Hypoglycemia risk with physical activity in type 1 diabetes: a data-driven approach.

Physical activity (PA) provides numerous health benefits for individuals with type 1 diabetes (T1D). However, the threat of exercise-induced hypoglycemia may impede the desire for regular PA. Therefore, we aimed to study the association between three common types of PA (walking, running, and cycling) and hypoglycemia risk in 50 individuals with T1D. Real-world data, including PA duration and intensity, continuous glucose monitor (CGM) values, and insulin doses, were available from the Tidepool Big Data Donation Project. Participants' mean (SD) age was 38.0 (13.1) years with a mean (SD) diabetes duration of 21.4 (12.9) years and an average of 26.2 weeks of CGM data available. We developed a linear regression model for each of the three PA types to predict the average glucose deviation from 70 mg/dl for the 2 h after the start of PA. This is essentially a measure of hypoglycemia risk, for which we used the following predictors: PA duration (mins) and intensity (calories burned), 2-hour pre-exercise area under the glucose curve (adjusted AUC), the glucose value at the beginning of PA, and total bolus insulin (units) within 2 h before PA. Our models indicated that glucose value at the start of exercise and pre-exercise glucose adjusted AUC (p < 0.001 for all three activities) were the most significant predictors of hypoglycemia. In addition, the duration and intensity of PA and 2-hour bolus insulin were weakly associated with hypoglycemia for walking, running, and cycling. These findings may provide individuals with T1D with a data-driven approach to preparing for PA that minimizes hypoglycemia risk.

Type 2 diabetes in prepubertal children.

OBJECTIVE: Puberty-induced insulin resistance is considered critical in the pathogenesis of type 2 diabetes (T2D) in youth. The development of T2D before puberty suggests distinct risk factors and pathophysiology but, because of its rarity, this has not been well studied. We aimed to describe the clinical characteristics of children with T2D diagnosed before the onset of puberty. RESEARCH DESIGN AND METHODS: We retrospectively studied all children with autoantibody-negative T2D and available pubertal development assessment seen at our center between July 2016 and July 2019, and compared characteristics of those at Tanner stage I (prepubertal, n = 35) versus those at Tanner II-V of pubertal development (n = 341). RESULTS: At T2D diagnosis, prepubertal children compared with those at Tanner II-V had higher body mass index z-score (p = 0.003) and higher C-peptide (p = 0.003) (while glucose levels were not significantly different), with differences retaining significance after adjustment for glucose, race/ethnicity and sex. Dyslipidemia occurred in 100% of prepubertal children versus 89.7% of those diagnosed later (p = 0.036). Of the prepubertal children diagnosed under age 10 (n = 13), 69.2% were female, 100% racial/ethnic minority, 100% had obesity with history of dyslipidemia and none with diabetic ketoacidosis. CONCLUSIONS: T2D, although rarely, can develop before puberty. Children with T2D diagnosed in the prepubertal period have more severe obesity, greater insulin resistance, and more frequent dyslipidemia than older youth. These findings suggest that children with prepubertal T2D are at increased risk for associated morbidity compared with older youth and underscore the significance of interventions to prevent and treat obesity in early childhood.

Sex differences in circulating leptin as a marker of adiposity in obese or overweight adolescents with type 1 diabetes.

