). Patients with GSD-Ib had severe recurrent bacterial infections and gingivitis. In patients with GSD-III, 67% (6 of 9) had increased creatinine kinase activity. Four of these patients had myopathy and cardiomyopathy., Conclusions: For GSD-Ia, hyperuricemia and pyelonephritis should be treated to prevent nephrocalcinosis and additional renal damage. For GSD-Ib, granulocyte-colony-stimulating factor may prevent bacterial infections. For GSD-III, more data are required to determine whether the myopathy and cardiomyopathy can be prevented. Most of the patients with GSD-I and GSD-III had 12 or more years of education and were either currently in school or employed.

We prospectively studied 63 children with transient hyperglycemia to determine their risk of acquiring insulin-dependent diabetes mellitus (IDDM) and to evaluate the predictive value of immunologic markers of prediabetes and of the intravenous glucose tolerance test. Children with transient hyperglycemia were identified by a prospective systematic review of the laboratory reports of a large children's hospital and an office-based pediatric practice and by referral from pediatricians. Transient hyperglycemia occurred in 0.46% of children seen in the children's hospital and in 0.013% of children attending a pediatric office practice. Insulin-dependent diabetes mellitus developed within 18 months of identification in 32% of children in whom transient hyperglycemia was discovered in the absence of a serious illness, compared with 2.3% of children identified during a serious illness (relative risk, 13.9; 95% confidence interval, 1.56 to 123.5). Islet cell antibodies and competitive insulin autoantibodies each had a 100% positive predictive value for IDDM; the negative predictive value of islet cell antibodies and competitive insulin autoantibodies was 96% and 98%, respectively. The stimulated insulin release during an intravenous glucose tolerance test, adjusted for age, had the highest overall accuracy of prediction. All children less than 6 years of age with stimulated insulin release levels < 85 pmol/L (12 microU/ml) subsequently had IDDM, as did an 11-year-old child whose stimulated insulin release level was below the 1st percentile of 170 pmol/L (24 microU/ml). To date, no child whose stimulated insulin release level was above the 5th percentile has had IDDM. We conclude that when transient hyperglycemia occurs during a serious intercurrent illness, the risk of progression to IDDM is low. In contrast, one third of children in whom transient hyperglycemia is identified without a serious illness can be expected to have IDDM within 1 year. A combination of islet cell antibodies, competitive insulin autoantibodies, and stimulated insulin release levels during an intravenous glucose tolerance test can accurately distinguish children with prediabetes from those with presumed benign transient increases in plasma glucose concentrations.

To determine the optimal daytime dietary regimen for type 1 glycogen storage disease (GSD), we used uncooked cornstarch (UCS) at a basal glucose production rate (GPR) in single and divided doses, with mixed meals at 0700 and 1700 h. This regimen was compared with a 1.5 times larger single dose of UCS at 0700 h, and with dextrose at GPR at 1200 h. Two-hour UCS loads (amount equal to GPR in 2 h) given with a mixed meal at 0700 h and 180 min later maintained mean blood glucose (BG) concentrations at greater than or equal to 4.2 mmol/L for 300 min. BG was significantly greater from 240 to 300 min compared with a single 4-h UCS load, and at 300 min compared with a single 6-h UCS load. Similar effects were noted when the divided UCS regimen was given with a mixed meal at 1700 h, but not when isoenergetic amounts of dextrose were given on the same schedules with a mixed meal at 1200 h. A daytime schedule of six UCS feedings (with the three main meals and 180 min later) at GPR maintains BG at concentrations that should minimize biochemical abnormalities and optimize clinical outcome in patients with GSD.

Hypoglycemia is the most common acute complication of insulin-dependent diabetes mellitus, yet data are sparse concerning its frequency and the factors that predispose children and adolescents to its occurrence. This study was undertaken, during a 2-year period, to determine the frequency of severe hypoglycemia and to identify its causative factors in 196 youth with insulin-dependent diabetes mellitus (mean age and duration of diabetes, 13.5 +/- 4.3 and 4.8 +/- 3.2 years, respectively) treated conventionally. The mean daily insulin dose was 0.85 +/- 0.23 U/kg, and 92% of patients received insulin twice daily. Severe hypoglycemia occurred at least once in 2 years in 29 of 196 (14.8%) patients, of whom 9 (31%) had two or more episodes. The mean level of glycosylated hemoglobin closest to the event was significantly lower than that of patients who did not have severe hypoglycemia, 10.6 +/- 1.8 vs 11.4 +/- 2.0, P less than .02; however, the mean insulin dose, 0.88 +/- 0.19 vs 0.85 +/- 0.23 U/kg every 24 hours, was similar. Severe hypoglycemia occurred with equal frequency during waking and sleeping, and it was not related to the species of insulin used. The use of human insulin, per se, did not increase the risk of severe hypoglycemia. Asymptomatic hypoglycemia was reported significantly more often in those who experienced severe hypoglycemia, 24% vs 8%, P = .01. Severe hypoglycemia was common (12.2 episodes per 100 patient-years), and symptomatic hypoglycemia universal in youth with insulin-dependent diabetes mellitus treated with conventional insulin therapy. Approximately two thirds of episodes were attributable to lapses in the application of basic principles of diabetes self-care.

