Hypoglycemia in pediatric renal allograft recipients

Symptomatic hypoglycemia developed 5 to 45 months after transplantation in nine children who had renal transplants before 6 years of age. During hypoglycemia, serum glucose levels ranged from 14 to 39 mg/dl (0.8 to 2.1 mmol/L). Hypoglycemic episodes occurred between 1.7 and 7.5 years of age. Six patients had generalized seizures; the remaining three had diaphoresis with stupor or lethargy. None of the children had serious infections, diabetes, congenital defects of glucose metabolism, or a history of treatment with insulin or oral hypoglycemic agents. Six patients had hypoglycemic symptoms after a prolonged fast, and at least four had ketosis. Eight of the nine patients were receiving propranolol when hypoglycemia occurred. No differences in the daily prednisone dose, the number of transplant rejection episodes, or the frequency of treatment with medications other than propranolol were noted between hypoglycemic patients and 56 normoglycemic age-matched renal transplant recipients. All hypoglycemic patients were subsequently treated with frequent feedings and discontinuation of propranolol. No further hypoglycemic episodes have occurred in eight of nine patients. Symptomatic hypoglycemia should be recognized as a potentially devastating complication of pediatric renal transplantation.     

Continuous glucose monitoring system (CGMS) in kidney‐transplanted children

NODAT and IGT are well‐known complications of immunosuppressive therapy after transplantation being a risk factor for cardiovascular disease affecting patient and graft survival. Therefore, early identification and treatment are of high importance. In this study, we examined the glycemic homeostasis of 20 renal‐transplanted children using routine laboratory tests and the continuous glucose monitoring system (CGMS). Six patients (30%) had IGT, and one patient had NODAT (5%). The HOMA index was in an abnormal range in 35% of all patients and was abnormal in 67% of the IGT patients. CGMS analysis showed that IGT patients had higher “lowest glucose” level, and the incidence of hypoglycemic episodes was significantly lower compared with patients with normal OGTT result. In IGT patients, glucose variability tended to be lower. Furthermore, in the whole patient cohort, glucose variability significantly decreased with time after transplantation. Summarizing, these novel data show that “lowest glucose” level and hypoglycemic episodes are significantly influenced and altered in renal‐transplanted patients with IGT. Furthermore, there is a decrease in glucose variability with time after transplantation. The mechanism and relevance of these data need further investigations.     

Glycaemic control with modified intensive insulin injections (MII) using insulin pens and premixed insulin in children with type-1 diabetes: a randomized controlled trial

The objective of this study was to compare glycemic control and insulin dosage in children with type 1 diabetes treated by a modified intensified insulin therapy MII using insulin pens (and premixed and regular insulin) with those on conventional insulin therapy. This was a longitudinal, randomized controlled trial for 6 months or more. From a cohort of 125 children with previously diagnosed type-1 diabetes (more than a year after diagnosis) two groups were randomly selected Group AI (n=20) and Group B (n=20). Group AI children and 10 children with recently diagnosed type 1 diabetes (Group AII) were allocated to MII using regular insulin and premixed insulin (30/70 and 40/60 and 50/50). Group B patients continued their conventional insulin therapy for the whole period of the trial. The main outcome measures were glycemic control measured by mean blood glucose concentration and percentage of glycated haemoglobin and total daily insulin dose. Mean blood glucose concentrations before the three main meals, and at midnight, (148, 147, 179 and 127 mg/dl, respectively) were lower in children receiving intensified MII compared with those receiving conventional insulin therapy (192, 174, 194 and 179 mg/dl, respectively) (standardized mean difference 34+/-15 mg/dl), equivalent to a difference of 1.9+/-0.8 mmol/l. This improved control during MII was achieved with no change in the average daily insulin dose in group-AI. In group-AII insulin dose decreased significantly during their first 6 moths of treatment (honeymooning). Glycemic control is better during MII using insulin pens and premixed and regular insulin compared with conventional insulin therapy, without any significant change in insulin dose needed to achieve this level of control. The difference in glycemic control between the two methods is significant and could reduce the risk of micro-vascular complications.     

