Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC.

OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, ß [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (ß [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, ß [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial.

AIMS/HYPOTHESIS: We aimed to determine the persistence of glycaemic control 1 year after a limited period of intensive glycaemic management of type 2 diabetes. METHODS: 4119 ACCORD Trial participants randomised to target HbA1c <6.0% (42 mmol/mol) for 4.0 ± 1.2 years were systematically transitioned to target HbA1c 7.0-7.9% (53-63 mmol/mol) and followed for an additional 1.1 ± 0.2 years. Characteristics of participants with HbA1c <6.5% (48 mmol/mol) or ≥6.5% at transition were compared. Changes in BMI and glucose-lowering medications were compared between those ending with HbA1c <6.5% vs ≥6.5%. Poisson models were used to assess the independent effect of attaining HbA1c <6.5% before transition on ending with HbA1c <6.5%. RESULTS: Participants with pre-transition HbA1c <6.5% were older with shorter duration diabetes and took less insulin but more non-insulin glucose-lowering agents than those with higher HbA1c. A total of 823 participants achieved a final HbA1c <6.5%, and had greater post-transition reductions in BMI, insulin dose and secretagogue and acarbose use than those with higher HbA1c (p < 0.0001). HbA1c <6.5% at transition predicted final HbA1c <6.5% (crude RR 4.9 [95% CI 4.0, 5.9]; RR 3.9 [95% CI 3.2, 4.8] adjusted for demographics, co-interventions, pre-intervention HbA1c, BMI and glucose-lowering medication, and post-transition change in both BMI and glucose-lowering medication). Progressively lower pre-transition HbA1c levels were associated with a greater likelihood of maintaining a final HbA1c of <6.5%. Follow-up duration was not associated with post-transition rise in HbA1c. CONCLUSIONS/INTERPRETATION: Time-limited intensive glycaemic management using a combination of agents that achieves HbA1c levels below 6.5% in established diabetes is associated with glycaemic control more than 1 year after therapy is relaxed.

Comparative effectiveness of oral diabetes drug combinations in reducing glycosylated hemoglobin.

AIMS: To provide evidence on the comparative effectiveness of oral diabetes drug combinations. METHODS: We performed a retrospective, observational cohort study of glycosylated hemoglobin change in outpatients newly exposed to dual- or triple-drug oral diabetes treatment. RESULTS: Adjusted response to a second drug added to metformin ranged from 0.85 to 1.21% glycosylated hemoglobin decline. Response to a third drug was smaller (0.53-0.91%). Higher baseline glycosylated hemoglobin was associated with larger response; sulfonylurea effectiveness declined over time; and thiazolidinediones were more effective in obese patients and women. CONCLUSION: Observational data provide results qualitatively consistent with the limited available randomized data on diabetes drug effectiveness, and extend these findings into common clinical scenarios where randomized data are unavailable. Sex and BMI influence the comparative effectiveness of diabetes drug combinations.

Diabetes control among Hispanics in the action to control cardiovascular risk in diabetes trial.

BACKGROUND: Hispanics in the United States represent diverse racial, ethnic, and socioeconomic groups, and manifest heterogeneous cardiovascular risks including diabetes. It is not known if there are residual differences in the control of diabetes among Hispanic groups given uniform access to diabetes care. OBJECTIVE: To evaluate glucose control differences among Mexicans, Puerto Ricans, and Dominicans receiving substantial diabetes care and support in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. DESIGN: Secondary analysis of data from a randomized trial comparing two treatment strategies: intensive, targeting glycated hemoglobin below 6.0 %, and standard, targeting glycated hemoglobin between 7.0 % and 7.9 %. PARTICIPANTS: Seven hundred and sixteen Hispanic and 6066 non-Hispanic white participants were recruited from 77 clinical sites across the United States and Canada. There were 243 Mexicans, 199 Puerto Ricans, and 150 Dominicans; and 135 of these Hispanic groups were born in the United States. MAIN MEASURE: Glycated hemoglobin RESULTS: Compared to Puerto Ricans, Mexicans were more likely (HR=1.38, CI:0.90-2.10) and Dominicans as likely (HR=1.01, CI:0.66-1.54) to achieve glycated hemoglobin goal in the intensive arm. Participants born in the United States achieved glycated hemoglobin goal at a higher rate than those born elsewhere (HR=1.57, CI:0.99-2.51 in the intensive arm, HR=1.51, CI:0.95-2.43 in the standard arm). These differences were not statistically significant. In the intensive arm, Puerto Ricans (OR=0.47, CI:0.31-0.71), and Dominicans (OR=0.41, CI:0.26-0.66) were less likely than non-Hispanic whites to achieve glycated hemoglobin goal, whereas the difference between non-Hispanic whites and Mexicans was not statistically significant, (OR=0.66, CI:0.43-1.02). CONCLUSIONS: Hispanic groups, given access to comprehensive diabetes care, differed from each other non-significantly and had a variable divergence from non-Hispanic whites in achieving intensive glycated hemoglobin goal. These differences, if confirmed, could be due to such factors as variable acculturation and functional health literacy levels that were not measured in the ACCORD trial, but should be further explored in future studies.

Hemoglobin A(1c) criterion for diabetes diagnosis among Hispanic and non-Hispanic populations.

