U-73122 does not specifically inhibit phospholipase C in rat pancreatic islets and insulin-secreting beta-cell lines.

Phospholipase C is activated in insulin secretion by islets of Langerhans and insulin-secreting beta-cells such as RINm5F and beta-TC3. We have examined the effects of the aminosteroid U-73122, a phospholipase C inhibitor, on insulin secretion and phospholipase C activation. U-73122 slightly inhibited glucose-induced insulin secretion from islets, but this effect was not specific since the structural "inactive" analogue U-73343 also inhibited insulin secretion. Likewise, in RINm5F cells, U-73122 did not inhibit glyceraldehyde-induced insulin secretion. Phospholipase C activity was assessed as the accumulation of inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) measured with a competitive binding assay: U-73122 failed to inhibit glucose-induced increase in Ins(1,4,5)P3. Similarly, when the effects of U-73122 and U-73343 were measured on [3H]phosphatidylinositol hydrolysis of islets, both compounds caused a slight, non-specific inhibition of phospholipase C activity. These observations suggest that U-73122 does not specifically inhibit phospholipase C in insulin-secreting cells.

Self-reported factors that affect glycemic control in college students with type 1 diabetes.

PURPOSE: This study examined the self-reported impact of different factors on the overall diabetes care of college students with type 1 diabetes. METHODS: An 18-item questionnaire was mailed to 164 students with type 1 diabetes attending college away from home; results from 42 students fulfilled study criteria and were analyzed. Metabolic control was assessed by relative changes in glycosylated hemoglobin (HbA1c) levels from medical records. RESULTS: HbA1c levels did not change significantly between high school and college, yet most college students reported that diabetes was more difficult to manage in college. Commonly reported barriers to diabetes control included diet, irregular schedules, lack of parental involvement, peer pressure, drugs and alcohol, fear of hypoglycemia, and finances. Factors identified as improving diabetes control were an increased sense of responsibility, increased frequency of blood glucose testing, exercise, contact with healthcare providers, fear of hyperglycemia, and knowledge of the results of the Diabetes Control and Complications Trial. Many students reported testing their blood more frequently and taking more injections than in high school; most were on intensive insulin regimens. CONCLUSIONS: Despite the perception that diabetes management was more difficult in college, metabolic control was maintained during college, possibly due to a more intensive treatment approach.

Diagnostic dilemma. The goiter.

The incidence of goiters in children is about 4% to 5%. The first step in the evaluation is to decide whether the swelling indeed involves the thyroid. After careful examination, one determines if the thyroid is diffusely or focally enlarged. A solitary nodule merits an extensive workup because of the high rate of malignancy. The evaluation of a diffuse goiter proceeds after deciding if the patient is euthyroid, hypothyroid, or hyperthyroid. In most cases, the child is euthyroid and the diagnosis is either CLT or simple colloid goiter. Laboratory tests for thyroid function and antibodies usually make the diagnosis. The hypothyroid patient most likely has CLT, although drugs or goitrogens, dyshormonogenesis, and thyroid resistance are also possible. The hyperthyroid patient usually has Graves' disease. The incidence of malignancy of solitary thyroid nodules is 15% to 40%; therefore, evaluation must be sensitive enough not to miss cancer. Ultrasonography helps to delineate the anatomy and to reveal if the nodule is cystic. Radionuclide scans are useful, as warm or hot lesions are rarely malignant. Cold nodules require further investigation, and in most institutions, this amounts to open biopsy. Fine-needle aspiration may be used if the clinician and pathologist are experienced. With this aggressive approach to thyroid nodules, malignancies are given early treatment. The prognosis is good in most thyroid carcinomas.

Growth in children after bone marrow transplantation for acute myelogenous leukemia as compared to acute lymphocytic leukemia.

Previous studies of growth in children following bone marrow transplantation for leukemia have demonstrated poor growth with little ability to "catch-up" two to four years after transplantation. Because of small patient numbers, these studies did not distinguish patients with differing types of leukemia. 12 children with acute myelogenous leukemia who survived over 3 years after transplantation were compared with 12 who survived transplantation for acute lymphoblastic leukemia. The initial height standard deviation scores were similar in both groups prior to transplantation. The height standard deviation scores in the acute lymphoblastic leukemia group decreased for each of the 5 years after transplantation while the height score for the acute myelogenous leukemia group after 5 years was not statistically different from pre-transplantation. The growth of the children with myelogenous leukemia was better possibly because these children were older, had received less cranial irradiation at the time of transplantation, and had a lower incidence of severe chronic graft-versus-host disease.

Identification of phosphatidylinositol 3,4,5-trisphosphate in pancreatic islets and insulin-secreting beta-cells.