Treatment with insulin glargine reduces asymptomatic hypoglycemia detected by continuous subcutaneous glucose monitoring in children and adolescents with type 1 diabetes

OBJECTIVE: Unsatisfactory basal insulin substitution may lead to asymptomatic hypoglycemia in children and adolescents with type 1 diabetes (T1D). To investigate the effects of multiple daily injections before and after changing to insulin glargine (IG), continuous glucose monitoring system (CGMS) data were used to analyze glycemic control and hypoglycemic episodes during the two different therapy regimens. METHODS: Basal insulin therapy was changed to one daily injection of IG in 30 pediatric patients with T1D (14 boys and 16 girls; age 4.5-18.3 yr, median 14.2 yr; diabetes duration 0.5-15.6 yr, median 4.6 yr) having elevated fasting glucose or recurrent hypoglycemia despite treatment with multiple injection therapy (basal insulin: two to four injections of neutral protamine Hagedorn (NPH) and/or zinc lente insulin). Ambulatory CGMS was applied before and 6-8 wk after treatment change. Frequency of hypoglycemic and hyperglycemic episodes, glucose area under the curve (AUC), and time below 60 mg/dL and above 180 mg/dL, respectively, were calculated from CGMS data during the day (8:00-22:00 hours) and at night (22:00-8:00 hours). RESULTS: Nocturnal hypoglycemia was detected by CGMS in 20 patients before and in 12 patients after the change to IG (p = .039), whereas both, the number of nocturnal and diurnal hypoglycemic episodes, decreased not significantly from 41 to 36 (p = .758) and 48 to 28 (p = .055), respectively. AUC and time below 60 mg/dL as well as hemoglobin A1c (HbA1c) were not significantly different before and after the change to IG. CONCLUSION: Under treatment with IG, asymptomatic hypoglycemia was reduced without increase of HbA1c.     

Reduced hypoglycemic episodes and improved glycemic control in children with type 1 diabetes using insulin glargine and neutral protamine Hagedorn insulin

OBJECTIVE: The purpose of this study was to evaluate the use of a new long-acting basal insulin, insulin glargine (IG), in children with type 1 diabetes.Study design Data from 114 subjects, age 2 to 18 years (mean, 12.2 years; 54 boys, 60 girls), were collected for 9 months before and 9 months after IG treatment. During IG therapy, all subjects received morning neutral protamine Hagedorn insulin (given with insulin lispro; Humalog) to provide daytime insulin coverage. The numbers of nonsevere and severe hypoglycemic events, hemoglobin A1c values, body weight, and daily insulin dose were recorded at each clinic visit. RESULTS: The mean (+/-1 SEM) frequency of nonsevere hypoglycemic events per week decreased from 2.0+/-0.1 to 1.3+/-0.1 (P<.001). Severe hypoglycemic episodes were reduced from a total of 22 in the 9 months before IG to nine in the 9 months after IG. Severe nocturnal events were similarly reduced from 14 to four episodes. The mean (+/-1 SEM) hemoglobin A1c levels were 9.6+/-0.1% (baseline), 9.4+/-0.1% at 3 months (P=.18), 9.3+/-0.1% at 6 months (P=.03), and 9.3+/-0.1% at 9 months (P=.01). CONCLUSION: Insulin glargine therapy can reduce hypoglycemic episodes in children and adolescents with suboptimal glucose control without jeopardizing glycemic control.     

