Time spent outside of target glucose range for young children with type 1 diabetes: a continuous glucose monitor study.

AIM: To assess the associations between demographic and clinical characteristics and sensor glucose metrics in young children with type 1 diabetes, using masked, continuous glucose monitoring data from children aged 2 to < 8 years. RESEARCH DESIGN AND METHODS: The analysis included 143 children across 14 sites in the USA, enrolled in a separate clinical trial. Eligibility criteria were: age 2 to <8 years; type 1 diabetes duration ≥3 months; no continuous glucose monitoring use for past 30 days; and HbA1c concentration 53 to <86 mmol/mol (7.0 to <10.0%). All participants wore masked continuous glucose monitors up to 14 days. RESULTS: On average, participants spent the majority (13 h) of the day in hyperglycaemia (>10.0 mmol/l) and a median of ~1 h/day in hypoglycaemia (<3.9 mmol/l). Participants with minority race/ethnicity and higher parent education levels spent more time in target range, 3.9-10.0 mmol/l, and less time in hyperglycaemia. More time in hypoglycaemia was associated with minority race/ethnicity and younger age at diagnosis. Continuous glucose monitoring metrics were similar in pump and injection users. CONCLUSIONS: Given that both hypo- and hyperglycaemia negatively impact neurocognitive development, strategies to increase time in target glucose range for young children are needed.

Novel measures of inflammation and insulin resistance are related to obesity and fitness in a diverse sample of 11-14 year olds: The HEALTHY Study.

BACKGROUND: GlycA is a novel serum marker of systemic inflammation. There is no information on GlycA in pediatric populations, how it differs by gender or its association with body mass index (BMI) or fitness. Lipoprotein insulin resistance index (LP-IR) is a serum measure of insulin resistance, which is related to changes in BMI group in adolescents, but its relationship with fitness is unknown. The current study examined the independent associations between fitness and BMI with GlycA and LP-IR among US adolescents. METHODS: Participants were 1664 US adolescents from the HEALTHY study with complete 6th and 8th grade BMI, fitness and blood data. GlycA and LP-IR were measured by nuclear magnetic resonance spectroscopy. Three BMI groups and three fitness groups were created. Linear mixed models examined associations between GlycA, LP-IR, fitness and BMI. RESULTS: LP-IR decreased between 6th and 8th grade. GlycA increased among girls but decreased among boys. At 8th grade, median GlycA values were 27 (7.6%) µmol l(-1) higher (381 versus 354) for girls than boys. Median GlycA 6th grade values were 9% higher in obese girls than healthy weight girls. Overall, there was strong evidence (P<0.001) that GlycA was higher in higher BMI groups. Fitness was negatively associated with GlycA (r=-0.37 and -0.35) and LP-IR (r=-0.34 and -0.18) at the 6th and 8th grade assessments. As BMI category increased and fitness category decreased, GlycA and LP-IR levels increased. Lowest GlycA was found in the low BMI/high fitness group. CONCLUSIONS: GlycA was associated with BMI and fitness among in US adolescents. These findings suggest that there are independent effects for BMI and fitness group with both GlycA and LP-IR. Future studies should validate the role of GlycA and LP-IR to evaluate the effects of interventions to modify obesity and fitness to improve systemic inflammation and insulin resistance.

Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. METHODS: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. RESULTS: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders. CONCLUSIONS/INTERPRETATIONS: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378508 FUNDING: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Cardiovascular risk factors in multi-ethnic middle school students: the HEALTHY primary prevention trial.

