Type 1 diabetes mellitus in a 3 1/2 year-old girl with Turner's syndrome

Turner's syndrome is associated with autoimmune disorders. Autoimmune endocrinopathy in Turner's syndrome seems to be limited to autoimmune thyroiditis. A small number of patients with Turner's syndrome has also been associated with celiac disease, inflammatory bowel disease and juvenile rheumatoid arthritis. Type 1 diabetes mellitus in Turner's syndrome has been rarely reported. We present here the youngest patient with Turner's syndrome who developed type 1 diabetes mellitus. At the age of 3.5 years she was hospitalized with diabetic ketoacidosis. Anti-islet cell and anti-insulin antibodies were positive and C-peptide level was low. When she was investigated for recurrent urinary tract infections, horseshoe kidney was detected by ultrasonography. Karyotype analysis revealed 45,XO. She has been followed for 2 years with an insulin dose of 0.9 U/kg per day. The prevalence of type 1 diabetes mellitus associated with Turner's syndrome is still unknown.     

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.     

Permanent neonatal diabetes mellitus: clinical presentation and epidemiology in Oman

AIM: To estimate the accurate incidence and prevalence of permanent neonatal diabetes mellitus, and to determine the clinical profile of this condition in the Sultanate of Oman. METHODS: All children diagnosed as having permanent neonatal diabetes mellitus between 1991 and 1995 in Oman were included in the study. RESULTS: The mean incidence was 2.2 per 100 000 live births/year and the prevalence among under 5s during 1995 was 2.0/100 000. Intrauterine growth retardation was noted in all (mean birthweight 1.86 kg), and diabetic ketoacidosis (mean plasma glucose 34.4 (SD 8.7) mmol/l, mean pH 7.17 (SD 0.09) in 80%. Hypertriglyceridaemia (mean serum triglyceride 19.06 (6.13) mmol/) was constant. No infant had clinical or immunological evidence of congenital viral infections. None had C-peptide excretion or circulating islet cell antibody during diagnosis or follow up. The other important features were parental consanguinity in all, HLA DR3/DR4 association in 80%, development of autoimmune hypothyroidism in one and observation of autoimmune disorders (insulin dependent diabetes mellitus and Hashimoto's thyroiditis) in family members. CONCLUSIONS: These findings strongly suggest an immune mediated aetiology for diabetes mellitus. The reported incidence of permanent insulin dependent neonatal diabetes mellitus in Oman is the highest in the world.     

Postprandial hyperlipidemia after a fat loading test in minority adolescents with type 2 diabetes mellitus and obesity