Impaired beta-cell and alpha-cell function in African-American children with type 2 diabetes mellitus--"Flatbush diabetes"

The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has substantially increased over the past decade. This is attributed to obesity, insulin resistance and deficient beta-cell function. In children a pubertal increase in insulin resistance and an inability to mount an adequate beta-cell insulin response results in hyperglycemia. Adults with T2DM have a diminished first phase response to intravenous glucose and a delayed early insulin response to oral glucose. Long-term studies show progressive loss of beta-cell function in T2DM in adults; however, such long-term studies are not available in children. To characterize beta- and alpha-cell function in African-American adolescents with established T2DM, we used mixed meal, intravenous glucagon and oral glucose tolerance testing and compared them to obese non-diabetic controls. T2DM was defined as fasting C-peptide >0.232 nmol/l and absent autoimmune markers. BETA-CELL FUNCTION: Meal testing in 24 children and adolescents with T2DM, mean age 14 years, BMI 30 kg/m2, Tanner stage II-V, HbA1c 8.9%, were compared with BMI- and age-matched controls. Forty percent presented with DKA. Half were treated with insulin and half with diet/oral anti-diabetic agents. Although absolute C-peptide response in both groups was similar, the incremental rise in C-peptide relative to plasma glucose in the patients with T2DM compared to controls was 40% and 35% lower 30 and 60 min after the meal, p <0.007 and p <0.026. Glucagon testing in 20 pediatric patients with T2DM compared with 15 matched controls showed significantly lower 6 min stimulated C-peptide relative to the ambient plasma glucose in patients with T2DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p <0.05). The clinical utility is that 78% of patients with a 6 min C-peptide <1.4 nmol required insulin, while 81% of those >1.4 nmol required oral anti-diabetic agents, p <0.0001. Furthermore, the duration of T2DM up to 5 years after diagnosis was associated with lower fasting and glucagon-stimulated C-peptide levels, implying worsening beta-cell function over time, even in children and adolescents. ALPHA-CELL FUNCTION: During meal testing, children and adolescents with T2DM had less suppression of plasma glucagon than non-diabetic controls; this was more severe with longer duration of T2DM and poorer glycemic control. BETA-CELL RECOVERY: In African-American and Hispanic adults, intensive treatment of blood glucose may achieve beta-cell recovery with 35-40% of newly diagnosed patients going into remission after 6 months treatment. They remain off anti-diabetic pharmacological agents in remission for a median of over 3 years with normal HbA1c levels. We hypothesize this to be due to removal of a critical component of glucose or lipotoxicity at the level of the beta-cell and/or peripheral tissue. Four of 20 African-American children presenting with mean glucose 650 mg/dl maintained normal HbA1c levels on small doses of metformin after initial treatment with multiple insulin injections with or without metformin. This suggests a marked recovery of beta-cell function, similar to that in adults. SUMMARY: T2DM in children, as in adults, is characterized by insulin deficiency relative to insulin resistance. Plasma C-peptide levels may be clinically useful in guiding therapeutic choices, since patients with lower levels required insulin treatment; beta-cell function is also diminished with longer duration of T2DM. The possibility exists that in children, as in adults, intensive glycemic regulation may allow for beta-cell recovery and preservation. Thus, optimum beta- and alpha-cell function are central to the prevention of DM and maintenance of good glycemic control in African-American and Hispanic children and adolescents with T2DM.     

An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission

AIMS: To examine derived indices of beta cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes currently in remission, repeated after a period of two or more years. METHODS: The standard intravenous glucose tolerance test (IVGTT) was used to measure the first phase insulin response (FPIR) cumulatively at one and three minutes. In addition, fasting insulin and glucose values were used to estimate insulinogenic indices (beta cell function) and QUICKI (insulin sensitivity). PATIENTS: Six patients with known previous transient neonatal diabetes currently in remission with no exogenous insulin requirement were tested. Control data from 15 children of a similar age were available for derived fasting indices of beta cell functional capacity and insulin sensitivity. RESULTS: One child had a subnormal insulin secretory response to intravenous glucose that remained abnormal two and four years later. The other children had relatively normal or entirely normal responses over two years. Measures of beta cell function and insulin sensitivity in the fasting state showed comparable results to those obtained from normal controls. CONCLUSIONS: Most children with transient neonatal diabetes in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state, although they might have been expected to show subtle defects given the tendency to relapse in adolescence. Measures of insulin response to intravenous glucose loading are often normal but suggest future recurrence if profoundly abnormal.     

