Daniel S. Hsia

Genetic variation in mouse beta globin cysteine content modifies glutathione metabolism: implications for the use of mouse models.

Allelic variation in the mouse beta globin gene complex (Hbb) produces structurally different beta globins in different mouse strains. Like humans, mice with HbbS alleles produce a single beta globin with one reactive cysteine (β Cys93). In contrast, mice with HbbD alleles produce two structurally different beta globins, each containing an additional cysteine (β Cys13). β Cys93 forms mixed disulfides with glutathione and plays a pivotal role in the activities of hemoglobin, glutathione, and nitric oxide. Similar roles for mouse β Cys13 have not been described. We used capillary electrophoresis to compare reduced glutathione (GSH), glutathione disulfide (GSSG), and S-glutathionyl hemoglobin levels in erythrocytes from inbred C57BL/6J (homozygous HbbS/S) and 129S1/SvImJ (homozygous HbbD/D) mice and their homozygous and heterozygous B6129S/F2J hybrid offspring. S-glutathionyl hemoglobin was nearly undetectable in inbred or hybrid mice with only monocysteinyl beta globins (HbbS/S) but represented up to 10% of total hemoglobin in mice with polycysteinyl beta globins (HbbS/D or HbbD/D). The stepwise increase in beta globin sulfhydryl group concentration in HbbS/S, HbbS/D, and HbbD/D F2 mice was associated with increasing hemoglobin-bound glutathione and decreasing free glutathione (GSH + GSSG) concentrations. Total erythrocyte glutathione (GSH + GSSG + hemoglobin-bound) was not significantly different between groups. In vitro studies showed that β Cys13 in mouse HbbD beta globins was more susceptible to disulfide exchange with GSSG than β Cys93. We conclude that reactive beta globin sulfhydryl group concentration is genetically determined in mice, and that polycysteinyl beta globins markedly influence intraerythrocyte glutathione distribution between free and hemoglobin-bound compartments. Although Hbb heterozygosity and polycysteinyl beta globins are common in wild mouse populations, all common human beta globins contain only one reactive cysteine, and homozygosity is the norm. These fundamental differences in mouse and human beta globin genetics have important implications for the study of mouse biology and for the use of some mouse strains as models for humans.

Impact of Lowering BMI Cut Points as Recommended in the Revised American Diabetes Association's Standards of Medical Care in Diabetes-2015 on Diabetes Screening in Asian Americans.

OBJECTIVE This study estimated the screening prevalence of prediabetes and diabetes using a lower BMI cutoff of 23 kg/m2 in Asians in the U.S. using the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2012. RESEARCH DESIGN AND METHODS A cross-sectional analysis was conducted of non-Hispanic Asians, aged 45 years and older, with available BMI, HbA1c, and fasting glucose data. These overall criteria were met by 341 participants. RESULTS Lowering the screening BMI to 23 kg/m2 increased the sensitivity of screening for prediabetes and diabetes from 50.2 to 74.1% (P < 0.0001) but decreased the specificity from 62.9 to 38.7% (P < 0.0001). CONCLUSIONS Although this will add additional health care costs resulting from more widespread screening, early identification of these conditions may be beneficial for primary and secondary prevention in this unique population that develops prediabetes and diabetes at lower BMI levels.

Characterization of unstable hemoglobin A1c complexes by dynamic capillary isoelectric focusing

Glucose spontaneously reacts with hemoglobin amino groups to produce unstable Schiff base complexes that can dissociate or rearrange to form stable Amadori products. We used dynamic capillary isoelectric focusing and boronate affinity chromatography to assess the formation and dissociation of unstable hemoglobin complexes in vitro. Formation was studied by incubating erythrocytes at 37°C for up to 24h in phosphate-buffered saline (PBS) supplemented with 0 to 55.6 mmol/L glucose. Dissociation was studied by incubating glucose-loaded erythrocytes in PBS without glucose. Dynamic capillary isoelectric focusing separated hemoglobin A1c into two subfractions identified as A1c1 and A1c2. The A1c1 subfraction contained both stable and unstable hemoglobin complexes. The A1c2 subfraction contained only unstable hemoglobin complexes. Both subfractions quantitatively increased in the presence of glucose and decreased in its absence. Rates of increase and decrease were faster and time to equilibrium was shorter for A1c2 (~4 h) compared with A1c1 (~20 h). Unstable hemoglobin complexes did not bind to boronate affinity columns but instead eluted intact in A1c1 and A1c2 subfractions from nonglycated affinity fractions. Cyanoborohydride reduction confirmed the presence of Schiff base complexes. Evidence of multiple unstable hemoglobin complexes with different rates of glycation suggests that new models are needed to describe nonenzymatic hemoglobin glycation.

