American College of Endocrinology Pre-Diabetes Consensus Conference: Part Three

What are the appropriate measures to monitor pre-diabetes and its treatment? Peter Wilson (Boston, MA) reviewed Framingham data, with 30-year follow-up now available, showing greater evidence of adverse cardiovascular disease (CVD) outcome with diabetes. It has been recognized for some time that there are clustered abnormalities within the metabolic syndrome spectrum. BMI, triglycerides, waist circumference, HDL cholesterol, and fasting and 2-h insulin form one group; fasting and 2-h insulin and glucose another; and BMI and diastolic and systolic blood pressure levels a third (1), with hyperinsulinemia a crucial factor in many of these associations (2). Homeostasis model assessment of insulin resistance is associated with left ventricular mass in women, though not in men (3). Meigs and colleagues (4) showed evidence that the coronary artery calcium score is associated with insulin resistance and with pre-diabetes. Metabolic syndrome is certainly related to outcome, with CVD two to three times and diabetes seven times more likely in those with 3–5 vs. 0–2 components of the syndrome. In t h i s a n a l y s i s , t h e p o p u l a t i o n attributable risk of metabolic syndrome is approximately one-third that of CVD and two-thirds that of diabetes for men, with glucose (as expected) the major determinant of diabetes risk among metabolic syndrome variables. Populationa t t r i b u t a b l e r i s k s o f m e t a b o l i c syndrome were somewhat lower for women. An alternative analysis divides metabolic syndrome factors into none vs. 1–2 vs. 3–5, with a suggestion of increased risk even in the intermediate group and of markedly increased risk in comparison with 3–5 vs. no metabolic syndrome factors. If a measure of insulin resistance is added to metabolic syndrome, both diabetes and CVD risks are markedly augmented (5). There are arguments against the use of metabolic syndrome, as its components are not all equally powerful in Framingham predictive models (6). Wilson also pointed out that waist circumference and BMI appear equivalent in the analysis of this population. In the Framingham population, 20% had impaired fasting glucose (IFG) only, 5% impaired glucose tolerance (IGT) only, and 6% both, with likelihood of developing diabetes, based on fasting glucose, 1.3% for those with neither, 4.3% for those with IGT only, 9.2% for those with IFG only, and 25.5% for those with both. Wilson stated that diabetes prediction based on age, sex, family history, BMI, blood pressure, and lipids is as good as that based on the presence of IFG and IGT, although using the actual glucose levels improves prediction, and speculated that it might be reasonable to define pre-diabetes and diabetes based on composite risk score, which he termed “a weighted metabolic syndrome,” rather than using glucose levels alone. Steven Haffner (San Antonio, TX) discussed “how and when pre-diabetes progresses to diabetes.” Isolated IFG and isolated IGT differ, with the latter more associated with insulin resistance and inflammation and the former with insulin deficiency. In a population of individuals with normal glucose tolerance, multivariate analysis shows that triglyceride, HDL cholesterol, systolic blood pressure, fasting glucose, and fasting insulin are significant markers of diabetes risk (7)— exactly the components of the metabolic syndrome as subsequently defined. Haffner reviewed analyses from San Antonio and Insulin Resistance Atherosclerosis Study datasets showing IGT somewhat more strongly associated with diabetes development than IFG. Both insulin resistance and decreased insulin secretion increase diabetes risk (8). Inflammatory measures are strongly correlated with insulin resistance, including C-reactive protein (CRP) and the leukocyte count (9), with both CRP and plasminogen activator inhibitor (PAI)-1 quartile associated with diabetes risk (10). Haffner analyzed the additional effect of metabolic syndrome in predicting diabetes. Individuals with metabolic syndrome without IGT had a 12% 7-year risk of diabetes, those with IGT without metabolic syndrome had a 25% risk, and those with both had a 55% risk, suggesting that they might be appropriate candidates for pharmacologic intervention (11). Another set of markers of diabetes risk pertains to its association with hepatic steatosis and to a progressive increase in the likelihood of diabetes associated with increasing alanine transaminase (ALT) levels (12), both of which are additive to the effect of CRP. This might offer another parameter useful in determining whether pharmacologic treatment would be indicated, with Haffner suggesting that those individuals whose annual likelihood of diabetes exceeded 8% might be candidates for such an intervention. For such a group, Haffner recommended use of IFG with a glucose cutoff of 110 mg/dl, plus IGT and metabolic syndrome, present in 7% of the population with a 10% annual diabetes risk. Adding ALT somewhat improved this. There is currently no information as to whether serial measurements of glucose levels would allow greater specificity. Another reason for performing a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●