Vascular Reactivity during the First Year of Diabetes in Children

ABSTRACT. Functional vascular response to hypoxia was studied in 24 children followed up prospectively for one year after diagnosis of type 1 diabetes mellitus. Postocclusive reactive hyperaemia was detected non-invasively in the skin using a transcutaneous PO₂ method at 37°C. Repeated experiments under standardized conditions were performed before institution of insulin treatment and 3, 7, 21, 30, 180 and 360 days after diagnosis. Impaired vascular reactivity was noted at the first experiment as compared with control children and slight but significant improvement was then noted up to the experiment at 180 days (p<0.01). At 30 and 180 days no significant difference between diabetic and control children was found. A small decrease in mean postocclusive reactive hyperaemia was observed at the experiment performed after 360 days. Fast normalization of urine glucose excretion, blood glucose and haemoglobin A₁ occurred during the first three weeks of treatment but these variables showed no significant correlation to vascular reactivity, either at diagnosis or later. Impaired vascular reactivity can thus be diagnosed even before the institution of insulin treatment and improves during the first months of treatment, reaching the range of controls. Other factors than indicators of carbohydrate control have to be studied in the search for explanations of the abnormal vascular function in newly diagnosed diabetic children. Key words: Diabetes mellitus, insulin dependent, hyperaemia, transcutaneous oxygen, skin blood flow, urinary glucose, blood glucose, haemoglobin A_I .     

Short-term insulin therapy in adolescents with type 2 diabetes mellitus

The optimum pharmacological treatment of type 2 diabetes mellitus (DM2) in youth for those who fail to achieve adequate glycemic control (HbA1c <7%) with lifestyle intervention is unknown. The aim of this pilot study was to observe the effect of short-term insulin therapy (<16 weeks duration) on glycemic control in youth with DM2. A pre-mix 30/70 insulin was given twice daily to 18 youth aged 10-18 years with DM2 for 8.7+/-4.3 weeks with a starting dose of 0.5 U/kg/day. HbA1c, body mass index (BMI) and episodes of hypoglycemia were monitored during the treatment period and for a 12-month period after insulin was stopped. Mean HbA1c decreased from 12.81% to 7.59% (95% CI 6.54, 8.64). This improvement persisted for 12 months without any further drug therapy. There was no significant change in mean BMI and there were no episodes of moderate or severe hypoglycemia. Decreasing beta-cell glucose toxicity with rapid improvement of blood glucose may play an important role in treatment of DM2 in adolescents. Early success in achieving target blood glucose levels is an important aspect of adolescent DM2 care.     

Familial permanent neonatal diabetes with KCNJ11 mutation and the response to glyburide therapy--a three-year follow-up

We describe 3 years follow-up of glyburide therapy in a child with permanent neonatal diabetes mellitus (PND) born to a 19 year-old mother with congenital diabetes mellitus. Genetic analysis identified a KCNJ11 mutation (R201H) in both the child and her mother. After 2 years of insulin therapy, the patient was switched to oral glyburide. After initial stabilization, glyburide therapy resulted in a marked decrease in glucose excursions in comparison to insulin. The patient had 3-10 episodes of hypoglycemia per week, including a total of eight episodes resulting in seizures, while on insulin. In contrast, no severe hypoglycemia was reported on glyburide. The patient's basal C-peptide was undetectable on insulin therapy (< 166 pmol/l) but was easily detectable on glyburide (189-761 pmol/l). The range of HbA1c improved significantly from 8-12% on insulin to 4.7-6% on glyburide. The frequency of glucose monitoring was gradually decreased from 4-8 times to 2-3 times a day on oral glyburide. This report confirms the superiority of sulfonylurea therapy in the treatment of PND with Kir6.2 mutations and shows sustained improved glycemic control over a 3-year follow-up period. Genetic exploration in other family members with diabetes might provide further insight into the nature of familial neonatal diabetes.     

