OBJECTIVE -We hypothesized that biological variation in HbA 1c , distinct from variation attributable to mean blood glucose (MBG), would predict risk for microvascular complications in the Diabetes Control and Complications Trial (DCCT).
RESEARCH DESIGN AND METHODS-A longitudinal multiple regression model was developed from MBG and HbA 1c measured in the 1,441 DCCT participants at quarterly visits. A hemoglobin glycation index (HGI ϭ observed HbA 1c -predicted HbA 1c ) was calculated for each visit to assess biological variation based on the directional deviation of observed HbA 1c from that predicted by MBG in the model. The population was subdivided by thirds into high-, moderate-, and low-HGI groups based on mean participant HGI during the study. Cox proportional hazard analysis compared risk for development or progression of retinopathy and nephropathy between HGI groups controlled for MBG, age, treatment group, strata, and duration of diabetes.RESULTS -Likelihood ratio and t tests on HGI rejected the assumption that HbA 1c levels were determined by MBG alone. At 7 years' follow-up, patients in the high-HGI group (higherthan-predicted HbA 1c ) had three times greater risk of retinopathy (30 vs. 9%, P Ͻ 0.001) and six times greater risk of nephropathy (6 vs. 1%, P Ͻ 0.001) compared with the low-HGI group.CONCLUSIONS -Between-individual biological variation in HbA 1c , which is distinct from that attributable to MBG, was evident among type 1 diabetic patients in the DCCT and was a strong predictor of risk for diabetes complications. Identification of the processes responsible for biological variation in HbA 1c could lead to novel therapies to augment treatments directed at lowering blood glucose levels and preventing diabetes complications.
Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.
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