Insulin management and metabolic control of type 1 diabetes mellitus in childhood and adolescence in 18 countries. Hvidøre Study Group on Childhood Diabetes.

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross-sectional, non-population-based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4-6.3%, mean 5.4%). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 +/- 1.3% (mean +/- SD) compared with 8.9 +/- 1.8% in those aged 12-18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg(-1) 24 h(-1)) in children aged 2-9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37% (n = 1071) used three or more. Of those on two or three injections daily, 37% used pre-mixed insulins, either alone or in combination with short- and intermediate-acting insulin. Pre-adolescent children on pre-mixed insulin showed similar HbA1c levels to those on a combination of short- and long-acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long-acting insulin. Among adolescent boys, lower HbA1c was related to use of more short-acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

Use of PRISM scores in triage of pediatric patients with diabetic ketoacidosis.

Triage guidelines are needed to help in the decision process of intensive care unit (ICU) versus non-ICU admission for patients with diabetic ketoacidosis (DKA). Pediatric risk of mortality (PRISM) scores have long been used to assess mortality risk. This study assess the usefulness of the traditional PRISM score and adaptation of that score (PRISM-ED, which uses presentation data only) in predicting hospital stay in pediatric patients with DKA. PRISM and PRISM-ED were tested for correlation with length of stay and length of ICU stay. A medical record review was conducted for patients admitted to The Children's Hospital of Alabama with DKA during an 18-month period (n = 79). Two scores were calculated for each study entrant: PRISM using the worst recorded values over the first 24 hours and PRISM-ED using arrival values. Median scores, median test, and Spearman rank correlations were determined for both tests. Median PRISM scores were PRISM = 11 and PRISM-ED = 12; Median PRISM and PRISM-ED scores for patients admitted to the ICU were less than median scores among floor-admitted patients: [table: see text] Spearman rank correlations were significant for both scores versus total stay: PRISM, rs = 0.29; P = 0.009; PRISM-ED, rs = 0.60, P < 0.001. Also, correlations were significant for both scores versus ICU stay: PRISM rs = 0.22, P = 0.05; PRISM-ED, rs = 0.41, P < 0.001. Triage guidelines for ICU versus floor admission for DKA patients could have significant economic impact (mean ICU charge = $11,417; mean charge for floor admission = $4,447). PRISM scores may be an important variable to include in a multiple regression model used to predict the need for ICU monitoring.

Diabetes insipidus and histiocytosis X: a case of isolated pituitary involvement.

Diabetes insipidus is associated with histiocytosis X in approximately 50% of cases with multiple lesions that involve both intracranial and extracranial structures. Although approximately 8% of cases of diabetes insipidus in children are caused by involvement of the hypothalamus or pituitary infundibulum (or both) by histiocytosis X, diabetes insipidus can be the initial manifestation in many disorders most commonly, intracranial neoplasms. Herein we report a case of isolated histiocytosis X of the pituitary gland in a child for whom medical assistance was sought because of symptoms of diabetes insipidus.

Alkylglycosides enhance systemic absorption of insulin applied topically to the rat eye.

A series of alkylglycosides with various alkyl chain lengths and carbohydrate residues were tested for their ability to enhance systemic absorption of insulin after topical ocular delivery in anesthetized rats. Several reagents, including tetradecyl-, tridecyl- and dodecylmaltoside and dodecylsucrose, were potent stimulators of insulin absorption when used at concentrations as low as 0.125%. Other alkylglycosides such as decylsucrose, decylmaltoside, nonylglucoside, octylmaltoside, heptylglucoside and hexylglucoside were less potent or ineffective as absorption-enhancing reagents. By comparison, the bile salt sodium glycocholate was effective only when used at concentrations of 0.5% or greater. All of the reagents were effective only when used at concentrations above their critical micelle concentration and the most hydrophobic alkylglycoside reagents were the most efficacious at promoting systemic insulin absorption. The possible utilization of eyedrops containing insulin plus an absorption-enhancing alkylglycoside reagent in humans is discussed.

Insulin delivery in nosedrops: new formulations containing alkylglycosides.

Insulin was administered to rats via nosedrops in the presence or absence of various alkylglycosides; systemic insulin absorption was measured as a fall in blood D-glucose concentration in animals made hyperglycemic by xylazine/ketamine anesthesia. Nosedrops (0.04 ml) containing alkylglycosides or regular porcine insulin alone were without effect. Nosedrops containing both a small amount of alkylglycoside (0.03-0.50%) and insulin (2 U regular porcine) caused a rapid decrease in blood D-glucose levels and a concomitant increase in serum immunoreactive insulin levels. The maximal hypoglycemic response was observed between 60 and 120 min after delivery of nosedrops. Decylmaltoside was less effective at enhancing systemic insulin absorption than dodecylmaltoside, tridecylmaltoside, or tetradecylmaltoside, whereas octylmaltoside was totally ineffective. Dodecylsucrose, a compound which differs from dodecylmaltoside only in one carbohydrate residue, had a similar effect on blood D-glucose values when it was included in the nosedrop formulation with insulin. Decylsucrose was considerably less potent than dodecylsucrose at enhancing systemic absorption of insulin. Nonylglucoside was effective at promoting insulin absorption from nosedrops only when used at higher doses (0.25-0.50%), whereas heptylglucoside and hexylglucoside were ineffective. These results indicated that nosedrops containing insulin plus an extremely low concentration (0.03%) of an absorption-enhancing agent such as tetradecylmaltoside can be used to lower blood D-glucose values.