Abnormal glucose tolerance in children with acute leukemia. Effect of induction chemotherapy including L-asparaginase

The glycemic and insulin response to an oral glucose load was studied in 17 children with acute lymphoblastic leukemia (ALL) and 13 normal controls. The patients were randomly assigned to either group A, receiving prednisone and vincristine, or group B, receiving these agents and, in addition, L-asparaginase from days 9-19 of the study. The glucose load was performed prior to (phase I), and on days 8 (phase II), and 19 (phase III) of chemotherapy. The mean glycemic response in both groups of patients was significantly higher than in controls at diagnosis and prior to any treatment, while mean insulin levels were not significantly different from controls. One week after initiation of treatment, the mean glycemic response improved, and was associated with hyperinsulinism. After the second week of treatment, the mean glucose and insulin response curves in group A were similar to controls. In group B, while insulin values returned to normal, blood glucose levels remained higher than in controls, but not significantly so. These findings suggest that: 1) The leukemic process itself, through mechanisms as yet undetermined, causes impairment of glucose tolerance, and 2) the diabetogenic effect of L-asparaginase is not manifested in all patients.     

Initiation of insulin glargine in children and adolescents with type 1 diabetes

BACKGROUND: Glargine (Lantus) is a recently approved, long-acting insulin analog that is increasingly being used in children with diabetes. The aim of this retrospective chart review was to summarize our experience in starting glargine in children and adolescents with diabetes. SUBJECTS AND STUDY METHODS: We reviewed the medical records of 71 children with type 1 diabetes (29 boys and 42 girls) who initiated glargine therapy to improve glycemic control between 1 June 2001 and 30 June 2002. Data were collected for 6 months before and 6 months after adding glargine. RESULTS: Subjects' mean age [+/-standard deviation (SD)] at diagnosis of diabetes was 7.5 +/- 4.1 yr. Mean age at initiation of glargine therapy was 11.5 +/- 4.9 yr. The total daily long-acting insulin dose decreased by about 20% after initiating glargine therapy. There were no significant differences in hemoglobin A1c (HbA1c) and blood glucose control prior to and after initiating glargine therapy (HbA1c at baseline 8.9 +/- 1.6% and HbA1c after 6 months of glargine therapy was 8.9 +/- 1.5%). Overall, blood glucose concentrations did not differ significantly throughout the study. Patients who switched to glargine because of nocturnal hypoglycemia had a 65% decrease in nocturnal blood glucose reading less than 50 mg/dL. There were three seizures in the first week after initiating glargine therapy. CONCLUSION: This retrospective study suggests that glargine is at least as effective as other long-acting insulins but that care must be taken during the conversion process to avoid hypoglycemia.     

Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis

Infantile cystinosis, a rare lysosomal storage disease of cystine, leads to Fanconi syndrome and end-stage renal failure. After renal transplantation, no recurrence of the disease occurs in the graft, but other organ involvement becomes evident later in life. Diabetes mellitus has been associated with cystinosis, but the mechanisms of impaired glucose tolerance have not yet been characterized. Here, we studied glucose tolerance, glucose constant decay (k-values), insulin and C-peptide by intravenous glucose tolerance test (IVGTT) in eight patients with infantile cystinosis (three with impaired GFR (CRF) and five after kidney transplantation (KTX)). For comparison, 15 age-matched children with CRF and 15 age-matched KTX patients were analysed. Both early and second insulin secretion phases were diminished in patients with infantile cystinosis, whereas in CRF, k-values were no different from control patients. After renal transplantation, k-values were significantly lower in cystinotic patients with a markedly reduced early insulin secretion phase. There was a significant negative correlation between k-values and age in patients with cystinosis. Repetitive IVGTTs in these patients demonstrated progressive but rather slow loss of first phase insulin secretion and C-peptide production, suggesting a slowly reducing secretion potential of the beta cell due to cystine storage. Conclusion Unlike type I diabetes mellitus, glucose intolerance in patients with infantile cystinosis is characterized by a slow, progressive loss of insulin secretion and C-peptide production. For these patients, the data indicate a 50% risk of developing glucose intolerance by the age of 18 years. We recommend to perform intravenous glucose tolerance tests at 5-year intervals. Received: 1 September 1997 / Accepted: 30 November 1997     

Immediate metabolic response to a low dose of insulin in children presenting with diabetes.