OBJECTIVE: To report on the performance of the recently recommended hemoglobin A(1c) (A1C) criterion for diabetes diagnosis in comparison with the standard fasting plasma glucose and 2-hour post-glucose challenge (PG) test criteria across racial and ethnic groups. METHODS: We evaluated local and national survey data from 689 Dominican, 4,862 Hispanic, 4,694 African American, and 6,883 white study subjects. We compared rates of diabetes classification by diagnostic criteria, agreement and disagreement between A1C and PG criteria for diagnosing diabetes, and differences in cardiometabolic risk among the 3 diagnostic groups across racial and ethnic stratifications. RESULTS: The A1C-based diabetes diagnoses were higher among Dominican and African American study subjects (81.6% and 67.0%, respectively), and lower among Hispanic and white subjects (46.0% and 37.9%, respectively). Among those not meeting any PG criterion for diabetes, the A1C criterion identified diabetes in 8.3% of Dominican, 3.5% of African American, 0.9% of Hispanic, and 0.5% of white study subjects. The A1C criterion, however, did not identify diabetes in 64.5% of white, 46.1% of Dominican, 44.0% of African American, and 41.9% of Hispanic subjects who were diagnosed with diabetes by a PG criterion. For single tests, the agreement was greatest between A1C and fasting plasma glucose test criteria among Dominican, Hispanic, and African American study populations-76.9%, 65.6%, and 60.7%, respectively. There was no clear difference in selected cardiometabolic risks between A1C and PG-only diabetes diagnoses across racial and ethnic groups. CONCLUSION: The A1C criterion yields racial- and ethnic-specific differences in diagnosing diabetes and in test agreements with PG-based criteria. Furthermore, diagnostic differences were observed between the Dominican subgroup and the Hispanic study population, of whom 91.5% were Mexican American.

Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial.

OBJECTIVE: Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality. RESEARCH DESIGN AND METHODS: Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0-7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models. RESULTS: Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6-9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%. CONCLUSIONS: These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.

Glucose testing and insufficient follow-up of abnormal results: a cohort study.

BACKGROUND: More than 6 million Americans have undiagnosed diabetes. Several national organizations endorse screening for diabetes by physicians, but actual practice is poorly understood. Our objectives were to measure the rate, the predictors and the results of glucose testing in primary care, including rates of follow-up for abnormal values. METHODS: We conducted a retrospective cohort study of 301 randomly selected patients with no known diabetes who received care at a large academic general internal medicine practice in New York City. Using medical records, we collected patients' baseline characteristics in 1999 and followed patients through the end of 2002 for all glucose tests ordered. We used multivariate logistic regression to measure associations between diabetes risk factors and the odds of glucose testing. RESULTS: Three-fourths of patients (78%) had at least 1 glucose test ordered. Patient age (> or = 45 vs. < 45 years), non-white ethnicity, family history of diabetes and having more primary care visits were each independently associated with having at least 1 glucose test ordered (p < 0.05), whereas hypertension and hyperlipidemia were not. Fewer than half of abnormal glucose values were followed up by the patients' physicians. CONCLUSION: Although screening for diabetes appears to be common and informed by diabetes risk factors, abnormal values are frequently not followed up. Interventions are needed to trigger identification and further evaluation of abnormal glucose tests.

Endocrine effects of oral dehydroepiandrosterone in men with HIV infection: a prospective, randomized, double-blind, placebo-controlled trial.

Dehydroepiandrosterone (DHEA) is commonly used by HIV-infected men, but its endocrine effects in this population are not well defined. We conducted an 8-week randomized, placebo-controlled trial to determine the effects of escalating doses (100-400 mg/d) of DHEA on the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, and on a number of metabolic parameters in 69 HIV-positive men (31 in DHEA-treated group, 38 in placebo group). High-dose (250 microg) corticotropin and luteinizing hormone-releasing hormone stimulation tests were carried out in all subjects. Fifty-four subjects (26 in the DHEA-treated group and 28 in the placebo group) also underwent optional corticotropin-releasing hormone test, and 67 subjects (31 in DHEA-treated group and 36 in placebo group) underwent optional low-dose (1 microg) corticotropin stimulation test. All tests were performed at baseline and at the end of week 8. Repeated-measures analysis of variance was used to analyze the data. We observed significant increases in circulating levels of DHEA, DHEA-sulfate, free testosterone, dihydrotestosterone, androstenedione, and estrone, and a decline in the serum concentration of sex hormone-binding globulin in the DHEA-treated group but not in the placebo group (P < .001). There were no differences between the groups in other endocrine or metabolic parameters or in the results of the stimulation tests. In conclusion, oral DHEA therapy in HIV-positive men significantly increases circulating levels of DHEA and DHEA-sulfate, free testosterone, dihydrotestosterone, androstenedione, and estrone and suppresses circulating concentration of sex hormone-binding globulin. Long-term studies are needed to assess the clinical significance of these hormonal changes in subjects with HIV infection receiving oral DHEA therapy.

Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus.

BACKGROUND: Cardiovascular disease causes severe morbidity and mortality in type 1 diabetes, although the specific risk factors and whether chronic hyperglycemia has a role are unknown. We examined the progression of carotid intima-media thickness, a measure of atherosclerosis, in a population with type 1 diabetes. METHODS: As part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), 1229 patients with type 1 diabetes underwent B-mode ultrasonography of the internal and common carotid arteries in 1994-1996 and again in 1998-2000. We assessed the intima-media thickness in 611 subjects who had been randomly assigned to receive conventional diabetes treatment during the DCCT and in 618 who had been assigned to receive intensive diabetes treatment. RESULTS: At year 1 of the EDIC study, the carotid intima-media thickness was similar to that in an age- and sex-matched nondiabetic population. After six years, the intima-media thickness was significantly greater in the diabetic patients than in the controls. The mean progression of the intima-media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima-media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima-media thickness of the common and internal carotid arteries, -0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima-media thickness was associated with age, and the EDIC base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT. CONCLUSIONS: Intensive therapy during the DCCT resulted in decreased progression of intima-media thickness six years after the end of the trial.