Kusiel Perlman

Is 95% Pancreatectomy the Procedure of Choice for Treatment of Persistent Hyperinsulinemic Hypoglycemia of the Neonate?

A 95% pancreatectomy became the treatment of choice for persistent hyperinsulinemic hypoglycemia of the neonate (PHHN, Nesidioblastosis) at the authors institution, when lesser resections failed to prevent hypoglycemia in 25% to 50% of cases. With few outcome data available in the literature, the authors reviewed their 25-year experience to assess the efficacy and the long-term consequences of this procedure. Since 1971, 27 infants underwent a 95% pancreatectomy for the treatment of PHHN. None had responded to medical treatment (glucose infusion, glucagon, octreotide, diazoxide), and two had 85% pancreatectomy that failed. The procedure consisted of resecting the pancreas including the uncinate process, leaving only the gland lying between the common bile duct (CBD) and the duodenum and a small rim of pancreas along the duodenal sweep. Hyperinsulinemia and hypoglycemia recurred in nine children (33%), all within 2 to 5 days. Seven of them were subsequently cured with near-total pancreatic resection. Partial pancreatic regrowth was evident at reoperation. In two cases hypoglycemia was controlled with diazoxide and frequent feedings because reoperation was refused. The gross anatomic findings and the histopathology were not predictive of treatment failure. Perioperative complications occurred in four of 27 children (15%) after 95% pancreatectomy and in four of seven children (57%) after near-total pancreatectomy. Clinical follow-up ranged from 0.5 to 18 years (mean, 8 years; median, 8 years). To date, diabetes has developed in 15 children (56%), nine of 20 (45%) after 95% pancreatectomy (mean age, 9.7 years) and six of seven (86%) after a near-total pancreatectomy (mean age, 1.7 years). After 95% pancreatectomy, the incidence of diabetes increased with age, developing in nine of the 13 (69%) children followed up for more than 4 years. The failure of 95% pancreatectomy to prevent hypoglycemia in one third of children with PHHN and the ultimate development of diabetes in a minimum of two-thirds, indicates that an alternative treatment strategy is needed for this disease.

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

Severe hypoglycemia in children with insulin-dependent diabetes mellitus: Frequency and predisposing factors

We surveyed 311 children with insulin-dependent diabetes mellitus to evaluate the frequency and characteristics of those children experiencing severe hypoglycemia (defined by an episode of coma, convulsion, or both). The children and their parents completed a questionnaire, and we reviewed the hospital records to confirm reported episodes. Ninety-seven (31%) reported severe hypoglycemia, and a further 50 (16%) reported moderate hypoglycemia requiring the assistance of another person but not resulting in coma or convulsion. In 164 children (53%) there was no history of either moderate or severe hypoglycemia. Sixty-nine (22%) reported the occurrence of more than one severe hypoglycemic episode (range 2 to 20); 52 (16%) reported such an event in a single year. A total of 285 episodes were reported, 39% during sleep and 61% while awake. Children reporting such events tended to have diabetes of longer duration and be younger at the time of the first episode. Hemoglobin A1c concentration at the time closest to the severe episode was significantly lower than in children reporting no hypoglycemia. All families had been taught to use glucagon to reverse severe hypoglycemia at home, but it was available in only 80 of the 97 homes and used in only 30. These data suggest that severe hypoglycemia is common in children with insulin-dependent diabetes mellitus who are treated conventionally. Greater vigilance and education are required both to prevent and to treat severe hypoglycemia in children with insulin-dependent diabetes mellitus.

Clinical and surgical aspects of hypothalamic hamartoma associated with precocious puberty in a 15-month-old boy.

A case is reviewed of precocious puberty associated with hypothalamic hamartoma in a 15-month-old boy. The authors believe this to be the first documented case in which significant reductions occurred in the level of serum testosterone and in the result of the luteinizing hormone-releasing hormone (LHRH) infusion test following surgical removal of the tumor. Such surgery appears to be safe when a planned microsurgical course is employed.

Self‐monitoring of blood glucose in children and teens with diabetes

Abstract:  Improved metabolic control has unequivocally been demonstrated to delay the onset and slow the progression of microvascular complications in adolescents and adults with diabetes mellitus. Growing evidence also supports the association of tighter glucose control and more frequent blood glucose monitoring. Therefore, self‐monitoring of blood glucose (SMBG) has become a fundamental part of diabetes care in children. Here, we review recent advances and ongoing trends in glucose monitoring in children with diabetes. Technologies have been developed to improve patient compliance with recommended monitoring, requiring less blood, involving less pain, and providing results more quickly. Alternate‐site testing (AST) is also a potential means of improving patient compliance with SMBG by avoiding the sensitive fingertip area. The Continuous Glucose Monitoring System (CGMS) and the GlucoWatch® Biographer are two recent tools that can track glucose levels continuously. However, inconsistency in their accuracy and precision remain challenges when using these technologies to guide management.

Continuous subcutaneous insulin infusion pump treatment in children with type 1 diabetes mellitus

Data were reviewed from 73 consecutive medical charts of children and adolescents with type 1 diabetes mellitus using insulin pumps for more than 6 months at The Hospital for Sick Children, Toronto, Canada. Statistically significant differences in HbA1c (-0.8%), body mass index (+1.45 kg/m2) and total daily dose of insulin (-0.23 U/kg/day) were found between the start of pump use and evaluation 6-30 months later. There was a close correlation between the HbA1c before and after 6-30 months of pump therapy.