Fluid management in pediatric patients with DKA and rates of suspected clinical cerebral edema

To compare outcomes of diabetic ketoacidosis (DKA) 6 yrs before and 6 yrs after changing rehydration fluids from ½ normal saline to Lactated Ringers and decreasing the total intended fluid volume administered in the first 24 hrs from 3500 mL/m2/d to ≤ 2500 mL/m2/d at Texas Childrens Hospital (TCH) in response to recommendations by the ESPE, LWPES, and ISPAD in 2004.

Youth Energy Expenditure During Common Free-Living Activities and Treadmill Walking

BACKGROUND Energy expenditure (EE) estimates for a broad age range of youth performing a variety of activities are needed. METHODS 106 participants (6-18 years) completed 6 free-living activities (seated rest, movie watching, coloring, stair climbing, basketball dribbling, jumping jacks) and up to 9 treadmill walking bouts (13.4 to 120.7 m/min; 13.4 m/min increments). Breath-by-breath oxygen uptake (VO2) was measured using the COSMED K4b2 and EE was quantified as youth metabolic equivalents (METy1:VO2/measured resting VO2, METy2:VO2/estimated resting VO2). Age trends were evaluated with ANOVA. RESULTS Seated movie watching produced the lowest mean METy1 (6- to 9-year-olds: 0.94 ± 0.13) and METy2 values (13- to 15-year-olds: 1.10 ± 0.19), and jumping jacks produced the highest mean METy1 (13- to 15-year-olds: 6.89 ± 1.47) and METy2 values (16- to 18-year-olds: 8.61 ± 2.03). Significant age-related variability in METy1 and METy2 were noted for 8 and 2 of the 15 evaluated activities, respectively. CONCLUSIONS Descriptive EE data presented herein will augment the Youth Compendium of Physical Activities.

An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus.

Purpose of review Sodium-glucose co-transporter-2 (SGLT2) inhibitors are the newest class of oral antihyperglycemic agents that have been approved for the treatment of diabetes mellitus. Over the past year, there have been significant developments in both the safety and efficacy of this class of medications that are presented in this review. Recent findings Apart from data on the glucose-lowering effect of SGLT2 inhibitors, other metabolic benefits have been demonstrated for this class of medications. Moreover, there have been three Food and Drug Administration Drug Safety Communications issued in 2015 that have led to additional drug labeling. The basic mechanism of action, indications, glucose-lowering benefits, other metabolic benefits, and adverse side-effects of SGLT2 inhibitors are presented in this review. Summary SGLT2 inhibitors are medications that have a unique mechanism of action and that lower glucose independent of insulin. Given the recent findings on efficacy and benefits, these agents are rapidly establishing their role in the treatment of diabetes. Especially in patients with type 2 diabetes not willing or not ready to start insulin, SGLT2 inhibitors may be another option in those patients requiring additional glucose lowering and in those with acceptable risk factor profiles. Although there appears to be some positive benefits in cardiovascular endpoints, more research on the long-term outcomes in people taking SGLT2 inhibitors is warranted.

Morbidly obese paediatric patients are not adequately screened for comorbidities

Although childhood obesity is common, many paediatric practitioners are not familiar with screening for its associated, serious comorbidities. We aimed to determine the adequacy of screening for nine well‐recognized comorbidities in outpatients with severe morbid obesity (body mass index [BMI] ≥50 kg m−2) seen in a large tertiary paediatric hospital. Patients with a BMI of ≥50 kg m−2 seen at Texas Childrens Hospital during calendar year 2009 were identified. Their medical records were reviewed for any documentation where hypertension, cardiac dysfunction, sleep apnoea, hepatosteatosis, diabetes, pseudotumour cerebri, dyslipidemia, orthopaedic issues and depression were noted and/or addressed as evidence of clinician awareness of these problems. We identified 123 patients seen at least once in 2009, with an average of 3.4 physician visits per patient and by an average of 2 different specialists. Hypertension screening was the most documented (91% of patients) and depression screening was the least documented (41%) in this patient cohort. Twelve patients (10%) had documented screening for all nine comorbidities. Overall, 55 patients (45%) had five or fewer of the nine comorbidities noted and/or addressed in the medical record. Adequate screening for comorbidities occurs in approximately half of children with severe morbid obesity, which means that many of these comorbidities are not being identified or treated. Educational programmes and new methodologies are needed to ensure comprehensive care of children with morbid obesity.