The signal transduction mechanisms involved in insulin secretion by the beta-cell are poorly understood. Glucose, the main physiological secretagogue, needs to be metabolized, but the identity of the intracellular messengers which couple glucose metabolism and insulin exocytosis is controversial. We now report the identification of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3), the end-product of phosphatidylinositol 3-kinase phosphorylation of polyphosphoinositides, in islets and in an insulin-secreting clonal beta-cell line, RINm5F, using a combination of thin layer chromatography and high performance liquid chromatography analyses and by demonstrating that sequential deacylation and deglyceration of PtdIns(3,4,5)P3 yields inositol 1,3,4,5-tetrakisphosphate. Unlike other cell types, significant levels of PtdIns(3,4,5)P3 were detected in beta-cells under non-stimulatory conditions. Insulin secretagogues (28 mM glucose + 0.5 mM carbachol) caused a rapid and transient increase in PtdIns(3,4,5)P3 levels which peaked at 2-5 min, corresponding to peak early phase insulin release.

Growth hormone deficiency in two siblings with Alström syndrome.

OBJECTIVE: To investigate if there is an endocrinologic explanation for the short stature in patients with Alström syndrome. DESIGN: Patient reports. SETTING: The Children's Hospital of Philadelphia, Pa. PARTICIPANTS: Two siblings with Alström syndrome who were referred to the Endocrine Division for evaluation of obesity, growth, and glucose metabolism. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: The low growth velocity in both patients prompted growth hormone evaluation. The abnormal results of two provocative tests of growth hormone function, as well as low concentrations in frequent overnight sampling of serum growth hormone, were compatible with growth hormone deficiency. However, the patients had advanced bone ages, early normal growth, and normal insulinlike growth factor 1 concentrations. The results of the glucose tolerance tests revealed marked elevation of insulin (5955 pmol/L and 7677 pmol/L) and glucose intolerance consistent with insulin resistance. Pituitary stimulation studies revealed normal thyroid and gonadotropin axes. CONCLUSIONS: Growth hormone deficiency may account for the short stature in some patients with Alström syndrome. The advanced bone age and normal early growth may be due to hyperinsulinism. A specific defect in the signal transduction of insulin action and possibly hormone spillover on another receptor may account for the existence of insulin resistance in the presence of normal growth and growth hormone deficiency.

Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism.

Octreotide, a long-acting analog of somatostatin that inhibits insulin release, has the potential to control hypoglycemia in infants with congenital hyperinsulinism. To examine the efficacy and side effects of octreotide, we evaluated therapy between 1988 and 1993 in 16 infants who did not respond to diazoxide. In nine patients with onset of severe hypoglycemia in the first days of life, octreotide was helpful in stabilizing plasma glucose levels and allowed reductions in the rates of glucose infusion; however, glucose control was inadequate to avoid subtotal pancreatectomy. In two of these nine patients postoperatively and in seven other infants, a trial of long-term treatment with octreotide was undertaken. Four were treated successfully for up to 4.3 years. Octreotide therapy was not associated with thyroid deficiency and caused only transient malabsorption. All patients receiving long-term therapy had some decrease in linear growth and two had subnormal plasma concentrations of insulin-like growth factor I and insulin-like growth factor binding protein 3 compatible with suppression of growth hormone by octreotide. Resistance to octreotide therapy, even with increasing doses, occurred in all patients. These results suggest that octreotide may aid in the acute or long-term treatment of congenital hyperinsulinism in a limited number of selected cases.

The new highly sensitive adrenocorticotropin assay improves detection of patients with partial adrenocorticotropin deficiency in a short-term metyrapone test.

This study was designed to evaluate a short term metyrapone test using a highly sensitive (HS) IRMA ACTH assay and to evaluate the usefulness of a morning ACTH level as a screening test for partial ACTH deficiency. ACTH, 11-deoxycortisol and cortisol levels were evaluated over four hours in the morning after a single 40 mg/kg oral dose of metyrapone was administered at 0800 hours. 26 control children and 32 possibly pituitary deficient patients were evaluated. Based on 11-deoxycortisol levels alone, 17 of the patients passed the test, 11 patients failed the test and the result was inconclusive in four patients (12.5%). Evaluation of the increase in ACTH levels (delta ACTH) following metyrapone identified three of the above four with partial ACTH deficiency. The delta ACTH was consistent with the 11-deoxycortisol results in the remainder of patients. There was no difference in morning ACTH levels between controls and patients with partial ACTH deficiency. The measurement of ACTH using the HS IRMA assay, increases the sensitivity of the metyrapone test in detecting patients with partial ACTH deficiency. This test may be used safely in pediatric patients on a repetitive basis, especially in those children who may have progressive ACTH failure following hypothalamic-pituitary irradiation.