OBJECTIVE: The objective of this study was to examine the effects of an integrated, multi-component, school-based intervention programme on cardiovascular disease (CVD) risk factors among a multi-ethnic cohort of middle school students. METHODS: HEALTHY was a cluster randomized, controlled, primary prevention trial. Middle school was the unit of randomization and intervention. Half of the schools were assigned to an intervention programme consisting of changes in the total school food environment and physical education classes, enhanced by educational outreach and behaviour change activities and promoted by a social marketing campaign consisting of reinforcing messages and images. Outcome data reported (anthropometrics, blood pressure and fasting lipid levels) were collected on a cohort of students enrolled at the start of 6th grade (∼11-12 years old) and followed to end of 8th grade (∼13-14 years old). RESULTS: Forty-two middle schools were enrolled at seven field centres; 4363 students provided both informed consent and CVD data at baseline and end of study. The sample was 52.7% female, 54.5% Hispanic, 17.6% non-Hispanic Black, 19.4% non-Hispanic White and 8.5% other racial/ethnic combinations, and 49.6% were categorized as overweight or obese (body mass index ≥ 85th percentile) at baseline. A significant intervention effect was detected in the prevalence of hypertension in non-Hispanic Black and White males. The intervention produced no significant changes in lipid levels. CONCLUSIONS: The prevalence of some CVD risk factors is high in minority middle school youth, particularly males. A multi-component, school-based programme achieved only modest reductions in these risk factors; however, promising findings occurred in non-Hispanic Black and White males with hypertension.

Atypical diabetes mellitus: time for a consensus?

A subgroup of diabetic patients presents with features typical of type 1 diabetes, but over months to years has variable insulin requirements and develops features of type 2 diabetes. This subgroup is referred to as atypical diabetes mellitus (ADM). Over a span of 50 yr, reports on disease epidemiology, clinical characteristics, and metabolic/genetic features of the entity now referred to as ADM remain conflicted. This article reviews the available literature on ADM, proposes atypical diabetes mellitus syndrome (ADMS) as an encompassing nomenclature, and recommends expansive criteria for disease definition pending the release of a consensus recommendation by a panel of experts.

Decreased hexosamine biosynthesis in GH-deficient dwarf rat muscle. reversal with GH, but not IGF-I, therapy.

Enhanced glucose flux via the hexosamine biosynthesis pathway (HNSP) has been implicated in insulin resistance. We measured L-glutamine:D-fructose-6-phosphate amidotransferase activity (GFAT, a rate-limiting enzyme) and concentrations of UDP-N-acetyl hexosamines (UDP-HexNAc, major products of HNSP) in muscle and liver of growth hormone (GH)-deficient male dwarf (dw) rats. All parameters measured, except body weight, were similar in 5-wk-old control and dw rats. Muscle GFAT activity declined progressively with age in controls and dw rats but was consistently 30-60% lower in 8- to 14-wk-old dw rats vs. age-matched controls; UDP-HexNAc concentrations in muscle were concomitantly 30% lower in dw rats vs. controls (P < 0.01). Concentrations of UDP-hexoses, GDP-mannose, and UDP in muscle were similar in control and dw rats. Muscle HNSP activity was similarly diminished in fed and fasted dw rats. In liver, only a small difference in GFAT activity was evident between controls and dw rats, and no differences in UDP-HexNAc concentrations were observed. Treatment with recombinant human GH (rhGH) for 5 days restored UDP-HexNAc to control levels in dw muscles (P < 0.01) and partially restored GFAT activity. Insulin-like growth factor I treatment was ineffective. We conclude that GH participates in HNSP regulation in muscle.

Endogenous mutations in human uncoupling protein 3 alter its functional properties.

Human uncoupling protein (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative phosphorylation and is a candidate gene for obesity. Expression of native human UCP3 mutations in yeast showed complete loss (R70W), significant reduction (R143X), or no effect (V102I and IVS6+1G > A) on the uncoupling activity of UCP3. It is concluded that certain mutations in UCP3 alter its functional impact on membrane potential (deltaphi), possibly conferring susceptibility to develop metabolic diseases.

Diabetes research in South Carolina: past, present, and future.

Medical investigators in South Carolina have been on the "cutting edge" of diabetes research for a number of decades. Despite this fact, our state ranks second in the nation in diabetes prevalence, and diabetes complications are more severe here than anywhere else. It is from the efforts of these investigators that our hope for a brighter future comes. Through a concerted effort toward prevention, improvements in care, and investigation of the pathophysiology of diabetes and its complications, researchers may reduce the substantial burden of diabetes in our state and throughout the world.

Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes.

Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative ATP phosphorylation. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. A missense polymorphism in exon 3 (V102I) was identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the splice donor junction of exon 6 were also identified in a compound heterozygote that was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6-splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.