Sustained Normoglycemia in Newly Diagnosed Type I Diabetic Subjects: Short-Term Effects and One-year Follow-up

The impact on remission of normalizing blood glucose levels immediately after diagnosis of type I diabetes was studied in 14 adolescents. Accordingly, in this randomized prospective primary intervention study, 7 of the subjects (i.v. group) received insulin by continuous intravenous (i.v.) infusion via a portable preprogrammed system for 28–62 days and 7 (s.c. group) received conventional subcutaneous (s.c.) therapy. Before therapy, the two groups did not differ significantly with respect to glycosylated hemoglobin, fasting plasma C-peptide, or 24-h urinary C-peptide excretion. During the infusion period, the overall mean fasting plasma glucose (FPG) concentration for the i.v. group was 84 mg/dl with a mean coefficient of variation of 18 ± 4% (mean ± SD). During the comparable period for the s.c. group, the mean FPG was 253 mg/dl with a coefficient of variation of 30 ± 20%. Twenty-four-hour urinary glucose excretions for the two groups were 0.29 ± 0.06 (mean ± SEM) and 59 ± 11 g/day, respectively. Daily insulin requirements in the i.v. group decreased from 1.47 ± 0.19 U/kg body wt/day at the start to 0.47 ± 0.10 U/kg/day at the end of the infusion period. Notably, 10–25 days after the infusion period, 5 of 7 subjects experienced a further decrease to a low of 0.27 ± 0.01 U/kg/day. The mean peak and low requirements in the s.c. group were 0.71 ± 0.15 and 0.33 ± 0.13 U/kg/day, respectively, with the only peak requirements being significantly different (P < 0.01). No patient was able to discontinue insulin therapy. The fasting plasma C-peptide level rose significantly (P < 0.05) by 1 mo in the i.v. group, but only achieved similar levels by 4 mo in the s.c. group. In the i.v. group, 24-h urinary C-peptide excretion decreased during the first week of therapy, rose through the infusion period, and finally peaked at 60 ± 14 μg day 3–30 days later. In the s.c group, the urinary C-peptide excretion gradually increased reaching a significantly lower peak (P < 0.05) of 36 ± 8 μg day at 113 ± 38 days. Glycosylated hemoglobin levels declined significantly only in the i.v. group with 4 subjects achieving normal levels. At 1 mo after diagnosis, the i.v. group had significantly higher (P < 0.05) fasting plasma C-peptide levels and lower (P < 0.005) glycosylated hemoglobin levels than did the s.c. group. Inspite of the higher peak urinary C-peptide excretion for the i.v. group, 4 and 12 mo after diagnosis the groups did not differ in mean 24-h urinary C-peptide excretion, fasting plasma C-peptide, insulin requirements, or glycosylated hemoglobin. We conclude that sustained strict glycemie control within normal limits at diagnosis of type I diabetes does not of itself augment the remission phase.

Waveform Requirements for Metabolic Normalization With Continuous Intravenous Insulin Delivery in Man

Devices and methods for long-term intravenous (i.v.) insulin infusion in ambulatory patients have recently been developed. However, to date optimal waveforms for open-loop insulin administration in severely insulin deficient patients have not been defined. We studied 7 nonobese uncomplicated type 1 diabetics aged 16.5 ± 0.2 yr who received insulin continuously for 14–23 days by central venous infusion. A pattern of i.v. insulin administration was developed and eventually refined to include a constant basal infusion rate augmented at meal time by a series of 3 pulses. The first pulse lasted 10–15 min with an infusion rate 1.5–2 times the basal rate. The second pulse was 60–100 min in duration with a rate 4–6 times the basal infusion rate. The third pulse lasted 40–100 min with an infusion rate 1.5–3 times the basal rate. Accompanying the evolution of this waveform, the mean fasting plasma glucose fell from 262 ± 40 mg/dl on conventional therapy to 92 ± 9 mg/dl during infusion with normal meal excusions (mean a.c. glucose 80 ± 3 mg/dl with a rise of 35 ± 3 mg/dl at 41 ± 3 min). Mean urinary glucose excretion decreased from 55 before to 1.9 g/day during the infusion period. Fasting serum cholesterol and triglycerides dropped from 220 ± 28 and 281 ± 94 to 138 ± 13 and 115 ± 24 mg/dl, respectively.Mean HbA, declined from 14.8% before to 10.7% at the conclusion of the infusion period. All indices of control showed improvement significant at P < 0.05. There were no catheter-related complications and the system was well accepted by all subjects. These studies confirm that continuous central venous insulin infusion with a relatively simple waveform is feasible for the prolonged normalization of glycemia and other indices of metabolic control in ambulatory adolescent diabetics.

Self-Monitoring of Blood Glucose: How Accurate Are Children with Diabetes at Reading Chemstrip bG?

Accuracy of self-monitoring of blood glucose (SMBG) using Chemstrip bG (Bio-Dynamics, Indianapolis, Indiana) was studied in 90 randomly selected children with insulin-dependent diabetes mellitus (IDDM). For 28 children (mean age 8.3 ± 3.6 yr) a parent routinely read the Chemstrip at home. The remaining 62 children (mean age 13.7 ± 2.8 yr) read the Chemstrip themselves. Each child or parent analyzed 20 capillary blood samples using Chemstrips and answered a questionnaire on SMBG. The accuracy of SMBG of the group was high (mean correlation coefficient = 0.89 ± 0.05), but consistency of measurement was variable (mean standard deviation = 1.90 ± 0.57) and there was a general tendency to underread Chemstrips (mean y-intercept = 1.05 ± 1.48; mean slope = 0.80 ± 0.17). For each subject, 0–65% (mean of 34%) of readings were within 10% of the laboratory measurement, and 17–100% (mean 68%) within 20%. These results indicate that most subjects were fairly accurate in reading Chemstrips; however, analysis of accuracy is useful in identifying individuals who are inaccurate or inconsistent in SMBG. Continuing supervision of SMBG is necessary in children with IDDM.