David J. Brillon

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.

Human Vascular Endothelial Cells: A Model System for Studying Vascular Inflammation in Diabetes and Atherosclerosis

The vascular endothelium is the inner lining of blood vessels serving as autocrine and paracrine organ that regulates vascular wall function. Endothelial dysfunction is recognized as initial step in the atherosclerotic process and is well advanced in diabetes, even before the manifestation of end-organ damage. Strategies capable of assessing changes in vascular endothelium at the preclinical stage hold potential to refine cardiovascular risk. In vitro cell culture is useful in understanding the interaction of endothelial cells with various mediators; however, it is often criticized due to the uncertain relevance of results to humans. Although circulating endothelial cells, endothelial microparticles, and progenitor cells opened the way for ex vivo studies, a recently described method for obtaining primary endothelial cells through endovascular biopsy allows direct characterization of endothelial phenotype in humans. In this article, we appraise the use of endothelial cell-based methodologies to study vascular inflammation in diabetes and atherosclerosis.

Splanchnic utilization of enteral alanine in humans

The splanchnic bed extracts the majority of the enteral nonessential amino acids glutamine and glutamate, while extracting a much smaller proportion of essential amino acids such as leucine and phenylalanine. Alanine is an abundant nonessential amino acid that plays an important role in hepatic gluconeogenesis and ureagenesis. However, its enteral fate has not been studied. Twelve normal healthy postabsorptive adults received a 7-hour infusion of [1-13C]alanine, 3.5 hours intravenously (IV) and 3.5 hours via a nasogastric tube (NG). The order of infusion was randomized among subjects. Alanine kinetics were calculated from the enrichments of plasma alanine 13C and expired 13CO2. The alanine appearance rate (Ra), measured during the IV tracer infusion, was 279+/-17 micromol/kg/h; 92%+/-2% of the IV-infused and 86%+/-2% of the NG-infused [1-13C]alanine tracer was recovered as 13CO2. From the difference in plasma alanine 13C enrichment between IV-infused and NG-infused tracers, we determined that the splanchnic bed extracted 69%+/-1% of the enterally delivered alanine tracer on the first pass during absorption. Only one third of the enteral alanine passed intact through the splanchnic bed and was made available to systemic tissues. Of the enteral alanine extracted, 83%+/-3% of the carboxyl-carbon label was recovered as CO2, leaving only 17% of the sequestered alanine available for use in splanchnic protein synthesis. Thus, the splanchnic bed, presumably the liver, extracts and metabolizes most of the enterally delivered alanine.

Splanchnic bed utilization of enteral α-ketoisocaproate in humans

Abstract The branched-chain ketoacids (BCKAs) are used as dietary supplements to spare essential amino acid nitrogen, yet little is known about their absorption and utilization in the body. To study the fate of enterally delivered α-ketoisocaproate (KIC), seven healthy adults were infused in the postabsorptive state with [1- 13 C]KIC and [phenyl- 2 H 5 ]phenylalanine intravenously (NGI) and with [5,5,5- 2 H 3 ]KIC by nasogastric tube (NG). After 3.5 hours, the routes of tracer infusion were switched for an additional 3.5 hours. Each subject received a second infusion study on a different day with the order of tracer infusion reversed. KIC and phenylalanine kinetics and first-pass uptake and disposal of the enteral tracer by the splanchnic bed were calculated from the tracer enrichments measured in plasma KIC, leucine, and phenylalanine and breath CO 2 . Phenylalanine flux was 39.5 ± 1.2 μmol/kg/h during the IV infusion periods. KIC flux was 33.1 ± 1.8 and 30.4 ± 1.4 μmol/kg/h measured with 13 C- and 2 H 3 -KIC, respectively, and these values were significantly different. The fraction of enterally delivered tracer sequestered by the splanchnic bed on the first pass was 30.9% ± 2.0%, 30.0% ± 1.4%, and 30.7% ± 2.7% for 13 C-KIC, 2 H 3 -KIC, and 2 H 5 -phenylalanine, respectively. The fraction of infused 13 C-KIC tracer recovered as 13 CO 2 was 27.1% ± 1.2% and 24.0% ± 0.9% during IV and NG infusion, respectively. From these data, the fraction of ng KIC tracer extracted and oxidized on the first pass was calculated to be 5.1% ± 1.1%. This fraction was greater than that previously reported for leucine extraction and oxidation (2%), but it was still only a small fraction of the overall extraction ( 5 30 = 16%). Because the only two fates of the KIC tracer extracted by the splanchnic bed are oxidation or transamination to leucine, the majority (84%) of the KIC tracer was extracted and converted to leucine. These results demonstrate that KIC delivered enterally to postabsorptive humans is rapidly extracted and predominantly converted to leucine by the splanchnic bed. This leucine appears to be available for use by both the splanchnic bed and the whole body.

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.

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.

Decreased rates of hypoglycemia following implementation of a comprehensive computerized insulin order set and titration algorithm in the inpatient setting

ABSTRACT Objectives: More than one-third of hospitalized patients have hyperglycemia. Despite evidence that improving glycemic control leads to better outcomes, achieving recognized targets remains a challenge. The objective of this study was to evaluate the implementation of a computerized insulin order set and titration algorithm on rates of hypoglycemia and overall inpatient glycemic control. Methods: A prospective observational study evaluating the impact of a glycemic order set and titration algorithm in an academic medical center in non-critical care medical and surgical inpatients. The initial intervention was hospital-wide implementation of a comprehensive insulin order set. The secondary intervention was initiation of an insulin titration algorithm in two pilot medicine inpatient units. Point of care testing blood glucose reports were analyzed. These reports included rates of hypoglycemia (BG < 70 mg/dL) and hyperglycemia (BG >200 mg/dL in phase 1, BG > 180 mg/dL in phase 2). Results: In the first phase of the study, implementation of the insulin order set was associated with decreased rates of hypoglycemia (1.92% vs 1.61%; p < 0.001) and increased rates of hyperglycemia (24.02% vs 27.27%; p < 0.001) from 2010 to 2011. In the second phase, addition of a titration algorithm was associated with decreased rates of hypoglycemia (2.57% vs 1.82%; p = 0.039) and increased rates of hyperglycemia (31.76% vs 41.33%; p < 0.001) from 2012 to 2013. Conclusions: A comprehensive computerized insulin order set and titration algorithm significantly decreased rates of hypoglycemia. This significant reduction in hypoglycemia was associated with increased rates of hyperglycemia. Hardwiring the algorithm into the electronic medical record may foster adoption.

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.