Insulin administration to the eyes of normoglycemic human volunteers.

Animal studies have shown that insulin eyedrops containing an absorption-enhancing agent can have a significant effect on blood glucose levels. When formulated as a topical solution, insulin might potentially be used to treat or augment the treatment of diabetes mellitus in humans. We sought to investigate the feasibility of using insulin eyedrops in humans by studying the local toxicity and efficacy of insulin administered without surfactant to the eyes of healthy volunteers. A prospective, randomized, placebo-controlled, single-masked study was conducted in which 8 subjects were given 50 microliters of sterile normal saline containing varying insulin concentrations randomized to one eye, and 50 microliters of placebo (sterile normal saline) to the fellow eye. Subjective ocular irritation was evaluated, and the eyelids, conjunctiva, cornea, and anterior chamber were examined objectively with slit lamp biomicroscopy. Subjects were evaluated for 2 hours following administration of a single dose of insulin. There was no statistically significant difference (P > 0.05) in toxicity observed by any parameter evaluated between eyes receiving insulin and placebo. No systemic absorption of insulin was observed; blood glucose levels and serum immunoreactive insulin levels were unchanged. The results of this study suggest that single-dose insulin in concentrations up to 100 U/ml formulated in saline has no detectable clinical toxicity to the anterior structures of the human eye.

Efficacy of insulin eyedrops.

Systemic absorption of insulin delivered via eyedrops has been studied in rats made transiently hyperglycemic by anesthesia with xylazine/ketamine. Insulin at a concentration of 2 mg/ml was not absorbed significantly when saline alone was used as the formulation for the eyedrops (0.04 ml). When various emulsant agents were added to the eyedrop formulation, systemic insulin levels were increased and concomitantly, blood D-glucose levels were decreased. Saponin, Brij-78, BL-9 and several alkylglycosides all increased the systemic absorption of insulin following delivery in eyedrops. Not all surfactant agents were effective in promoting systemic insulin absorption from eyedrops, as evidenced by the failure of some non-ionic surfactants to increase insulin absorption. Similar results were obtained when nosedrops containing insulin plus non-ionic surfactants were administered to rats. In conclusion, systemic insulin absorption was greatly accelerated by the addition of certain emulsants to the eyedrop formulation and physiologically important levels of insulin could be delivered systemically following eyedrop administration.

Toxicity of insulin administered chronically to human eye in vivo.

Insulin administered in eyedrop from with a surfactant agent has been shown to be clinically effective in treating diabetes in animal models. Concentrations of insulin as high as 100 U/ml in saline were shown to produce no detectable clinical toxicity to human eyes in single-dose administration. We sought to investigate the local toxicity of insulin in human eyes during long-term, multidose administration. A prospective, randomized, placebo controlled, double-masked study was conducted involving eight healthy volunteers. Subjects were given 50 microliters sterile saline containing 100 U/ml crystalline porcine insulin randomized to one eye and 50 microliters placebo (sterile saline) to the fellow eye administered twice daily for 8 weeks. Subjective ocular irritation and visual acuity and objective assessment of the eyelids, conjunctiva, cornea, anterior chamber, crystalline lens, pupil size, and intraocular pressure were evaluated. Blood D-glucose levels were monitored to assess glycemic levels. There was no statistically significant difference (p > 0.05) observed between insulin-treated and placebo-treated eyes. Eyedrops containing insulin were subjectively as comfortable and objectively as clinically innocuous as sterile saline alone. The results of this study demonstrate that insulin (100 U/ml) in saline is nontoxic to the human eye after long-term, multi-dose exposure. Topical administration of insulin combined with an absorption-promoting agent may be a practical and feasible alternative to multiple daily subcutaneous injections or implanted pump devices currently used in the long-term treatment of diabetes mellitus if a nonirritating absorption-promoting agent can be identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucagon administration to the rat via eye drops.

Systemic absorption of glucagon from eye drops containing an emulsant caused an elevation in blood D-glucose concentrations in anesthetized rats. Glucagon (0.03 mg) delivered to the eye in buffered saline had no significant hyperglycemic action. However, delivery of glucagon in eye drops containing 0.25% saponin caused a rapid, dose-dependent increase in blood D-glucose values. Maximal absorption was observed 20 minutes after eye drop administration and values returned to baseline after 60 minutes. Immunoreactive glucagon levels measured 20 minutes after administration of eye drops containing saponin plus glucagon were increased by 2.4-fold compared to basal values. Glucagon administration via eye drops was ineffective when 0.5% Brij78 or BL-9 was substituted for saponin. These results demonstrate that in the rat, systemic absorption of glucagon delivered in eye drops is possible, but the choice of an emulsant may be critical.