Thirteen patients with type 1 glycogen-storage disease (GSD-1) were studied to compare the effects on biochemical control and growth of 2 y of therapy with intermittent feedings of uncooked cornstarch (UCS) at the fasting glucose production rate and therapy with continuous overnight glucose (COG) and dextrose feedings during the day. Mean biochemical abnormalities for the groups were minimized but not normalized by either COG or UCS. Growth progressed normally when COG was started by 1.2 y of age and normal growth rate was maintained by UCS. Weight increased from 101 +/- 3% ideal body weight at onset of COG to 127 +/- 5% during COG and the first year of UCS therapy but did not increase further in the second year. When growth failure occurred before onset of COG [-3.7 SD score for chronological age (SDSCA)], only partial correction (-1.9 SDSCA) to genetic potential for height occurred. Intermittent feeding of UCS provides an effective alternative to COG for the treatment of GSD-1.

Responses to uncooked cornstarch (UCS), dextrose (Dex), and a 3:1 mixture (UCS:Dex) were determined in seven children with type 1 glycogen-storage disease (GSD-1). UCS maintained blood glucose (BG) and serum insulin concentrations between 3.5 +/- 0.3 and 4.0 +/- 0.4 mmol/L (mean +/- SEM) and 50 +/- 7 and 79 +/- 22 pmol/L, respectively, in six of the seven patients for 4 h. Only four of seven patients completed the 4-h test after UCS:Dex (BG 2.9 +/- 0.3 mmol/L): After Dex, tests had to be stopped in all patients by 150 min after initiation (BG 2.7 +/- 0.4 mmol/L). Two methods of providing dietary glucose overnight, continuous intragastric glucose infusion (COG) and intermittent UCS at 2100 and 0200, were compared by monitoring metabolites and glucoregulatory hormones. The use of UCS in amounts equal to the calculated glucose production rate is an effective method of providing a continuous dietary source of glucose overnight to patients with GSD-1.

This study was undertaken to test the glycemic response of five infants with glycogen storage disease type 1, aged 0.7 to 1.5 years, to uncooked cornstarch under various dietary conditions, and to evaluate the long-term effects of a dietary regimen consisting of uncooked cornstarch in milk every 4 hours, in addition to three meals daily, on biochemical values and physical growth. The results were compared with previous experience in treating six infants with continuous overnight glucose infusion via gastrostomy plus multiple daily feedings containing an adequate source of glucose. A test dose of cornstarch (1.6 to 1.8 gm/kg) providing four times the calculated hourly glucose production rate, when given in water 15 to 30 minutes after a continuous overnight intragastric glucose infusion was stopped, did not maintain normoglycemia. When the same dose was given in 2% cow milk 4 hours later, mean blood glucose levels remained greater than 68 mg/dl (3.8 mmol/L) for up to 4 hours. A regimen of uncooked cornstarch in 2% cow milk at 4-hour intervals in addition to three meals daily prevented hypoglycemia, and maintained blood lactate at nearly normal levels and serum uric acid and cholesterol within the normal range; triglyceride levels were increased only modestly. Overnight blood glucose levels were comparable to those achieved with continuous intragastric glucose infusion. With this regimen the five infants have maintained linear growth rates normal for their age and genetic potential; the mean percentage of ideal body weight for length percentile did not change significantly, although two of the five patients were overweight (123% and 124% of ideal body weight respectively) after 3 years of treatment. We conclude that a trial of uncooked cornstarch in feedings of milk every 4 hours should be attempted as soon as a more frequent feeding schedule with dextrose-containing formulas proves ineffective, because the former has the potential to provide the continuous glucose required by infants with glycogen storage disease type 1 in a safer and less invasive fashion than continuous intragastric glucose infusion.

Cross-sectional and longitudinal findings drawn from a 4-year longitudinal study of an onset cohort of preadolescents and early adolescents with insulin-dependent diabetes and their families are presented. Patient and parent perceptions of the family environment near the time of diagnosis are used to examine patterns of adherence in the first year of illness as well as over the four follow-up years. We found that family conflict, cohesion, and organization were strongly associated with independently rated first-year adherence levels. The strongest predictor of longer term adherence was family conflict, as experienced by the patients. In addition, parents' and youngsters' perceptions of family cohesion predicted improved adherence as well as overall higher levels of patient adherence. The findings are discussed with respect to the clinical implications of discovering those family characteristics that can, shortly after diagnosis, predict short- and long-term adherence. In addition, we present planned investigations intended to further clarify paths from family perceptions to individual diabetes behaviors.

