Evaluation of β-cell function in diabetic Taiwanese children using a 6-min glucagon test

This study evaluates the effects of glucagon 30 μg/kg (maximal 1 mg) on β-cell function in children by C-peptide determined before and 6 min after intravenous administration. From 1990 to 2005, 118 Taiwanese children with newly diagnosed diabetes mellitus (98 children with type 1 and 20 children with type 2) and 29 normal Taiwanese children were enrolled in this study. Fasting and 6-min post-glucagon C-peptide levels were analyzed. In the pre-pubertal group, the median fasting serum C-peptide levels were 0.2 and 0.8 nmol/l in type 1 diabetes and normal children, respectively. These levels rose to 0.3 and 1.9 nmol/l after glucagon stimulation. In the pubertal group, the median fasting serum C-peptide levels were 0.3, 1.0 and 0.9 nmol/l in type 1 diabetes, type 2 diabetes and normal children, respectively. They rose to 0.4, 2.5 and 2.7 nmol/l after glucagon stimulation. Both fasting and post-glucagon C-peptide levels in type 1 diabetes patients were significantly lower than those of normal children and children with type 2 diabetes. The optimal cut-off values to distinguish type 1 diabetes patients from those with type 2 as determined by the receiving operating characteristic curve were 0.7 and 1.1 nmol/l, respectively. The sensitivities of both C-peptide values were 93%. The post-glucagon C-peptide level was more powerful in distinguishing type 1 diabetes from type 2 diabetes with higher specificity (95% vs. 85%). The 6-min glucagon test is valuable in assessing β-cell function in children and can help pediatricians in the differential diagnoses of diabetes mellitus in children.     

Transient neonatal diabetes mellitus,type 4, type 1 diabetes mellitus,or MODY: which disease is it,anyway?

A 30year-old Hispanic male who presented with transient neonatal diabetes mellitus at 4 months has been intensively studied with 12 islet-cell secretagogues from 4 months to 24 years. He was both ICA- and GAD-65-negative, but at 28 years was diagnosed with hypothyroidism due to positive thyroperoxidase antibodies. The course of his disease(s) and the various presentations of hyperglycemia are documented and illustrated by the responses in islet cell hormone secretion, namely, insulin, glucagon, and C-peptide. Insulin secretion gradually fell over 24 years, glucagon secretion persisted from infancy to 24 years but was only minimal during i.v. glucose at 24 years, and C-peptide secretion remained normal, although modest, throughout the 24 years. These data suggest that, despite changing presentations of diabetes mellitus over time, the islets continued to process proinsulin, although the patient required insulin therapy.     

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.     

Latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and Celiac disease

Latent autoimmune diabetes mellitus in adults (LADA) is characterized by clinical presentation as type 2 diabetes mellitus after 25 years of age, initial control achieved with oral hypoglycemic agents for at least 6 months, presence of autoantibodies and some immunogenetic features of type 1 diabetes mellitus. An 8.3 year-old girl was referred to our pediatric endocrinology department because of incidental glucosuria. She did not complain of polyuria, polydipsia, or weight loss. Her body mass index (BMI) was at the 80th percentile. Fasting glucose was 126 mg/dl, and OGTT glucose level at 120 min was 307 mg/dl. Although C-peptide levels were normal, her first phase insulin response (FIR) was lower than the 1st percentile. Anti-insulin antibody (AIA), islet cell antibody (ICA), and anti-glutamic acid decarboxylase (antiGAD) were negative. According to the clinical and laboratory findings, she was diagnosed as having type 2 diabetes mellitus. She was started with oral anti-diabetic treatment for a period of 1 year. Insulin had to be initiated for worsening of HbA1c levels. In the fourth year of follow-up, she was admitted to our hospital with diabetic ketoacidosis although she was on an intensive insulin regimen. At this time, C-peptide levels were low, antiGAD and AIA were positive with HLA DR3/DQ2 haplotype. In addition, her thyroid peroxidase antibody and endomysium antibody were found to be high at follow-up. Small intestinal biopsy revealed celiac disease. This patient may represent the first case of latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and celiac disease.     