A Church-Based Weight Loss Intervention in African American Adults using Text Messages (LEAN Study): Cluster Randomized Controlled Trial

Background African American adults experience a high prevalence of obesity and its associated comorbidities, including diabetes. Church-based interventions have been shown to be effective in decreasing weight in this population. mHealth interventions can address two needs for obesity treatment in this community, including enhancing weight loss and providing wide dissemination. Objective This study aimed to assess the feasibility and efficacy of a church-based weight loss intervention that incorporates mHealth technology. Methods In this study, 8 churches (n=97) were randomly assigned to the intervention or delayed intervention condition (control group). We recruited participants through their respective church. Volunteer church members were trained by study staff to deliver the 10-session, 6-month intervention. Participants in the intervention group attended group sessions and received automated short message service (SMS) text messages designed to reinforce behavioral strategies. Conversely, participants in the delayed intervention condition received SMS text messages related to health conditions relevant for African American adults. We obtained measures of body composition, blood pressure, blood glucose, and cholesterol. Results We successfully recruited 97 African American adults, with a mean age of 56.0 (SE 10.3) years and a mean body mass index of 38.6 (SE 6.4) kg/m2 (89/97, 91.8% females), who attended the churches that were randomized to the intervention (n=68) or control (n=29) condition. Of these, 74.2% (72/97) of the participants (47/68, 69.1% intervention; 25/29, 86.2% delayed intervention) completed the 6-month assessment. The average intervention group attendance was 55%. There was a significant difference in weight loss (P=.04) between participants in the intervention (–1.5 (SE 0.5) kg) and control (0.11 (SE 0.6) kg) groups. Among participants in the intervention group, the correlation between the number of SMS text messages sent and the percent body fat loss was r=.3 with P=.04. The participants reported high satisfaction with the automated SMS text messages. Conclusions Automated SMS text messages were well-received by participants, suggesting that more enhanced mHealth technologies are a viable option for interventions targeting African American adults. Trial Registration ClinicalTrials.gov NCT02863887; https://clinicaltrials.gov/ct2/show/NCT02863887 (Archived by WebCite at http://www.webcitation.org/71JiYzizO)

Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts

OBJECTIVE To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes. RESEARCH DESIGN AND METHODS This is a multicenter (n = 22 sites), randomized, double-blind, placebo-controlled, primary prevention clinical trial testing effects of oral daily 4,000 IU cholecalciferol (D3) compared with placebo on incident diabetes in U.S. adults at risk for diabetes. Eligible participants were at risk for diabetes, defined as not meeting criteria for diabetes but meeting at least two 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100–125 mg/dL, 2-h postload glucose (2hPG) after a 75-g oral glucose load 140–199 mg/dL, and/or a hemoglobin A1c (HbA1c) 5.7–6.4% (39–46 mmol/mol). RESULTS A total of 2,423 participants (45% of whom were women and 33% nonwhite) were randomized to cholecalciferol or placebo. Mean (SD) age was 60 (9.9) years and BMI 32.1 (4.5) kg/m2. Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA1c criteria only. Black participants had the highest mean HbA1c and lowest FPG concentration compared with white, Asian, and other races (P < 0.01); 2hPG concentration did not differ among racial groups. When compared with previous prediabetes cohorts, the D2d cohort had lower mean 2hPG concentration but similar HbA1c and FPG concentrations. CONCLUSIONS D2d will establish whether vitamin D supplementation lowers risk of diabetes and will inform about the natural history of prediabetes per contemporary ADA criteria.

A randomized controlled exercise training trial on insulin sensitivity in African American men: The ARTIIS study☆ Major category: study design, statistical design, study protocols

BACKGROUND Lack of regular physical activity at prescribed intensity levels is a modifiable risk factor for insulin resistance and the development of diabetes. African American men are at increased risk for developing diabetes and most African American men are not meeting the current recommended levels of physical activity. The primary objective of the Aerobic Plus Resistance Training and Insulin Resistance in African American Men (ARTIIS) study is to determine the effectiveness of an exercise training intervention aimed at reducing diabetes risk factors in African American men at risk for developing diabetes. METHODS Insufficiently active 35-70 year old African American men with a family history of diabetes were eligible for the study. The 5-month randomized controlled trial assigns 116 men to an exercise training or healthy living control arm. The exercise training arm combines aerobic and resistance training according to the current national physical activity recommendations and is conducted in community (YMCA) facilities. The healthy living arm receives information promoting healthy lifestyle changes. OUTCOMES Insulin response to an oral glucose load is the primary outcome measure, and changes in physiological parameters, cardiorespiratory fitness, strength, body composition, and psychological well-being comprise the secondary outcomes. CONCLUSIONS The ARTIIS study is one of the first adequately powered, rigorously designed studies to investigate the effects of an aerobic plus resistance exercise training program and to assess adherence to exercise training in community facilities, in African American men.