TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

OBJECTIVE: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. RESULTS: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. CONCLUSIONS: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.

Obstructive Lung Disease and Obstructive Sleep Apnea (OLDOSA) cohort study: 10-year assessment.

STUDY OBJECTIVES: Asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea (OSA) are very prevalent disorders. Their coexistence in the same individual has an unclear effect on natural history and long-term outcomes. METHODS: The OLDOSA (Obstructive Lung Disease and Obstructive Sleep Apnea) cohort enrolled 4,980 veterans with an acute hospitalization and in whom asthma, COPD, OSA, overlapping conditions, or none of these disorders at baseline had been diagnosed. Pulmonary function, polysomnography, positive airway pressure (PAP) recommendations and adherence, and vital status were collected and analyzed. Various proportional hazards models were built for patients with OSA to test the effect of PAP therapy on survival. RESULTS: Ten-year all-cause cumulative mortality rate was 52.8%; median time to death was 2.7 years. In nonoverlapping asthma, OSA and COPD, mortality rates were 54.2%, 60.4%, and 63.0%, respectively. The overlap syndromes had the following mortality: COPD-OSA 53.2%, asthma-COPD 62.1%, asthma-OSA 63.5%, and triple overlap asthma-COPD-OSA 67.8%. In patients with OSA not on PAP therapy, after adjustment for age, comorbidities, and lung function, risk of death was 1.34 (1.05-1.71) times higher than those undergoing treatment. Similarly, in patients with OSA nonadherent to PAP therapy the adjusted risk of death was 1.78 (1.13-2.82) times higher versus those using it at least 70% of nights and more than 4 hours nightly. CONCLUSIONS: In this large longitudinal cohort of hospitalized veterans with high comorbid burden, asthma, COPD, OSA and their overlap syndromes had very high long-term mortality. In patients with OSA, PAP initiation and superior therapeutic adherence were associated with significantly better survival.

Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved ß-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved ß-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.