Cyclosporine A for the treatment of new-onset insulin-dependent diabetes mellitus

It is not known whether early immunosuppressive treatment can preserve long-term endogenous insulin secretion in subjects with insulin-dependent diabetes mellitus. In the present study, clinical remissions during the first year and C-peptide production for 3 years were followed after 43 subjects with newly diagnosed insulin-dependent diabetes mellitus were randomly assigned to a cyclosporine A treatment group for 4 months or to a control group. Of the six cyclosporine A-treated subjects who had remissions, five were 19 years of age or younger, compared with two of the four in the control group. C-peptide production was present in 98% of all subjects after 4 months, in 88% after 1 year, and in 43% after 3 years. There were no significant differences in numbers of subjects with C-peptide production or in mean hemoglobin A1 levels, between cyclosporine A-treated and control subjects after 3 years. Cyclosporine A treatment of subjects with newly diagnosed insulin-dependent diabetes mellitus for a period of 4 months does not have the ability to preserve residual beta-cell function.     

Hypoglycaemia in Childhood Diabetes I.

ABSTRACT. Hypoglycaemia (blood glucose 1.3–2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and Cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.     

Urinary C-Peptide Excretion at Onset of Insulin Dependent Diabetes Mellitus in Children

ABSTRACT. The 24-hour urinary excretion of C-peptide and the plasma C-peptide concentration were measured at the onset of insulin dependent diabetes mellitus (IDDM) in children. The excretion of C-peptide was twice as high as that found in normal control subjects, whereas the plasma C-peptide values were markedly lower, indicating increased urinary leakage of C-peptide in this phase of the disease. In the diabetic children under seven years of age the mean value of C-peptide excretion was clearly lower than in the older children.     

Urinary C-peptide excretion at onset of insulin dependent diabetes mellitus in children

The 24-hour urinary excretion of C-peptide and the plasma C-peptide concentration were measured at the onset of insulin dependent diabetes mellitus (IDDM) in children. The excretion of C-peptide was twice as high as that found in normal control subjects, whereas the plasma C-peptide values were markedly lower, indicating increased urinary leakage of C-peptide in this phase of the disease. In the diabetic children under seven years of age the mean value of C-peptide excretion was clearly lower than in the older children.     

PANCREATIC ISLET CELL FUNCTION AND METABOLIC CONTROL IN AN INFANT WITH PERMANENT NEONATAL DIABETES

ABSTRACT. A girl with typical clinical manifestations of neonatal diabetes was observed for 16 months with consecutive evaluations of pancreatic beta and alpha-cell function and metabolic control. At the diagnosis both the plasma immunoreactive insulin (IRI) and C-peptide concentrations were inappropriate for the contemporaneous hyperglycemia. During the follow-up, the C-peptide fell twice below the detection limit but the beta-cell function recovered partially on both occasions. Based on 24-hour urinary C-peptide excretion, the endogenous insulin secretion was less than 10% of that in non-diabetic infants. When diagnosed the patient had plasma immunoreactive glucagon (IRG) and glucagon-like immunoreactivity (GLI) concentrations below the reference range for normal neonates. The IRG normalised within the first month, while the GLI increased to a level exceeding the reference range. Hemoglobin A₁ had already risen at the time of diagnosis and subsequently rose to a level indicating poor metabolic control. The findings indicate an immature function of both beta- and alpha-cells at the diagnosis with the alpha-cells maturing within the first month. The recovery of the beta-cell function, after two failures in this patient with permanent neonatal diabetes, suggests that the beta-cell damage was at least partially reversible.     

Active detection of glucose tolerance disorders among populations with diabetes mellitus risk factors]

The authors carried out studies of carbohydrate metabolism, C-peptide, immunoreactive insulin, T3, T4 and cholesterol in children and adolescents at risk for diabetes mellitus. Based on the data obtained it is concluded that disturbed glucose tolerance and diabetes mellitus mostly occur in the groups of subjects who suffered viral infections, in those with obesity and other conditions. The established parameters of glycemia can be used for assessing glycemia standards, which is of importance for early diagnosis of diabetes mellitus and disturbed glucose tolerance.     

