None.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We carried out a GWA study on glycaemic response to metformin in 1024 Scottish patients with type 2 diabetes. Replication was in two cohorts consisting of 1783 Scottish patients and 1113 patients from the UK Prospective Diabetes Study. In a meta-analysis (n=3920) we observed an association (P=2.9 *10−9) for a SNP rs11212617 at a locus containing the ataxia telangiectasia mutated (ATM) gene with an odds ratio of 1.35 (95% CI 1.22 to 1.49) for treatment success. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMPK in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMPK, and variation in this gene alters glycaemic response to metformin.

Bayer AG.

OBJECTIVE -Patients with diabetes have a higher case fatality rate in myocardial infarction (MI) or stroke than those without diabetes: that is, MI and stroke are more often fatal if diabetes is present. We investigated whether the risk of MI or stroke being fatal in type 2 diabetes can be estimated using information available around the time diabetes is diagnosed.RESEARCH DESIGN AND METHODS -Analyses were based on 674 cases of MI (351 fatal) that occurred in 597 of 5,102 U.K. Prospective Diabetes Study (UKPDS) patients for whom covariate data were available during a median follow-up of 7 years. Multivariate logistic regression was used to examine differences in risk factors, measured within 2 years of diagnosis of diabetes, between fatal and nonfatal MI. Similar analyses were performed for 234 strokes (48 fatal) that occurred in 199 patients.RESULTS -Patients with fatal MI had higher HbA 1c than those with nonfatal MI (odds ratio 1.17 per 1% HbA 1c , P ϭ 0.014). Patients with fatal stroke had higher HbA 1c than those with nonfatal stroke (odds ratio 1.37 per 1% HbA 1c , P ϭ 0.007). Other risk factors for MI case fatality included increased age, blood pressure, and urine albumin level.CONCLUSIONS -The risk of MI or stroke being fatal in type 2 diabetes is associated with risk factors, including HbA 1c , measured many years before onset of MI or stroke. Equations have been added to the UKPDS Risk Engine to estimate likely case fatality rates in MI and stroke. Diabetes Care 27:201-207, 2004M yocardial infarction (MI) and stroke are more common among people with diabetes than those without (1-3). Diabetes is also a risk factor for MI case fatality: that is, MI is more often fatal in people with diabetes compared with MI in those without diabetes (4 -7). Hyperglycemia has been shown to be a risk factor for MI case fatality in people with and without diabetes (4,8 -11), but studies have been limited mainly to risk factor measurements taken after admission to hospital for MI (4,8 -10). Some authors have regarded hyperglycemia as a metabolic consequence of severe MI rather than a cause (12-14), and it is known that insulin therapy to reduce blood glucose levels can improve prognosis after MI in patients with diabetes (15).We have used data from the U.K. Prospective Diabetes Study (UKPDS) to examine differences in risk factors measured during the first 2 years after diagnosis of diabetes between those with fatal MI and those with nonfatal MI. We also examine differences between those with fatal stroke and nonfatal stroke. The prospective design of the UKPDS allows this analysis to include all cases of MI and stroke, not just those surviving to reach hospital, and permits the assessment of risk factors measured many years before the MI or stroke occurs. The UKPDS Risk Engine is a risk calculator specific to type 2 diabetes that can be used to estimate the risk of MI (16) or stroke (17) occurring within a given time period. The present analysis adds to the risk engine equations for MI and stroke case fatality to enable es...