Seventeen new cases of diabetes in childhood were given an initial mean dose of insulin of 0-29 unit/kg body weight by intramuscular injection (mean age of patient 7-4 years). This resulted in a fall in blood glucose over the first 2 hours at a mean rate of 88 mg/100 ml per hour. Over the same time the mean total blood ketones fell from 3-23 to 2-3 mmol; and plasma insulin levels rose from a mean of 6 muU/ml to a mean of 65 muU/ml. Thus, with this small initial dose of insulin the 2-hour plasma insulin values were within the range which in adults has been associated with a maximum fall in blood glucose concentration. Three children with established diabetes presenting with ketoacidosis were also treated with a small initial dose of intramuscular insulin, 0-1 unit/kg in 2 of the patients and 0-5 unit/kg in the third. In 2 during a period of rehydration before insulin was given, blood glucose fell at a rate of 100 mg/100 ml per hour. Over the 2 hours after the initial dose of insulin the mean rate of fall of blood glucose for all 3 patients was 73 mg/100 ml per hour. None of these children developed hypoglycaemia nor hypokalaemia during treatment. We conclude that an initial intramuscular injection of soluble insulin in the dose range of 0-1-0-5 units/kg body weight may be more appropriate and possibly safer for the treatment of diabetic ketoacidosis in children than the currently recommended larger doses divided between intravenous and intramuscular routes. Adequate rehydration must, however, remain the first priority in the management of such cases.     

Immediate metabolic response to a low dose of insulin in children presenting with diabetes

Seventeen new cases of diabetes in childhood were given an initial mean dose of insulin of 0-29 unit/kg body weight by intramuscular injection (mean age of patient 7-4 years). This resulted in a fall in blood glucose over the first 2 hours at a mean rate of 88 mg/100 ml per hour. Over the same time the mean total blood ketones fell from 3-23 to 2-3 mmol; and plasma insulin levels rose from a mean of 6 muU/ml to a mean of 65 muU/ml. Thus, with this small initial dose of insulin the 2-hour plasma insulin values were within the range which in adults has been associated with a maximum fall in blood glucose concentration. Three children with established diabetes presenting with ketoacidosis were also treated with a small initial dose of intramuscular insulin, 0-1 unit/kg in 2 of the patients and 0-5 unit/kg in the third. In 2 during a period of rehydration before insulin was given, blood glucose fell at a rate of 100 mg/100 ml per hour. Over the 2 hours after the initial dose of insulin the mean rate of fall of blood glucose for all 3 patients was 73 mg/100 ml per hour. None of these children developed hypoglycaemia nor hypokalaemia during treatment. We conclude that an initial intramuscular injection of soluble insulin in the dose range of 0-1-0-5 units/kg body weight may be more appropriate and possibly safer for the treatment of diabetic ketoacidosis in children than the currently recommended larger doses divided between intravenous and intramuscular routes. Adequate rehydration must, however, remain the first priority in the management of such cases.     

