Vatcharapan Umpaichitra

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.

Plasminogen Activator Inhibitor-1 and Tissue-Plasminogen Activator in Minority Adolescents with Type 2 Diabetes and Obesity

Increased plasminogen activator inhibitor-1 (PAI-1) and decreased tissue-plasminogen activator (t-PA) activities lead to impaired fibrinolysis, which is critical for cardiovascular disease. We studied these hemostatic factors at fasting state and after an oral fat load in 12 type 2 diabetic and 17 nondiabetic obese adolescents, matched for age, sex, body mass index, and sexual maturation. Plasma PAI-1, t-PA, and glucose as well as serum C-peptide, insulin, total cholesterol, triglyceride, and HDL and LDL cholesterol levels were measured at 0, 2, 4, and 6 h after the fat load. Metabolic responses were expressed as the area under the curve (AUC). PAI-1 activities were significantly greater in patients than in control subjects [fasting, 23.4 ± 2.6 versus 12.9 ± 2.0 U/mL (p < 0.004); AUC, 101.7 ± 12.1 versus 57.6 ± 6.5 U · h−1 · mL−1 (p < 0.003)]. Fasting t-PA activities were significantly lower in the patients than in the control subjects (0.8 ± 0.3 versus 6.5 ± 2.7 U/mL; p < 0.001). Triglyceride was the only lipid parameter that was significantly different in the patients than in the control subjects [fasting, 1.5 ± 0.2 versus 0.9 ± 0.1 mM (p < 0.05); AUC, 15.7 ± 2.9 versus 7.9 ± 0.6 mmol · h−1 · L−1 (p < 0.02)]. The PAI-1 activities decreased significantly during the loading tests (p < 0.0001), whereas the t-PA activities did not change. Insulin resistance estimated by the homeostasis model assessment was greater in the patients than in the control subjects (14.4 ± 2.8 versus 4.6 ± 0.7; p < 0.0001). We conclude that elevated PAI-1 and diminished t-PA activities, suggestive of suppressed fibrinolysis, are present in our adolescents with type 2 diabetes; adding another risk factor for cardiovascular disease and acute high fat load does not further negatively affect this suppressed fibrinolysis.

Hypocalcemia in Children: Pathogenesis and Management

Hypocalcemia can be devastating if unrecognized. Neuromuscular dysfunction occurs in severe cases. A review and an update on the topic may assist general pediatricians. The authors provide a general overview of pathogenesis and management of hypocalcemia in children.

Ambulatory Blood Pressure Monitoring in Lean, Obese and Diabetic Children and Adolescents.

Aim: To determine if children and adolescents who have obesity (Ob) or type 2 diabetes (T2DM) of relatively short duration have impaired cardiovascular function compared with lean subjects using 24-hour ambulatory blood pressure as a surrogate measure of evaluation. Methods: We enrolled 100 African-Caribbean subjects (45 males/55 females), mean ages 14.4-15.2 years (range 11.8-18.5 years) and Tanner stage 4.2-4.8. Mean BMI for the Ob (n = 40), T2DM (n = 39) and lean (n = 21) groups were 40.3, 34.2 and 20.8, respectively (p < 0.01, Ob and T2DM vs. lean). Mean hemoglobin A1c in lean and Ob was 5.4 and 5.5% compared to 8.8% in T2DM (p < 0.001, T2DM vs. lean and Ob). Ambulatory blood pressure was recorded every 20 min over 24 h using Spacelabs 70207. Results: Mean 24-hour, daytime and nighttime systolic blood pressure was significantly higher in Ob and T2DM compared with lean subjects (mean 24-hour 117 and 120 vs. 109 mm Hg; daytime 121 and 123 vs. 113 mm Hg; and nighttime 109 and 115 vs. 101 mm Hg; p < 0.01 for all time periods). The nocturnal systolic dip in Ob and T2DM did not differ from that of lean, whereas nocturnal diastolic dip decreased significantly in Ob and T2DM compared to lean (11.5 and 10.4 vs. 20.6 mm Hg; p < 0.01). Mean pulse pressure was significantly increased in the Ob and T2DM groups compared to lean subjects (51 and 54 vs. 45 mm Hg; p < 0.01). Conclusion: Adolescent Ob and T2DM groups share adverse risk factors, which may be harbingers of adult cardiovascular events.