Reversible suprasellar pituitary mass secondary to hypothyroidism.

Sellar enlargement and suprasellar extension of a pituitary mass, demonstrated by magnetic resonance imaging or computed tomographic scanning in three children with primary hypothyroidism, resolved after treatment with levothyroxine sodium. This condition, a logical consequence of the pathogenesis of primary hypothyroidism, must be considered in patients with pituitary and suprasellar masses.

Receptors for IGF-I, but not for IGF-II, on proximal colon epithelial cell apical membranes.

Rabbit proximal colon epithelial cell apical membranes, which are known to contain receptors for insulin, were isolated by a Ca2+-precipitation technique. Binding assays with 125I-insulin-like growth factor I (IGF-I) revealed the presence of specific high-affinity binding sites, with 50% inhibition of binding observed at a concentration of 13.7 ng/ml IGF-I. In contrast, 50% inhibition of 125I-IGF-I binding was observed at an insulin concentration of 1.37 micrograms/ml, suggesting that 125I-IGF-I was not binding to insulin receptors present in this tissue. Cross-linking studies revealed an 125I-IGF-I binding subunit of relative molecular weight (Mr) of 130,000 under reducing conditions on docecyl sulfate-polyacrylamide gel electrophoresis that was similar to the IGF-I binding subunit in human placental membranes (Mr 140,000). Binding and cross-linking studies with 125I-insulin-like growth factor II (IGF-II), however, failed to reveal a specific receptor for this peptide in colon epithelial cell membranes. These results establish the coexistence of receptors for IGF-I and insulin, but not IGF-II, on rabbit proximal colon epithelial cell apical membranes and demonstrate that colon epithelial cells are capable of selective synthesis of various peptide hormone receptors.

Colonic absorption of insulin: an in vitro and in vivo evaluation.

Rectal administration of insulin as a suppository or p.o. administration of a proteolysis-resistant insulin analog lowers serum glucose levels, suggesting uptake and/or diffusion of intact insulin across the epithelium of the large intestine; however, no rigorous studies of insulin degradation and/or transepithelial flux in vitro have been reported with isolated colonic epithelium. Everted and noneverted sacs of rat distal colonic epithelium were prepared and incubated at 37 degrees C with porcine [125I]insulin and less than 1% of the [125I]insulin crossed the epithelial barrier under these in vitro conditions. The apical surface degraded [125I]insulin at a rate of 0.071 fmol/mg of dry wt./min, whereas the submucosal surface degraded insulin at a rate of 0.045 fmol/mg of dry wt./min. Over 60% of the available [125I]insulin was degraded by the apical surface of the distal colon during a 15-min incubation, whereas approximately 40% of the radioligand was degraded by the submucosal surface under identical conditions. Degradation of [125I]insulin was inhibited partially by the addition of excess unlabeled insulin and inhibited completely by the addition of bacitracin (1 mg/ml). These results indicate that the mammalian colonic epithelium is an effective barrier to transepithelial flux of insulin and identify insulin-degrading activity on both the apical and submucosal surfaces of the colonic epithelium. Although the colonic epithelium represents a significant physiological barrier to the uptake of insulin from the intestinal lumen, paradoxically, administration of large doses of unlabeled insulin into the distal colon or into the entire large intestine caused a dose-dependent increase in serum insulin levels during a 15-min experiment in vivo.

Paradoxical organ-specific adaptations to streptozotocin diabetes mellitus in adult rats.

Adult male Fisher rats injected with streptozotocin (Stz) to produce diabetes mellitus demonstrated a significant loss of total body weight associated with adipose and muscle tissue wasting. Paradoxically, intestinal mass and length were increased in Stz-treated rats despite catabolism of other tissues. Concomitant with increased intestinal mass, food and water intake increased significantly in Stz-diabetic animals. Renal weight was not reduced despite the fall in total body weight. It is proposed that the adult Stz-diabetic rat responds to a loss of available insulin by polyphagia, polydipsia, and catabolism of adipose and muscle tissue and that a large percentage of available synthetic fuel is devoted to the production of additional intestinal tissue.

Successful use of plasma exchange in a child with refractory immune hemolytic anemia.

Immune hemolytic anemia (IHA) in children is commonly a self-limited disorder that can usually be managed with a combination of corticosteroid therapy and transfusions. We describe a 2 10/12-year-old child with severe IHA that rapidly progressed during the first 24 h of conventional treatment but that responded dramatically to plasma exchange (PE). Unique features of this case include the use of PE to avoid splenectomy, the complete and permanent clearance of detectable antibody following PE, and the rapid correction of anemia by infusing packed erythrocytes during the procedure. The role of PE in the treatment of childhood IHA is discussed.