The continuing increase in the incidence of type 2 diabetes mellitus (DM2) and obesity in children and adolescents is attributable to excessive caloric intake. Abnormal lipid metabolism in the postprandial state leads to long exposure of the vasculature to hyperlipidemia. Most children and adolescents with DM2 are obese, and many have fasting hypertriglyceridemia. Clustering of hyperlipidemia, DM2 and obesity increases the risk for cardiovascular disease. We therefore studied lipids, insulin, C-peptide, and glucose in response to an oral fat load simulating the fat content of a high-fat, fast-food meal in 12 type 2 diabetic obese, 15 non-diabetic obese, and 12 non-diabetic non-obese (control) adolescents (aged 10-19 yr; 87% African-Americans). All three groups were age-, sex-, and sexual maturation-matched. Mean body mass indices were similar in the diabetes and obese groups (32.7 +/- 1.1 vs 35.8 +/- 1.6 kg/m2). All patients with DM2 had fasting C-peptide > 0.2 nmol/l (0.7 ng/ml) and negative diabetes-associated autoantibodies. Serum total cholesterol, triglyceride, high- and low-density lipoprotein cholesterol, insulin, C-peptide, and plasma glucose levels were measured at 0, 2, 4, and 6 h after the fat load. The area under the curve (AUC) was calculated by trapezoidal estimation. Triglyceride AUC was significantly greater in the diabetes group than in the other two groups (15.7 +/- 2.9 vs 9.2 +/- 0.7 and 7.5 +/- 0.7 mmol x h/l [1389 +/- 258 vs 819 +/- 60 and 663 +/- 62 mg x h/dl]; p < 0.02 and <0.004, respectively), as were insulin, C-peptide, and glucose AUCs. Incremental triglyceride response (delta triglyceride = peak - fasting) in the diabetes group was significantly higher than that in the control group (2.1 +/- 0.7 vs 0.8 +/- 0.1 mmol/l 189.7 +/- 58.4 vs 71.2 +/- 11.1 mg/dl]; p < 0.04). Insulin resistance was estimated using the homeostasis model assessment (HOMA), which was greater in the diabetes group than in the obese and control groups (14.4 +/- 2.8 vs 5.2 +/- 0.8 and 3.2 +/- 0.4; p < 0.001 and < 0.0001, respectively). The diabetes group was divided into subgroups of high and normal fasting triglycerides on the basis of triglyceride levels above and below the 95th percentile. The delta triglyceride in the subgroup with high fasting triglycerides was substantially greater than in the subgroup with normal fasting triglycerides (3.4 +/- 1.1 vs 0.8 +/- 0.2 mmol/l [305.2 +/- 96.8 vs 74.2 +/- 18.0 mg/dl]; p < 0.001). Total cholesterol and triglyceride AUCs were much greater in the high vs normal fasting triglycerides subgroup (33.0 +/- 2.9 vs 24.2 +/- 1.9 and 23.6 +/- 3.5 vs 7.8 +/- 0.6 mmol x h/l [1274 +/- 113 vs 934 +/- 72 and 2085 +/- 309 vs 692 +/- 49 mg x h/dl]; p < 0.02 and <0.0001, respectively), as were insulin and C-peptide AUCs. HOMA was greater in the high vs normal fasting triglycerides subgroup (20.8 +/- 4.0 vs 8.0 +/- 1.6; p < 0.0001). In addition to elevated plasma glucose levels, there were no significant differences in either insulin or lipid parameters among the diabetes subgroup with normal fasting triglycerides, the obese group, and controls. Our data suggest that postprandial hyperlipidemia in response to a fat loading test is present in adolescents with DM2 who already have fasting hypertriglyceridemia. The degree of insulin resistance as an underlying abnormality--not DM per se--determines the degree of postprandial lipemia.     

Autoimmune hypoglycemia in type 1 diabetes mellitus

Background

Antibodies against exogenous insulin are common in type 1 diabetes mellitus patients. They can cause hypoglycemia, albeit uncommonly.

Case Characteristics

A 14-year-old girl with type 1 diabetes mellitus presented with recurrent hypoglycemia. Outcome: High insulin, low C-peptide and raised insulin antibody levels documented during hypoglycemia. Plasmapheresis led to remission of hypoglycemia.

Message

Antibodies to exogenous insulin should be considered as a cause of recurrent refractory hypoglycemia in type 1 diabetes mellitus patients.

     

Newly diagnosed T1 diabetes presenting with hypoglycemia due to simultaneous co‐existence of Addison disease

Type 1 diabetes mellitus (TIDM) classically presents with symptomatic hyperglycemia and many patients develop diabetic ketoacidosis prior to their diagnosis. However, non‐classical presentation or co‐presentation with associated diseases may delay diagnosis or lead to challenges in acute, clinical management. An 18‐yr‐old girl presented to hospital with severe, symptomatic hypoglycemia. Clinical history and serum electrolyte concentrations suggested a diagnosis of adrenal insufficiency. She remained hypoglycemic until glucocorticoid replacement was commenced, at which point she developed persistent hyperglycemia requiring insulin therapy. Subsequent follow up confirmed the diagnosis of Addison's disease (AD), the treatment of which unmasked co‐existing type 1 diabetes. Autoimmune diseases often cluster together in affected patients and first‐degree relatives. Approximately 1 in 200 patients with T1DM develop AD. However, months or more commonly years usually elapse between the presentation of different autoimmune conditions. The co‐diagnosis T1DM and AD in the acute setting is rare. Moreover, the first presentation of T1DM with severe hypoglycemia is even more exceptional. This case highlights the need for vigilance during the acute, emergency management of patients with autoimmune conditions and, in particular, to consider the possibility of concurrent antibody‐mediated diseases which may need to be addressed during resuscitation.     