Type 2 diabetes mellitus in African-American adolescents: impaired beta-cell function in the face of severe insulin resistance.

We have previously demonstrated abnormalities in insulin secretion in adolescents with type 2 diabetes mellitus (DM2) in response to the mixed meal test and to glucagon. In order to further assess beta-cell function in DM2, we measured insulin and C-peptide responses to oral glucose in adolescents with DM2 in comparison to non-diabetic obese and lean adolescents. We studied 20 patients with DM2, 25 obese adolescents with matching body mass index (BMI) (33.8 +/- 1.4 vs 34.3 +/- 1.0 kg/m2), and 12 non-obese control adolescents (BMI 22.6 +/- 0.6 kg/m2). Mean age, sex and sexual maturation did not differ between the three groups. All adolescents with DM2 had negative islet cell antibodies (ICA); five patients were on diet and 15 on insulin treatment. Fasting lipid profiles were determined in all participants. Plasma glucose and serum C-peptide and insulin levels were measured at 0, 30, 60, 90, and 120 min after an oral glucose load. The C-peptide increment (deltaCP) was calculated as peak minus fasting C-peptide. Area under the curve (AUC) was estimated using the trapezoid method. Insulin resistance was estimated using the HOMA model (HOMA-IR). The first phase of insulin secretion (PH1) was computed using a previously published formula. Serum triglyceride levels were significantly higher in the patients with DM2 compared to the non-obese controls (1.4 +/- 0.1 vs 0.9 +/- 0.1 mmol/l; p = 0.02). Plasma glucose AUC was greater in the patients with DM2 compared to the obese and non-obese control groups (1,660 +/- 130 vs 717 +/- 17 vs 647 +/- 14 mmol/l x min; p < 0.0001). ACP was lower in adolescents with DM2 than in obese and non-obese adolescents (761 +/- 132 vs 1,721 +/- 165 vs 1,225 +/- 165 pmol/l; p < 0.001). Insulin AUC was lower in the patients with DM2 compared to obese controls (888 +/- 206 vs 1,606 +/- 166 pmol/l x h; p = 0.009), but comparable to that of the non-obese controls (888 +/- 206 vs 852 +/- 222 pmol/l x h; p = 0.9). Insulin AUC was also higher in the obese than in the non-obese group (p = 0.05). PH1 was significantly higher in the obese group compared to the patients with DM2 as well as to the non-obese controls (2,614 +/- 2,47.9 vs 929.6 +/- 403.5 vs 1,946 +/- 300.6 pmol/l, respectively; p = 0.001). PH1 was also higher in the non-obese controls than in the patients with DM2 (p = 0.05). HOMA-IR was three-fold higher in the patients with DM2 than in the BMI-matched obese group, and five-fold higher than in the lean controls (14.3 +/- 1.2 vs 5.4 +/- 0.8 vs 2.9 +/- 0.4; p = 0.0002). Adolescents with DM2 have dyslipidemia, a significant cardiovascular risk factor. Decreased beta-cell function is characteristic of adolescents with DM2 in the presence of severe insulin resistance.

Unusual glycogenic hepatopathy causing abnormal liver enzymes in a morbidly obese adolescent with well-controlled type 2 diabetes: resolved after A1c was normalized by metformin.

We report, for the first time, a case of an accumulation of glycogen in the liver causing elevation of liver enzymes in a 15‐year‐old morbidly obese adolescent male with well‐controlled type 2 diabetes. Notably, the patient did not have poorly controlled type 1 diabetes and did not require insulin. After normalization of the A1c with metformin, elevated liver enzymes returned to normal.