Management of diabetes mellitus in children younger than 5 years of age

Optimal treatment for children younger than 5 years of age with insulin-dependent diabetes mellitus is not well defined. Nineteen young children with this disease were treated with a program in which frequent home blood-glucose monitoring was used as the basis for an educational program emphasizing parental adjustment of insulin in response to current glucose levels and anticipated diet and exercise. Eleven children were treated from diagnosis (group I) and another eight (group D) were referred after less intensive treatment. The mean duration of observation of group I children was 13.6 months (range, six to 24 months). For group D, the mean time between diagnosis and referral was 14.9 months (range, seven to 24 months) and 14.6 months (range, six to 24 months) after referral. Before referral, there were 11 hospitalizations in group D. During the intensified program there were two hospitalizations in group D and one in group I. There were 3.3 episodes of severe hypoglycemia per child per 18 months in group D before referral, 1.7 episodes after referral, and 0.4 episodes in group I. Ten of 14 severe hypoglycemic episodes during intensified treatment occurred when there was no or infrequent home blood-glucose monitoring. Only four episodes seemed to have been unpredictable and unpreventable. Mean glycosylated hemoglobin levels were higher in group D patients when compared with both the duration of insulin-dependent diabetes mellitus and the time of initiation of intensified treatment. Mean daily insulin doses increased progressively in group I patients following diagnosis, and were comparable with those in group D patients at 15 and 18 months' duration of illness. Thus, frequency of hospitalization and severe hypoglycemia can be decreased in young children. Frequent home blood-glucose monitoring is required and extensive educational and psychosocial support is necessary for families to implement this intensive approach. The long-term effects on psychoneurological development need evaluation.     

Follow-up of children of insulin dependent (type I) and gestational diabetic mothers. Growth pattern, glucose tolerance, insulin response, and HLA types

Fifty-three children of insulin dependent (IDM) and 20 children of gestational diabetic mothers (IGDM) representing 80 and 91%, respectively, of all surviving infants of diabetic mothers born between 1969 and 1972 at Sabbatsberg's hospital, Stockholm, participated in the follow-up study. The first follow-up examination was performed when the children had reached approximately 5 years of age and included measurement of height and weight, insulin response to intravenous glucose, and HLA typing. When the children were approximately 11 years old, a search was performed in the national register for type I diabetes in children in order to ascertain the frequency of type I diabetes mellitus in the total series (n = 88). The majority of children had a normal height for age and desirable weight for height. At the first follow-up all children had normal glucose disappearance rates (kt) and the insulin response including the early insulin response to glucose were not different between IDM and IGDM groups. The frequency distribution of HLA antigens (A, B, C) was not different from normal and there was no association between HLA B 8 and/or B 15 and early insulin response or kt values. At the second follow-up, two children of type I diabetic mothers had acquired type I diabetes, both were HLA B 15 positive, had normal kt values at the first follow-up, one with low, one with a high early insulin response. The frequency of type I diabetes in offspring of insulin dependent diabetic mothers was 3%.     

Insulin glargine improves hemoglobin A1c in children and adolescents with poorly controlled type 1 diabetes

Abstract:  The pediatric diabetes team at the University of Minnesota made a clinical decision to switch patients with type 1 diabetes with a hemoglobin A1c level greater than 8.0% to insulin glargine in an effort to improve glycemic control. Retrospective chart analysis was performed on 37 patients 6 months after the switch to insulin glargine therapy.
Results:  After 6 months, the average hemoglobin A1c level in the entire cohort dropped from 10.1 ± 2.0 to 8.9 ± 1.6% (p = 0.001). Thirty patients responded with an average hemoglobin A1c drop of 1.7 ± 1.5%, from 10.3 ± 2.2 to 8.6 ± 1.5% (p < 0.001). Seven patients did not respond to insulin glargine therapy, with an average hemoglobin A1c rise of 1.0 ± 0.8% from a baseline of 9.5 ± 1.0% to 10.4 ± 1.4% (p = 0.01). The greatest response was seen in children with an A1c > 12.0%, who dropped their hemoglobin A1c by 3.5 ± 1.9%. Compared with responders, non-responders had significantly less contact with the diabetes team in the form of clinic visits and telephone conversations both before and after initiation of glargine therapy. Sixty-two per cent of patients received insulin glargine at lunchtime, when injections could be supervised at school. Three episodes of severe hypoglycemia occurred after initiation of insulin glargine therapy.
Conclusions:  Insulin glargine substantially improved glycemic control in children and adolescents with poorly controlled type 1 diabetes. This response was most remarkable in those with a baseline hemoglobin A1c level > 12.0%, and may have been related to increased supervision of injections.     