Three-year prevalence and incidence of diabetes among American Indian youth in Montana and Wyoming, 1999 to 2001

OBJECTIVES: To estimate the prevalence and incidence of type 2 diabetes among American Indian youth. STUDY DESIGN: Medical records were reviewed annually for all patients with diabetes who were <20 years of age at 6 Indian Health Service facilities in Montana and Wyoming. All cases < or =5 years of age or weight per age < or =10th percentile at diagnosis or with islet cell antibodies were considered as probable type 1. Among the remaining cases, probable type 2 diabetes was defined when a child had one or more of the following characteristics: weight per age > or =95th percentile or acanthosis nigricans at diagnosis, elevated C-peptide or insulin, family history of type 2 diabetes; treatment with oral agents with or without insulin or no hypoglycemic therapy after 1 year of follow-up. RESULTS: From 1999 to 2001, 53% of prevalent cases and 70% of incident cases were categorized as probable type 2 diabetes. The average annual prevalence of probable type 1 and type 2 diabetes was 0.7 and 1.3 per 1000. The average annual incidence rates for probable type 1, and type 2 diabetes were 5.8, 23.3 per 100,000. CONCLUSIONS: The incidence of probable type 2 diabetes was approximately 4 times higher than type 1 diabetes among American Indian youth in Montana and Wyoming     

Zöliakie bei Diabetes mellitus Typ I

Patients and Results

To determine the prevalence of celiac disease in patients with type 1 diabetes and investigate the clinical symptoms, we screened 183 patients with type 1 diabetes for gliadin antibodies (IgA and IgG) and IgA endomysium antibodies. In 14 (7.7%), high antibody titers were found and histology confirmed celiac disease in small-bowel biopsies. Classic symptoms were present in 2. These 14 patients (11 girls, 3 boys) were 4.3 years (mean; 1.0–10.1) old when their diabetes became manifest, 6 having been under 6. Celiac disease was diagnosed at that time or later in all but 1. Three girls also had autoimmune thyroiditis. After 1 year of gluten-free diet BMI-SD increased from 0.01 to 0.36 in 7 prepubertal children. No catch-up growth followed, and no increase in insulin dose per unit of bodyweight or change in frequency of hypoglycemic episodes.

Conclusion

We find celiac disease with surprising frequency in patients with type 1 diabetes; girls with early manifestation of diabetes type 1 seem to be at high risk. Clinical symptoms can be absent, making screening essential in such patients. Long-term studies must determine the importance of gluten-free diet in silent forms of celiac disease.     

Simultaneous occurrence of diabetes mellitus and juvenile dermatomyositis: report of two cases

The simultaneous occurrence of juvenile dermatomyositis (DMS) and diabetes mellitus is described in 2 pediatric patients. Both these patients presented with significant weight loss, polyuria, and polydypsia within a short time of being diagnosed with JDMS, while these patients were taking oral prednisone (40-60 mg/day in divided doses). Laboratory evaluation detected ketonuria, significant hyperglycemia (696 and 913 mg/dL) and low serum levels of insulin and C-peptide. Both these patients were treated with high doses of insulin. Islet cell and GAD65 antibodies were found to be positive in 1 of the patients, pointing toward a diagnosis of insulin-dependent diabetes mellitus. The other patient tested negative for these antibodies and required insulin therapy for approximately 6 months. Steroid-induced diabetes mellitus seemed highly likely in this case. We hypothesize that a common environmental trigger possibly a viral infection might have been responsible in causing 2 different autoimmune pathologies in these genetically predisposed individuals.     

Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young

The association between maturity onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM) has been rarely described. We report two patients affected by MODY who developed T1DM. Case 1: a 4-yr-old girl referred for glycosuria presented hemoglobin A1c (HbA1c) of 6.6%. Islet cell antibodies (ICA) and anti-glutamic acid decarboxylase (GADA) were initially negative. As her father, uncle and grandmother showed mild hyperglycemia, they were screened for MODY 2. A novel mutation in glucokinase gene was found in the family. Few months later, her glycemic control worsened consistently and she required insulin treatment. A high titer of GADA and ICA was then detected. Six years afterwards insulin requirement is 0.8 U/kg and HbA1c 6.7%. Case 2: a 15-yr-old boy treated for growth hormone deficiency was found with a blood glucose level of 106 mg/dL. HbA1c was 7.2%, ICA and GADA were negative. Family history was positive for autoimmune diseases and type 2 diabetes mellitus. The patient was investigated for MODY 2 and MODY 3, and a mutation of hepatocyte nuclear factor-1 alpha gene was found. The same mutation was found in the mother who had never been referred for hyperglycemia. After 1 yr, due to an unjustified worsening of the metabolic control, autoimmunity was again investigated and a mild positivity was found. He then required insulin therapy and after 5 yr current HbA1c was 8.2%. The diagnosis of MODY does not exclude the risk of developing T1DM. Therefore autoimmunity should be investigated when ordinary treatments fail and metabolic control unexpectedly worsens.     