Screening for autoimmune thyroiditis and celiac disease in minority children with type 1 diabetes

Abstract Background: Hashimoto’s thyroiditis (HT) and celiac disease (CD) are commonly associated with type 1 diabetes (T1DM). There is no consensus on screening, however, the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend testing for thyroid function (TFT), thyroid antibodies and anti-tissue transglutaminase antibodies (TTG) IgA soon after diagnosis. TFT should be repeated every 1–2 years while TTG IgA should be tested for within 2 and 5 years. We hypothesize that the rate of HT and CD in our T1DM children is lower, so screening may need to be revised to reflect their underlying risk. Methods: An Institutional Review Board (IRB)-approved retrospective chart review was conducted on children with T1DM in the past 10 years. Age, sex, race, A1C, TFT, thyroid and celiac antibodies were obtained. t-Tests, the Wilcoxon-Mann-Whitney test and stepwise regression were performed. Results: Of 222 children with T1DM, with a mean age of 15.8±5.53 years, followed for 6.1±4.0 years, 53% female, mean A1C 11.1±1.9% and 87% African American (AA). Three had Graves’ disease (1.3%), three had HT (1.3%) and 97% were euthyroid. TFT were assessed on average every 1.3 years and thyroid antibodies every 2.5 years. Positive thyroid antibody was found in 11%, negative in 57% and unknown in 32%. The positive antibody group had higher mean A1C and TSH. No biopsy confirmed cases of CD (0%) were found when screened every 2.3 years. Conclusions: The number of individuals who screened positive for hypothyroid HT and CD was lower than expected in our population. Further studies are needed to assess the optimal screening frequency for HT and CD in minority children with T1DM.

A Unique Case of Bilateral Hürthle Cell Adenoma in an Adolescent

Background: Hürthle cell (HC) neoplasms are rare among pediatric thyroid cancers. HC adenomas (HCA) are typically benign and localized unilaterally without recurrence, and they are thus treated by hemithyroidectomy. HC carcinomas (HCC) can be bilateral and are more aggressive, necessitating total thyroidectomy. Diagnosis relies upon surgical histopathology demonstrating invasion for classification as HCC or lack of invasion in HCA, since fine needle aspiration fails to differentiate between the two. Methods: We report a case of a 14-year-old adolescent female with bilateral HCA. She had an initial left hemithyroidectomy for a large nodule measuring 2 × 1.5 × 1.2 cm3 in the left lobe, while smaller subcentimeter nodules remained under surveillance in the right. One year later, a nodule in the right lobe doubled in size, necessitating a right hemithyroidectomy which also revealed HCA. Conclusion: To our knowledge, this is the first reported case of bilateral HCA in pediatrics. It highlights the importance of close surveillance of persistent small nodules, even in patients with previously documented benign lesions such as HCA, which are typically thought to be unilateral and localized. Both HCA and HCC remain unpredictable in behavior, and treatment of HCA should be individualized.

Presence of 21-Hydroxylase Antibodies in a Boy with X-Linked Adrenal Hypoplasia Congenita

Background: X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency (PAI) in children due to mutations in NR0B1/DAX1 (nuclear receptor subfamily 0, group B, member 1/dosage-sensitive sex reversal-adrenal hypoplasia congenita at the critical region of the X chromosome, gene 1). Another rare cause of PAI in children is autoimmune adrenal disease (AAD) which could be either isolated or as part of autoimmune polyglandular syndrome. Antibody to major auto-antigen, 21-hydroxylase, is highly specific for AAD. Methods: We report a now 19-month-old male with PAI due to NR0B1 gene mutation and positive adrenal antibodies. Initially, he presented at 15 days of life with isolated hypoaldosteronism which later unfolded into complete PAI. Data analysis was done via retrospective chart review. Results: Genetic analysis of the NR0B1 gene revealed a known hemizygous mutation in c.1069C>T; p.Gln357X. Simultaneously, he was noted to have positive 21-hydroxylase antibodies. Conclusion: According to our knowledge, this is the first case in the literature with NR0B1 mutation causing adrenal insufficiency with coexistent positive adrenal antibodies. In addition to his already compromised adrenal function due to NR0B1 mutation, he is now at risk for the development of associated autoimmune conditions requiring close follow-up.