An onset cohort of adolescents and children with insulin-dependent diabetes mellitus was studied over a 4-year period. Individual patient psychosocial and demographic factors were assessed at study inception and used to examine aspects of adherence over the follow-up. We found that initial assessment of patient coping (defense level, adaptive strength, and locus of control) and adjustment at study inception were predictive of the level of patient adherence to diabetic regimen over the 4 years of study. Psychosocial variables predicted adherence outcomes independent of patient age. This was found for three domains of adherence, i.e., diet, insulin adjustment, and metabolic monitoring, and for the composite index derived from the separate adherence scales. Preadolescents (ages 9-12) at study entry were more adherent than patients who were already adolescent (ages 13-16) when diagnosed. Using multiple regression, three factors (age, adjustment, ego defense level) accounted for 47% of the variance in adherence. No factors were predictive of change in adherence during the follow-up. Thus, psychosocial characteristics of diabetic children assessed shortly after diagnosis predicted typical or average adherence over a 4-year period. Identification of such characteristics may be useful in developing strategies for intervention early in the course of illness.

Body fuels were measured in 45 normal children and 17 growth hormone-deficient patients after 24 hours of fasting. After three months of therapy with human Growth Hormone (hGH) 16 of the patients were restudied. In all groups, beta-hydroxybutyrate (BOHB) concentrations correlated inversely with age and with glucose concentrations. When adjusted for these factors, the concentrations of BOHB were significantly lower in the growth hormone-deficient patients than in the control children, before (P less than 0.01) as well as after therapy (P less than 0.01). Only the five youngest patients became hypoglycemic. During fasting, ketones, which serve as an alternative fuel for the brain, spare glucose. Thus, a shortage of ketones would compromise the ability of the patient to conserve glucose and predispose the patient to fasting hypoglycemia. Accordingly, we propose that hypoketonemia is a critical factor in the genesis of fasting hypoglycemia in growth hormone deficiency.

Clinically apparent cerebral edema is a rare and often fatal complication of diabetic ketoacidosis. To determine whether subclinical brain swelling occurs more commonly, we obtained cranial CT scans in six children with diabetic ketoacidosis treated with fluid resuscitation and continuous low-dose insulin therapy. Control scans were obtained before hospital discharge. Compared with the scans during convalescence, the early scans of all six children showed a narrowing of the brain's ventricular system, compatible with brain swelling. Average changes in diameter were 1.3 +/- 0.1 mm for the third ventricle and 3.7 +/- 0.8 mm for the lateral ventricles (P less than 0.01). In addition, a narrowing of the subarachnoid spaces was subjectively noted during a blind reading of the early scans. Although no single scan was overtly indicative of cerebral edema, the data suggest that subclinical brain swelling may be a common occurrence during treatment of diabetic ketoacidosis in children. Sequential CT scans of the brain may provide a means of evaluating modifications of standard therapy aimed at preventing cerebral edema.

A patient with classical Albright's pseudohypoparathyroidism was investigated because of oligomenorrhoea. Hypo-oestrogenism was associated with elevated basal gonadotrophin values [mean basal serum LH and FSH were 272 +/- 84 (SD) ng/ml and 593 +/- 83 ng/ml, resplectively (normal less than or equal to 220 and less than or equal to 400, respectively)]. The response to gonadotrophin releasing hormone (Gn-RH) was exaggerated, with maximal LH and FSH increments of 1688 and 458 ng/ml, respectively. These results and the findings on ovarian biopsy were compatible with partial ovarian resistance to gonadotrophins. This resistance could be overcome by administration of human menopausal gonadotrophins. This is the first evidence for gonadotrophin resistance in pseudohypoparathyroidism. The plasma cyclic adenosine-3',5'-monophosphate response to glucagon administration by two different protocols was about 70% that of normal control subjects. Other endocrine glands whose responses to hormones are mediated via the adenylate cyclase system evidenced minor abnormalities of questionable significance. This indirect evidence is compatible with a more extensive defect in the adenylate cyclase system in pseudohypoparathyroidism than has hitherto been suspected.

Calcitriol was used successfully to treat a patient with hypoparathyroidism during pregnancy. Increasing dosage of calcitriol were needed during the last trimester with a prompt decrease in the requirement after delivery. The dosage changes appear to mirror the pattern of endogenous synthesis of calcitriol in normal pregnant women.

Transient hyperglycemia may represent the earliest manifestation of IDDM. In a series of 30 children referred for transient hyperglycemia, 8/30 (27%) developed IDDM within 10 months of their initial evaluation. Three children with detectable cytoplasmic islet cell antibodies (ICA) and/or positive insulin autoantibodies (CIAA) all developed IDDM, compared to 21% of ICA negative children and 13% who were CIAA negative. Of those with impaired glucose tolerance, 6/11 (55%) developed IDDM, as did 1/14 with normal OGTT. Of the children with a low "K rate" on IVGTT, 75% developed IDDM, compared to 1/13 with a normal "K rate". All four children (100%) whose first phase (1' + 3') insulin secretion never exceeded the first percentile developed IDDM within nine months, while no child with first phase insulin secretion above the first percentile (0/16) developed IDDM during 19 +/- 9 months (mean +/- SD) of follow-up. Thus, in our experience the oral glucose tolerance test is a less accurate predictor of impending IDDM; immunological abnormalities have the highest positive predictive value, while the first phase insulin secretion during an intravenous glucose tolerance test has the highest negative predictive value and the greatest overall accuracy of prediction.