INTRODUCTION: We aimed to test whether the serum adipokines leptin and adiponectin are more strongly associated with body fat percentage (BF%) than body mass index (BMI) in adolescents with type 1 diabetes (T1D) and overweight/obesity. RESEARCH DESIGN AND METHODS: We studied all participants in the T1D Exchange Metformin Study (n=122, median age 12.9 years, range 12-19.5; 32% males; 77% non-Hispanic whites, 100% overweight or obesity; median diabetes duration 6.7 years, range 1.4-15) with a baseline serum sample where we measured leptin and adiponectin concentrations. Anthropometric, clinical, laboratory and dual-energy X-ray absorptiometry (DEXA) scan measurements were analyzed. We compared correlation coefficients between variables of interest. RESULTS: BF% by DEXA was significantly correlated with BMI Z-score (r=0.38, p<0.0001), BMI per cent of the 95th percentile (BMI%95) (r=0.45, p<0.0001), waist circumference (r=0.46, p<0.0001), leptin (r=0.58, p<0.00001) and leptin/adiponectin ratio (r=0.36, p<0.0001), while it was not significantly correlated with absolute body weight, adiponectin or insulin dose (total or basal). BF% was significantly more strongly correlated with leptin than with BMI Z-score in the overall group (p=0.022). However, there were sex-based differences. Among the significant correlations in the overall group, BF% was most strongly associated with leptin (r=0.75) in boys (n=39) but with waist circumference (r=0.58) in girls (n=83) (all p<0.0001). CONCLUSIONS: Serum leptin could be used as a surrogate convenient marker of adiposity in overweight/obese adolescent boys with T1D, equivalent to BMI Z-score or BMI%95. In girls, waist circumference was the best performing marker overall, and was also strongly correlated with %BF in boys.

Challenges in the diagnosis of diabetes type in pediatrics.

The incidence of diabetes, both type 1 and type 2, is increasing. Health outcomes in pediatric diabetes are currently poor, with trends indicating that they are worsening. Minority racial/ethnic groups are disproportionately affected by suboptimal glucose control and have a higher risk of acute and chronic complications of diabetes. Correct clinical management starts with timely and accurate classification of diabetes, but in children this is becoming increasingly challenging due to high prevalence of obesity and shifting demographic composition. The growing obesity epidemic complicates classification by obesity's effects on diabetes. Since the prevalence and clinical characteristics of diabetes vary among racial/ethnic groups, migration between countries leads to changes in the distribution of diabetes types in a certain geographical area, challenging the clinician's ability to classify diabetes. These challenges must be addressed to correctly classify diabetes and establish an appropriate treatment strategy early in the course of disease for all. This may be the first step in improving diabetes outcomes across racial/ethnic groups. This review will discuss the pitfalls in the current diabetes classification scheme that is leading to increasing overlap between diabetes types and heterogeneity within each type. It will also present proposed alternative classification schemes and approaches to understanding diabetes type that may improve the timely and accurate classification of pediatric diabetes type.

Inherited Deletion of 1q, Hyperparathyroidism and Signs of Y-chromosomal Influence in a Patient with Turner Syndrome

We report a detailed phenotypic, cytogenetic and molecular characterization of a patient prenatally diagnosed with Turner syndrome (TS). In addition to having typical TS clinical characteristics including webbed neck, high arched palate and coarctation of the aorta, the patient had features less frequently seen in TS. These included recurrent parathyroid adenomas, growth along the 75th-90th centiles on the TS height curve despite minimal treatment with growth hormone, behavioral problems and evidence of gonadal dysgenesis with testicular-like structures, such as seminiferous tubules lined by Sertoli cells and a contiguous nodule of Leydig cells. While fluorescence in situ hybridization (FISH) failed to detect Y-chromosome material in gonadal tissue or blood samples, chromosomal microarray analysis (CMA) confirmed X monosomy and a 4.69 Mb copy number loss on 1q31.2q31.3 (bp 192,715,814 to 197,401,180). This region contains the CDC73 gene which has been associated with hyperparathyroidism-jaw tumor syndrome, features of which include recurrent, functional parathyroid adenomas and behavioral issues. This case illustrates how atypical features in a TS patient, such as robust growth and recurrent parathyroid adenomas, may suggest an underlying molecular etiology that should be explored by additional genetic diagnostic modalities. It is therefore appropriate in such cases to conduct further genetic testing, such as CMA and FISH, to explore other diagnostic possibilities and possibly prevent further complications.

Alkaline Phosphatase: Discovery and Naming of Our Favorite Enzyme.