Early postnatal hypoglycaemia in newborn infants of diabetic mothers

This study found that early postnatal hypoglycaemia was mainly induced by foetal hyperinsulinaemia, in close relation to maternal hyperglycaemia. even in well-controlled pregnancies of 59 mothers with insulin-treated diabetes mellitus, 29 with insulin-dependent diabetes mellitus and 30 with gestational diabetes mellitus. Ten of the newborn children (17%) had a blood glucose concentration below 1.0mmol 1^-1 at 2h postnatally. Cord insulin-like growth factor-1 or glucagon concentrations were not related to the early decline of blood glucose.     

Pancreatic endocrine response to the first feed in term newborn infants

Blood glucose, insulin, C-peptide and glucagon were evaluated in 36 newborn term infants at birth, and before and 60 min after the first feed during the first day of life. Under basal conditions glycaemia diminished during the first day of life and glucagon increased, while insulin and C-peptide did not show any variation. The C-peptide: insulin molar ratio was higher in the newborn than in adults because of the longer half-life of C-peptide, probably due to reduced renal function in the neonatal period.The subjects were divided into two groups: 18 newborn infants were given a feed of commercially available milk powder reconstituted in water at 10% (5 ml/kg); the other 18 were given a feed of 5 ml/kg 10% glucose solution. In each group 6 were given the first feed after a fast of 6 h, 6 after a fast of 12 h, and 6 after a fast of 24 h from birth. After the first feed with milk, the average increase of glycaemia was 19.83 mg%, of insulin 6.06 U/ml, and of C-peptide 1.88 ng/ml. After the first feed with glucose the average increase of glycaemia was 13.59 mg%, of insulin 2.46 U/ml, and of C-peptide 0.59 ng/ml. Glucagon did not show significant changes after the first feed.     

Congenital pancreatic hypoplasia: a syndrome of exocrine and endocrine pancreatic insufficiency

We describe two brothers with small size at birth, early-onset insulin-dependent diabetes, and pancreatic exocrine insufficiency. In contrast to the findings in pancreatic aplasia, their serum C-peptide and glucagon levels were measurable. These findings, in concert with their clinical courses, are consistent with the diagnosis of congenital pancreatic hypoplasia.     

Diabetes mellitus in newborns and infants

Diabetes mellitus is uncommon in infancy and newborn period. The two common forms seen are the transient and permanent forms of diabetes mellitus of the newborn. They have to be differentiated from the transient hyperglycemic states (Blood sugar >125 mg/dl) seen in newborns who receive parenteral glucose infusions and in those with septicemia and CNS disorders. Transient diabetes mellitus of the newborn (TDNB) is defined as hyperglycemia occurring within the first month of life lasting at least 2 weeks and requiring insulin therapy. Most of these cases resolve spontaneously by 4 months. It has a reported incidence of 1 in 45,000 to 60,000 live births. The most likely etiology is a maturational delay of cAMP mediated insulin release. The clinical features include small for datedness, proneness for birth asphyxia, open-eye alert facies, dehydration, emaciation, polyuria and poydipsia. These children are prone to septicemia and urinary tract infections. They have hyperglycemia, glucosuria, absent or mild ketonuria, low basal insulin, C-peptide and IGF-1 levels. Treatment consists of hydration and judicious administration of insulin with close monitoring. Thirty percent of these children are likely to develop permanent neonatal diabetes. Compared to transient form, permanent diabetes mellitus is uncommon. It is usually due to pancreatic dysgenesis often associated with other malformations and rarely due to type 1 diabetes mellitus. The diagnosis is based on the demonstration of both exocrine and endocrine pancreatic dysfunction. These children are managed as type 1 diabetes mellitus. They are prone to develop the vascular complications of diabetes at an earlier date.     

Hypoglycaemia in childhood diabetes. I. Clinical signs and hormonal counterregulation

Hypoglycaemia (blood glucose 1.3-2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.     