The effects of a high-protein, low-fat, ketogenic diet on adolescents with morbid obesity: body composition, blood chemistries, and sleep abnormalities.

OBJECTIVE: To evaluate the efficacy and metabolic impact of a high-protein, low-carbohydrate, low-fat ketogenic diet (K diet) in the treatment of morbidly obese adolescents with initial weights of >200% of ideal body weight. METHODS: Six adolescents, aged 12 to 15 years, weighing an average of 147.8 kg (range, 120.6-198.6 kg) and having an average body mass index of 50.9 kg/m (39.8-63.0 kg/m), consumed the K diet for 8 weeks. Daily intake consisted of 650 to 725 calories, which was substantively in the form of protein (80-100 g). The diet was very low in carbohydrates (25 g) and fat (25 g). This was followed by 12 weeks of the K diet plus two carbohydrates (30 g) per meal (K+2 diet). MAIN OUTCOME MEASURES: Anthropometric data and blood and urine were collected at enrollment, during week 1, and at 4-week intervals throughout the course of the study. Resting energy expenditure was measured by indirect calorimetry. Body composition was estimated using dual-energy x-ray absorptiometry, bioelectrical impedance analysis, and urinary creatinine excretion at enrollment and on completion of each phase of the diet. Nocturnal polysomnography and multiple sleep latency testing were conducted at baseline and repeated after an average weight loss of 18.7 kg to determine sleep architecture, frequency and duration of apneas, and daytime sleepiness. RESULTS: Subjects lost 15.4 +/- 1.4 kg (mean +/- SEM) during the K diet and an additional 2.3 +/- 2.9 kg during the K+2 diet. Body mass index decreased 5.6 +/- 0.6 kg/m(2) during the K diet and an additional 1.1 +/- 1.1 kg/m(2) during the K+2 diet. Body composition studies indicated that weight was lost equally from all areas of the body and was predominantly fat. Dual-energy x-ray absorptiometry showed a decrease from 51.1% +/- 2.1% body fat to 44.2% +/- 2.9% during the K diet and then to 41.6% +/- 4.5% during the K+2 diet. Lean body mass was not significantly affected. Weight loss was accompanied by a reduction in resting energy expenditure of 5.2 +/- 1.8 kcal/kg of fat-free mass per day. Blood chemistries remained normal throughout the study and included a decrease in serum cholesterol from 162 +/- 12 to 121 +/- 8 mg/dL in the initial 4 weeks of the K diet. An increase in calcium excretion was accompanied by a decrease in total-body bone mineral content. A paucity of rapid eye movement sleep and excessive slow-wave sleep were seen in all subjects at enrollment. Weight loss led to an increase in rapid eye movement sleep (P < .02) and a decrease in slow-wave sleep (P < .01) to near normal levels. CONCLUSIONS: The K diet can be used effectively for rapid weight loss in adolescents with morbid obesity. Loss in lean body mass is blunted, blood chemistries remain normal, and sleep abnormalities significantly decrease with weight loss.

Suppression and recovery of the neonatal hypothalamic-pituitary-adrenal axis after prolonged dexamethasone therapy.

OBJECTIVE: To evaluate the duration and level of hypothalamic-pituitary-adrenal (HPA) axis suppression in premature infants treated with a prolonged course of glucocorticoids for chronic lung disease. STUDY DESIGN: We evaluated HPA axis function in nine very low birth weight (VLBW) infants before and 48 hours after a prolonged (14 to 42 days) dexamethasone (Dex) course. Seven of these infants underwent serial testing in the Clinical Research Center to evaluate the time course of HPA axis recovery. Adrenal function was assessed directly with synthetic adrenocorticotropic hormone (ACTH) stimulation, pituitary function with ovine corticotrophin releasing hormone (oCRH) stimulation, and combined axis function with 3-hour metyrapone testing. RESULTS: Baseline cortisol values were higher before Dex therapy (18.6 +/- 3.9 microg/dl; mean +/- SEM) than after (5.77 +/- 1.45 microg/dl; p < 0.01), as were ACTH-stimulated cortisol levels (24.8 +/- 1.7 microg/dl vs 12.0 +/- 2.2 microg/dl; p < 0.001). ACTH response to oCRH decreased after Dex treatment (22.8 +/- 7.6 pg/ml vs 11.5 +/- pg/ml), but this was not statistically significant (p = 0.18). 11-Deoxycortisol (11-DOC) response to metyrapone dropped from 11.1 +/- 0.5 microg/dl to 4.7 +/- 1.0 microg/dl after Dex therapy (p < 0.0001). Longitudinal testing reveals that adrenal suppression may be short-lived, while recovery of higher centers is more delayed. CONCLUSIONS: Basal cortisol levels may be used as a screening test, but if the level is less than 15 microg/dl, more definitive testing should be performed. The sluggish recovery of higher HPA axis centers is most reliably evaluated by using 11-DOC response to a single dose of metyrapone in VLBW infants after prolonged Dex therapy.

Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families.

We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.

A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency.

The dipeptides carnosine and anserine, found exclusively in meats, are hydrolyzed in serum by the enzyme carnosinase. Several reports of serum carnosinase deficiency describe a variable phenotype, which ranges from normal to severe psychomotor retardation, hypotonia, and myoclonic seizures in the first year of life. We report the case of a 30-mo-old girl with hypotonia, developmental delays, and tremor. Although consuming nominal quantities of meal, she excreted large amounts of carnosine and anserine. A strict meat-free diet ameliorated, but did not eliminate, these abnormalities. Serum carnosinase activity was found to be extremely low. Analysis of this child's chromosomes revealed a terminal deletion of chromosome 18 with breakpoint at q21.3. Neither parent exhibited this deletion, suggesting it was generated de novo in the patient or in a parental germ cell. Molecular studies showed that the patient's paternal chromosome 18 was deleted. Urinary carnosine excretion and serum carnosinase activity were normal in the patient's father. The mother had low carnosinase activity. The patient's brother exhibited moderate hypercarnosinuria and intermediate enzyme activity, consistent with the carrier state for carnosinase deficiency. Cumulatively, these findings suggest that the locus for this enzyme resides on the distal long arm of chromosome 18, and they are consistent with an unusual mechanism for the inheritance of this, typically autosomal recessive, condition. We conclude that this patient is likely hemizygous for the defect, having received the deficiency allele from her mother and, by virtue of the chromosomal deletion, no allele from her father. This represents the first report of a chromosomal abnormality in association with serum carnosinase deficiency and should aid in further localization of the gene encoding serum carnosinase.

Xp pseudoautosomal gene haploinsufficiency and linear growth deficiency in three girls with chromosome Xp22;Yq11 translocation.

Colony stimulating factor-2 receptor alpha (CSF2RA) and interleukin-3 receptor alpha (IL3RA), two genes from the chromosome Xp and Yp pseudoautosomal region (PAR), have been suggested as candidate genes for short stature in Turner syndrome. We report three girls with X;Y translocation (46,X,der(X)t(X;Y)(p22;q11) initially detected by amniocentesis. The terminal portion of the X chromosome distal to the translocation breakpoint at Xp22 was deleted on the derivative X chromosome in all three patients. Each had normal stature at birth, with greater than expected deceleration of growth velocity by the second year. Using fluorescence in situ hybridisation (FISH), we have shown deletion of the CSF2RA and IL3RA loci on the derivative X chromosomes of all three patients. The role of CSF2RA and IL3RA haploinsufficiency in linear growth and final adult stature is discussed. Additional studies, particularly of molecular deletions within the PAR, are needed to improve our understanding of the role of these and other PAR loci in the genetic control of adult stature.

Growth in children after bone marrow transplantation for acute myelogenous leukemia as compared to acute lymphocytic leukemia.

Previous studies of growth in children following bone marrow transplantation for leukemia have demonstrated poor growth with little ability to "catch-up" two to four years after transplantation. Because of small patient numbers, these studies did not distinguish patients with differing types of leukemia. 12 children with acute myelogenous leukemia who survived over 3 years after transplantation were compared with 12 who survived transplantation for acute lymphoblastic leukemia. The initial height standard deviation scores were similar in both groups prior to transplantation. The height standard deviation scores in the acute lymphoblastic leukemia group decreased for each of the 5 years after transplantation while the height score for the acute myelogenous leukemia group after 5 years was not statistically different from pre-transplantation. The growth of the children with myelogenous leukemia was better possibly because these children were older, had received less cranial irradiation at the time of transplantation, and had a lower incidence of severe chronic graft-versus-host disease.