Alkaline phosphatase can be considered "our favorite enzyme" for reasons apparent to those who diagnose and treat metabolic bone diseases or who study skeletal biology. Few might know, however, that alkaline phosphatase likely represents the most frequently assayed enzyme in all of medicine. Elevated activity in the circulation is universally recognized as a marker for skeletal or hepatobiliary disease. Nevertheless, the assay conditions in many ways are nonphysiological. The term alkaline phosphatase emerged when it became necessary to distinguish "bone phosphatase" from the phosphatase in the prostate that features an acidic pH optimum. Beginning in 1948, studies of the inborn-error-of-metabolism hypophosphatasia would identify the natural substrates and establish the physiological role of alkaline phosphatase, including in biomineralization. Here, we recount the discovery in 1923 and then eventual naming of this enzyme that remains paramount in our field. © 2017 American Society for Bone and Mineral Research.

Severity of clinical presentation in youth with type 1 diabetes is associated with differences in brain structure.

OBJECTIVE: Differences in cognition and brain structure have been found in youth with type 1 diabetes compared with controls, even after relatively short disease duration. To determine whether severity of clinical presentation contributes to these differences, we obtained structural magnetic resonance imaging (MRI) scans in youth ages 7-17 who were either newly diagnosed with type 1 diabetes (<3.5 months from diagnosis, n = 46) or a sibling without diabetes (n = 28). RESEARCH DESIGN AND METHODS: Severity of presentation was measured by the presence of diabetic ketoacidosis (DKA) and degree of hyperglycemia exposure [hemoglobin A1c (HbA1c)] at diagnosis. MRI were obtained using T1-weighted, T2-weighted, and diffusion-weighted sequences. RESULTS: Within the group with type 1 diabetes, 12 subjects presented in DKA and 34 did not. After controlling for age, sex, and multiple comparisons, the type 1 diabetes group had lower volume in the left temporal-parietal-occipital cortex compared with controls. Within the type 1 diabetes group, DKA at presentation was associated with lower radial, axial, and mean diffusivity (MD) throughout major white matter tracts and higher HbA1c was associated with lower hippocampal, thalamic, and cerebellar white matter volumes, lower right posterior parietal cortical thickness, and greater right occipital cortical thickness. CONCLUSION: These data suggest that severity of clinical presentation is an important factor in predicting brain structural differences in youth with type 1 diabetes approximately 3 months after diagnosis.

Clinical presentation and memory function in youth with type 1 diabetes.

OBJECTIVE: While cerebral edema and diabetic ketoacidosis (DKA) in type 1 diabetes (T1DM) have well-described acute effects on cognition, little is known about the impact of clinical presentation on longer term cognitive outcomes. We hypothesized that clinical factors (degree of hyperglycemia exposure and DKA) at the time of diagnosis would relate to cognition within 3.5 months later in children with T1DM. METHODS: Cognitive testing was performed on children 7-17 years old with T1DM (n = 66) within 3.5 months of diagnosis and siblings without T1DM (n = 33). Overall intelligence, processing speed, and memory (including a sensitive long-delay spatial memory test; spatial delayed response or SDR) were assessed. Medical records were reviewed for hemoglobin A1c (HbA1c), DKA status, and other clinical factors at diagnosis. RESULTS: Within the group with T1DM, 17 children presented in DKA and 49 did not. After adjusting for age, gender, and socioeconomic status, the subgroup with T1DM and DKA at diagnosis performed worse on the long-delay SDR task compared to sibling controls (p = 0.006). In addition, within the group with T1DM, higher HbA1c at diagnosis was associated with worse performance on the long-delay SDR task (p = 0.027). Performance on the other cognitive tasks was not different across groups or subgroups. CONCLUSIONS: DKA and degree of hyperglycemia exposure at diagnosis have implications for long-delay spatial memory function within 3.5 months of diagnosis. These findings suggest that early detection of T1DM, which decreases risk for prolonged exposure to hyperglycemia and DKA, may avoid negative effects on memory function.