Clinical similarity and diagnostic difficulties in differentiation of diabetes mellitus type 1 and type 2 in adolescence - case report

The authors would like to present the difficulties in differentiation of diabetes mellitus type 1 and type 2 in adolescence on the basis of two 17 years-old patients. In both patients' cases the following symptoms: polydipsia, polyuria and weight loss with hyperglycemia and glycosuria have been observed for a few months. During laboratory studies some additional abnormalities were observed: elevated HbA1c, dyslipidemia and high level of liver enzymes. Normal level of insulin as well as C-peptide lack of ketonuria and negative parameters of autoimmunologic reaction the supported diagnosis of diabetes mellitus type 2. Due to insulin therapy and metformin a correct level of glycemia was achieved. CONCLUSION: Decompensated diabetes mellitus type 2 in adolescents may be difficult to differentiate with type 1.     

Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes

Kaas A, Max Andersen ML, Fredheim S, Hougaard P, Buschard K, Petersen JS, de Beaufort C, Robertson KJ, Hansen L, Mortensen HB, Nielsen LB, On behalf of The Hvidoere Study Group on childhood diabetes. Proinsulin, GLP‐1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes. Objective: Proinsulin is a marker of beta‐cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose‐adjusted haemoglobin A1c (IDAA1C), glucagon‐like peptide‐1 (GLP‐1), glucagon, and remission status the first year after diagnosis of type 1 diabetes. Methods: Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C ≤9%. The patients had a liquid meal test at the 1‐, 6‐, and 12‐month visits, which included measurement of C‐peptide, proinsulin, GLP‐1, glucagon, and insulin antibodies (IA). Results: Patients in remission at 6 and 12 months had significantly higher levels of proinsulin compared to non‐remitting patients (p < 0.0001, p = 0.0002). An inverse association between proinsulin and IDAA1C was found at 1 and 6 months (p = 0.0008, p = 0.0022). Proinsulin was positively associated with C‐peptide (p < 0.0001) and IA (p = 0.0024, p = 0.0068, p < 0.0001) at 1, 6, and 12 months. Glucagon (p < 0.0001 and p < 0.02) as well as GLP‐1 (p = 0.0001 and p = 0.002) were significantly lower in remitters than in non‐remitters at 6 and 12 months. Proinsulin associated positively with GLP‐1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002). Conclusions: In type 1 diabetes, patients in partial remission have higher levels of proinsulin together with lower levels of GLP‐1 and glucagon compared to patients not in remission. In new onset type 1 diabetes proinsulin level may be a sign of better residual beta‐cell function.     

Management of diabetes in pediatric resident continuity clinics

General pediatricians provide comprehensive care for many children with insulin-dependent diabetes mellitus. To assess and improve our ambulatory training program, we first evaluated diabetes-specific care behaviors by residents in their continuity clinics and then introduced a structured visit encounter form. Based on established guidelines provided to the residents, a chart audit indicated appropriate measurement of glycosylated hemoglobin 40% of the time, cholesterol 90% of the time, urine protein 50% of the time, and thyroxine 66.7% of the time. Height was plotted 23% of the time, blood pressure was noted 66% of the time, and ophthalmologic referrals were documented 60% of the time. Requests for assistance from nonphysician members of a multidisciplinary diabetes team were minimal. After introduction of the structured visit encounter form, care behaviors did not improve. New training approaches to prepare general pediatric residents to provide excellent diabetes care are needed.     

Comparative HGH response to i.v. glucagon and i.v. arginine stimulation tests in children and adolescents

Thirty-seven children and adolescents of several diagnostic entitites (constitutional growth retardation, diabetes mellitus and pituitary insufficiency) were tested with an i.v. bolus injection of glucagon for plasma human growth hormone (HGH) response. Most of the subjects were also tested for the same purpose by the arginine stimulation test, and the data were compared.It was found that i.v. glucagon is a potent stimulus of human growth hormone release. The HGH is released in two peaks, the first one occuring within 30 min, most probably by a direct effect. The second peak occurs after 120 min, most probably as a secondary effect caused by the drop in blood glucose after its initial rise, which is induced by glucagon. The peak concentrations of HGH induced by glucagon, were very similar to those provoked by i.v. arginine in the same subjects.