Neurocognitive deficits in morbidly obese children with obstructive sleep apnea.

Neurocognitive abilities were measured in 14 morbidly obese children, five of whom had obstructive sleep apnea as determined by polysomnography. As in adults, children with obstructive sleep apnea had deficits in learning, memory, and vocabulary. Moreover, apneic/hypopneic events were inversely related to memory and learning performance among the entire sample.

Clinical and biochemical characterization of short-chain acyl-coenzyme A dehydrogenase deficiency.

OBJECTIVE: We identified two additional patients with short-chain acyl-coenzyme A (CoA), further characterized the clinical and biochemical features of this defect, and compared it with other fatty acid oxidation defects. DESIGN: We have measured the in vitro short-chain acyl-coenzyme A dehydrogenase (SCAD) activity in six affected persons with the electron-transfer flavoprotein-linked assay in the presence and absence of anti-medium-chain acyl-CoA dehydrogenase antibody. Urine organic acids, acylglycines, acylcarnitines, and radiolabeled substrate catabolism by skin fibroblasts were also examined. RESULTS: All patients had some neurologic abnormalities, including hypotonia, hypertonia, or seizures. None of the patients had episodes of hypoglycemia; in the only patient tested, fasting ketogenesis was not impaired. Four patients were initially seen in the neonatal period, two with profound metabolic acidosis and two with mild acidemia; the other two cases were recognized in infancy. Enzymatic analysis of cultured skin fibroblasts demonstrated approximately 10% activity of SCAD when compared with control fibroblasts. Gas chromatography and mass spectrometry of urine revealed that ethylmalonic acid was present in all samples but not always at elevated concentrations; methylsuccinic acid and butyrylglycine were sporadically elevated. n-Butyrylcarnitine was often found in urine and plasma. Radiolabeled substrate metabolism was reduced to 40% to 60% of control values. CONCLUSIONS: Because affected persons do not consistently excrete characteristic metabolites, the diagnosis of this enzymatic deficiency is difficult. It is necessary to collect and analyze several urine and plasma specimens when the diagnosis is being considered in patients with neurologic abnormalities suggestive of this disorder.

Long-term treatment of osteopetrosis with recombinant human interferon gamma.

BACKGROUND: Congenital osteopetrosis is a rare osteosclerotic bone disease characterized by both a defect in osteoclastic function and reduced generation of superoxide by leukocytes. The disease is frequently fatal during the first decade of life. A six-month trial of therapy with recombinant human interferon gamma-1b in eight patients with osteopetrosis provided evidence of benefit, prompting this study of more prolonged therapy. METHODS: We studied 14 patients with severe osteopetrosis treated with subcutaneous injections of recombinant human interferon gamma-1b (1.5 micrograms per kilogram of body weight per dose) three times per week for at least 6 months; 11 patients were treated for 18 months. We assessed the effect of therapy by evaluating the patients' clinical status, measuring blood counts and biochemical markers of bone turnover, and performing bone marrow imaging and bone biopsies. RESULTS: After 6 months of therapy, all 14 patients had decreases in trabecular-bone area (determined by histomorphometric analysis of bone-biopsy specimens) and increases in bone marrow space (determined by marrow imaging), and the improvement was sustained in the 11 patients treated for 18 months. The mean (+SD) hemoglobin concentration increased from 7.5 +/- 2.9 to 10.5 +/- 0.3 g per deciliter (P = 0.05), and superoxide generation by granulocyte-macrophage colonies increased (P < 0.001) after 18 months of therapy. In six patients for whom pretreatment data were available, there was a 96 percent decrease in the frequency of infections requiring antibiotic therapy during interferon treatment. There were no side effects necessitating the discontinuation of therapy. CONCLUSIONS: Long-term therapy with interferon gamma in patients with osteopetrosis increases bone resorption and hematopoiesis and improves leukocyte function.