Postprandial hyperinsulinaemic hypoglycaemia and type 1 diabetes mellitus.

A patient with severe postprandial hyperinsulinaemic hypoglycaemia (PPHH) for 4 years developed type 1 diabetes mellitus. She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. PPHH prior to the onset of type 1 diabetes mellitus has not been previously described and may be a prodrome of type 1 diabetes mellitus.     

Postprandial hyperinsulinaemic hypoglycaemia and type 1 diabetes mellitus

A patient with severe postprandial hyperinsulinaemic hypoglycaemia (PPHH) for 4 years developed type 1 diabetes mellitus. She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. PPHH prior to the onset of type 1 diabetes mellitus has not been previously described and may be a prodrome of type 1 diabetes mellitus.     

Severe hypothyroidism due to autoimmune atrophic thyroiditis--predicted target height and a plausible mechanism for sexual precocity

Autoimmune thyroiditis, the most frequent cause of acquired hypothyroidism in childhood and adolescents, is characterized by raised levels of the specific antibodies to thyroperoxidase (TPOAb) and thyroglobulin (TgAb). We report a girl aged 10 years and 9 months who presented with arrested growth and breast development (thelarche). She also exhibited myxedema of the face and legs, prominent striae on the thighs, dry, cold skin, and hypertrichosis on her back. There was no goiter, no history of thyroid pain and no family history of thyroid disease. She complained occasionally of a transient headache. The patient's height was below the 3rd percentile, while her body weight was at the 50th percentile and bone age was normal. Laboratory tests proved severe hypothyroidism (fT4 0 ng/dl, fT3 0.99 pg/ml, TSH >100 microIU/ml plus an increased titer of TPOAb). Thyroid ultrasound supported the diagnosis of thyroiditis. Pituitary PRL and FSH levels and peripheral estradiol were all elevated. L-Thyroxine therapy, instituted following diagnosis, improved the growth velocity to 11 cm/year and the FSH and E2 levels were normalized to prepubertal values. Complete regression of the breast development was observed within 4 months. However, 4 months later a true (central), isosexual LHRH-dependent puberty started. The pubertal features at the time of the original diagnosis might be explained by: 1. the direct action of elevated TRH on gonadotropes to stimulate gonadotropin secretion and on lactotrophes to stimulate PRL secretion, and 2. TSH action on LH and mostly FSH receptors (homologous to TSH receptors) in the ovary, stimulating the secretion of estradiol.     

Immunologic and biochemical factors of coincident celiac disease and type 1 diabetes mellitus in children

The objective of the study was to investigate whether immunologic and biochemical events occurring in the course of type 1 diabetes mellitus might play a role in the development of the celiac disease. The study was carried out on 223 children with long-standing diabetes mellitus type 1 (DM1). All the patients had TSH, fT4, fT3, urinary albumin secretion rate, IgA, level of antigliadin antibodies (AGA) IgA and IgG, antitissue transglutaminase IgA antibodies, antiendomysium (EmA) IgA and IgG antibodies and antitireoglobulin antibodies, antithyroid peroxidase antibodies evaluated. Serum TNF-alpha, IL-6, and IL-10 levels were also measured. The group of children with coincident DM1 and celiac disease and without autoimmune thyroiditis was characterized by significantly higher glycosylated hemoglobin, higher serum TNF-alpha, IL-6 but lower serum IL-10 in relation to the remaining diabetic patients. A statistically significant positive correlation was observed between IgA-anti-tTG and serum TNF-alpha (R = 0.28, p = 0.026); between IgG AGA and serum IL-6 (R = 0.31, p = 0.023); and between glycosylated hemoglobin and IgA-anti-tTG (R = 0.21, p = 0.001) and IgA antiendomysium (R = 0.22, p = 0.001). Poor metabolic control, persistent elevated levels of proinflammatory cytokines, and decreased level of antiinflammatory cytokines occurring in the course of type 1 diabetes mellitus might influence the incidence of celiac disease.     