A randomized, controlled study of insulin pump therapy in diabetic preschoolers

OBJECTIVE: To compare glycemic control, safety, and parental satisfaction in preschool-aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or intensive insulin injection therapy. STUDY DESIGN: This clinical trial enrolled 42 patients <5 years of age who had been diagnosed with diabetes for at least 12 months. Children were randomly assigned to CSII (n = 21) or intensive insulin injection therapy (n = 21). Hemoglobin A1c (HbA1c) level was measured at baseline, 3, and 6 months. Secondary outcomes included severe hypoglycemic events, meter-detected hypoglycemia, blood sugar variability, body mass index (BMI), and satisfaction with therapy. RESULTS: Thirty-seven patients completed 6 months of therapy. There was a significant decrease in HbA1c during the study period for both groups (from 8.9% +/- 0.6% to 8.6% +/- 0.6% at 3- and 6-month visits). At 3 months, children using pumps had a significantly lower HbA1c than the injection group (8.4% vs 8.8%); however, by 6 months the two groups were similar (8.5% vs 8.7%). No differences in pre-meal blood sugar variabilities were seen between groups. Children on pumps had increases in the number of meter-detected episodes of hypoglycemia. Pump therapy was safe and well tolerated. No episodes of ketoacidosis occurred in either group, whereas one hypoglycemic seizure occurred in each group. Parents reported satisfaction with CSII, with 95% of families continuing on CSII beyond the 6-month study period. CONCLUSION: Pump therapy in preschool-aged children was not associated with clinically significant differences in glycemic control as compared with intensive injection therapy. The rationale for initiating CSII in this age group should be based on patient selection and lifestyle preference.     

Beta-cell response to intravenous glucagon in African-American and Hispanic children with type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus (DM) in children and adolescents has substantially increased over the past decade. The present study was conducted to evaluate the beta-cell response to intravenous glucagon (a non-glucose secretagogue) in children with type 2 DM. Twenty pediatric patients with type 2 DM were compared to 15 control subjects matched for body mass index and sexual maturation. The patients' ages ranged between 10 and 19 years. The duration of DM ranged from 1 to 5 years. Nine patients were on insulin treatment and 11 were on diet alone (3 patients) or metformin (8 patients). The criteria for type 2 DM were absent islet cell (IA-2) and glutamic acid decarboxylase (GAD65) antibodies and a fasting serum C-peptide level of > or = 0.23 nmol/l. Plasma glucose and serum C-peptide levels were determined in the fasting state and six minutes after an intravenous injection of 1 mg of glucagon. The fasting and stimulated plasma glucose levels and the fasting serum C-peptide levels (1.02 +/- 0.43 vs 0.79 +/- 0.26 nmol/l, p < 0.05) were higher in the patients with DM compared to weight-matched control subjects. While the absolute C-peptide responses to glucagon were not different between the two groups, the stimulated C-peptide to glucose ratios were significantly lower in the patients with DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p < 0.05). Patients with DM treated with diet or oral therapy had significantly greater basal and stimulated C-peptide concentrations, incremental C-peptide, and C-peptide to glucose ratios than patients on insulin treatment. Both the fasting and the stimulated C-peptide levels were inversely correlated with the duration of DM (r = -0.53, p < 0.05). HbA1c at one year follow-up was inversely correlated with glucagon-stimulated C-peptide levels at the time of the study (r = -0.658, p < 0.01) and positively correlated with the duration of diabetes (r = 0.671, p = 0.002). The apparently normal serum C-peptide levels measured after glucagon challenge in these children with type 2 DM reflect their higher glucose levels. The lower stimulated C-peptide to glucose ratios in these children with type 2 DM compared to normal controls demonstrate their diminished beta-cell response to intravenous glucagon, a non-glucose secretagogue. Among the patients with DM, a higher glucagon-stimulated serum C-peptide response was associated with diet/metformin treatment, a shorter duration of DM and predicted improved glycemic control up to one year later. Thus, the fasting and glucagon-stimulated serum C-peptide levels provide an estimate of the potential insulin secretory capacity of the beta-cell and may predict glycemic control in pediatric type 2 DM.