Identification of a novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome presenting with neonatal diabetes mellitus and galactosaemia

We describe a patient with Fanconi-Bickel syndrome diagnosed by clinical manifestations and the identification of a novel mutation in the GLUT 2 gene. She was initially diagnosed with neonatal diabetes mellitus due to hyperglycaemia and glycosuria at 3 days of life. In addition, newborn screening for galactosaemia revealed hypergalactosaemia. Thereafter, she was managed with lactose-free milk and insulin therapy. However, she failed to grow and her liver became progressively enlarged. Her liver function deteriorated with increased prothrombin time. A liver biopsy done at age 9 months showed micronodular cirrhosis with marked fatty changes and she succumbed to hepatic failure with pneumonia at 10 months of age. DNA sequencing analysis of the GLUT 2 gene using her genomic DNA revealed a novel mutation in codon 5, lysine5 stop(K5X).     

Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management

Type 1 diabetes (T1DM) is often associated with autoimmune diseases such as: autoimmune thyroid disease (ATD), celiac disease (CD), autoimmune gastritis (AIG), pernicious anemia (PA) and vitiligo. Autoimmune thyroid disease is the most prevalent endocrinopathy among diabetic patients. Hypothyroidism, celiac disease or Addison's disease in patients with type 1 diabetes may deteriorate glycemic control and can lead to an increased rate of hypoglycemia. Autoimmune gastritis, pernicious anemia and celiac disease can cause malabsorption and anemia which additionally impair the quality of life in patients with T1DM. The presence of organ-specific autoantibodies can be used to screen patients who are at higher risk of developing autoimmune diseases. Such procedure can help to identify patients, who need to undergo treatment in order to decrease the rate of possible complications in the future. In this clinical review we present current opinions in terms of diagnosis, management and screening in the most common type 1 diabetes-associated autoimmune diseases.     

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.     

Neonatal diabetes with hyperchylomicronemia

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia occurring in the first few weeks of life. It can be either transient (TNDM) or permanent (PNDM). A 25 days old newborn was brought to the hospital with restlessness, respiratory depression and cyanosis. He was born at term with a birth weight of 2,000 g. There was no consanguinity between his parents. His physical examination findings were as follows: Weight and height were under 3th percentile, he was hypoactive and dehydrated. Serum glucose level was 800 mg/dl; C-peptide was 0.41 ng/ml. Upon investigation for dyslipidemia in association with his neonatal diabetes, hyperchylomicronemia was found both in the patient and his father. Pancreatitis, anemia and cholestasis were also observed. Insulin treatment was started for his diabetes together with a special diet for dyslipidemia. At the end of 28 months of follow-up, dyslipidemia has resolved but the need for insulin therapy was still existing. However, TNDM was considered in differential diagnosis because he was small for gestational age (SGA) at birth and his symptoms had started at the 25th day of the neonatal period. Delayed recovery from insulin dependency brought out the possibility of PNDM. Furthermore, neonatal diabetes combined with hypechylomicronemia is a rare clinical picture. Reported cases of NDM with different clinical evaluation will help to better understanding of this disorder.     

Early onset of type I diabetes mellitus, Hashimoto's thyroiditis and celiac disease in a 7-yr-old boy with Down's syndrome

Abstract:  Patients with Down's syndrome are at higher risk for developing autoimmune diseases than those of the general population. Autoimmune diseases like Hashimoto's thyroiditis, Graves' disease, diabetes mellitus type I, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo and hypoparathyroidism are recognized associations with Down's syndrome. We describe the case of a very young boy with Down's syndrome who was diagnosed with diabetes mellitus type I, Hashimoto's thyroiditis and celiac disease before 8 yr of age. Unspecific symptoms like weight loss, unstable blood sugar with high amplitudes, behavioural problems and dry skin were suspicious for other endocrine disorders or celiac disease in our case. The boy was showing the typical human leukocyte antigen profile for these autoimmune diseases. The prevalence of these autoimmune diseases is higher in Down's syndrome than in general population. Therefore, we advice to follow children with Down's syndrome who develop more than two autoimmune diseases very carefully.