Type 2 diabetes mellitus is an important disabling condition[1], and its prevalence is increasing. Type 2 diabetes mellitus is generally understood to be a metabolic disorder defined by hyperglycemia and insulin resistance combined with abdominal obesity, dyslipidemia and hypertension. The current focus of management of diabetes mellitus has moved from controlling hyperglycemia alone to a multifactorial approach to risk reduction[2, 3].

An association has recently been established between type 2 diabetes and variation in the transcription factor TCF7L2 gene in a large Icelandic study[4]. Two additional cohorts showed similar associations, giving a combined odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.41 to 1.73, p = 4.7 × 10^-18 per allele. The rs7903146 single nucleotide polymorphism (SNP) in TCF7L2 is in linkage disequilibrium with the risk microsatellite, and has been recommended for use in replication studies[4]. In a separate study of progression to diabetes in the Diabetes Prevention Program, Florez et al[5] found that the same variant in TCF7L2 was associated with an increased risk of diabetes incidence among people with impaired glucose tolerance. Several case-control studies have now replicated these findings [6–11].

Thus far, the available evidence for TCF7L2 has been from case-control comparisons or intervention trial volunteers, and not representative general populations; data from elderly populations, in whom risks of type 2 diabetes are highest, are scarce. As Sackett and Haynes[12] have pointed out, many biomarkers have appeared promising in comparisons of clear-cut cases and controls, only to perform poorly in the general population. In maturity onset diabetes of the young, the clinical presentation and treatment needs of patients varies markedly by genotype[13]; whether such clinical heterogeneity by genotype is present for TCF7L2 and type 2 diabetes is unclear.

Our study aimed to investigate whether the presentation of diabetes and related features is associated with TCF7L2 genotype in a representative population of older people. We genotyped the TCF7L2 SNP rs7903146, and correlated genotype with diabetes-related biochemical changes and measures of diabetes complications.

The data were from the InCHIANTI Study[14] of aging, a representative sample of 1155 people aged ≥ 65 years in two towns in Tuscany, Italy. Subjects had an initial assessment at home followed by two clinic visits between September 1998 and March 2000. The participants were all of white European origin. The Italian National Institute of Research and Care of Aging Institutional Review Board approved the study.

The InCHIANTI cohort has been studied extensively for phenotypic measures of aging, including biochemical and physical tests. We analyzed data on fasting plasma glucose and insulin levels, and calculated Homeostasis Model Assessment (HOMA2) scores using a formula from the Oxford Centre for Diabetes, Endocrinology and Metabolism (http://www.dtu.ox.ac.uk, accessed June 2006). Fasting insulin was determined using a commercial double-antibody, solid-phase radioimmunoassay (Sorin Biomedica, Milan, Italy) with an intra-assay coefficient of 3.1%[15]. Fasting blood glucose was determined by an enzymatic colorimetric assay using a modified glucose oxidase-peroxidase method (Roche Diagnostics GmbH, Mannheim, Germany) and a Roche-Hitachi 917 analyzer.

Diseases were ascertained by an experienced clinician using pre-established criteria combining self-reported physician diagnoses, current pharmacologic treatment, medical records, clinical examinations, and blood tests[16]. The "diabetes" group in this analysis had fasting blood glucose levels of ≥ 7.0 mmol/l or a physician diagnosis of diabetes with diabetes diet or drug treatment in the previous 2 weeks. Impaired fasting glucose was defined according to American Diabetes Association (ADA) criteria[17, 18] as a fasting glucose of 5.6–6.9 mmol/L, excluding cases diagnosed as diabetic.

A 24-hour urine collection was performed, and urinary and serum creatinine were measured using a modified Jaffe method. A creatinine clearance of ≤ 30 mL/min was considered renal insufficiency, a threshold previously shown to be associated with anemia in older people in this dataset[19]. For metabolic syndrome, measures were dichotomized in accordance with the Adult Treatment Panel III (ATP III) definitional criteria[20]: men are classified ashaving abdominal obesity if their waist circumference is > 1020 mm, women if their waist circumferenceis > 880 mm. For both sexes a high triglyceride level was considered to be ≥ 150 mg/dL. Men were classified as having low high-density lipoprotein (HDL) levels if the serum level was ≤ 40 mg/dL; for women the cut-point was ≤ 50 mg/dL.

The TCF7L2 (rs7903146) polymorphism is the most powerful single genetic variant influencing type 2 diabetes risks identified to date[21]. In this study, we aimed to explore the effects of this polymorphism in a general elderly population, rather than in selected cases and controls. We found that the TCF7L2 polymorphism is associated with higher fasting glucose and lower insulin and HOMA2b levels across this sample, suggesting beta-cell impairment. Unexpectedly, however, we also found that the rarer allele (T) is also associated with a more protective lipid profile of higher HDL levels and lower triglyceride levels. This latter finding was still significant after adjusting for insulin resistance, suggesting that it is not secondary to the possible increase in insulin sensitivity that we observed. The improved lipid profile was present even in the population without diabetes or IFG (in whom a smaller waist circumference was also found) and therefore this finding is unlikely to be an artifact of TCF7L2 polymorphism carriers developing diabetes at lower levels of abdominal obesity.

We also found that within the group of patients with diabetes and IFG, T allele carriers were less likely to have metabolic syndrome features (p = 0.047) including hypertension, or to have had a myocardial infarction (p = 0.037). This suggests a lower macrovascular risk factor loading in the T allele group compared with the common CC genotype. In contrast to the lower lipid risk profile, however, T allele carriers with diabetes and IFG were more likely to have certain microvascular-related complications, including poor renal function and perhaps a higher rate of retinopathy. The association with physician diagnoses of dementia in the T carriers with diabetes and IFG was also unexpected, but may fit into the profile of raised microvascular risk factors. The existence of an association between dementia and diabetes was supported by a recent systematic review[22].

The incidence of hypertension, macrovascular disease and type 2 diabetes all increase with age[23], and prior to the discovery of TCF7L2 it was suggested that a common mechanism might be responsible for all of these pathological states, as these conditions appear to cluster in the same individuals. Patients with diabetes mellitus have a much higher rate of cardiovascular disease (CVD) than the general population, and dyslipidemia and other metabolic syndrome features seen in diabetes are accepted as the major risk factors for CVD[24, 25]. Clinical trials have confirmed that lipid-lowering therapies result in a substantial reduction of cardiovascular risk in patients with type 2 diabetes[26]. Our finding of lower rates of myocardial infarction, although based on small numbers, is consistent with patients with diabetes who carry the T allele having a lower risk profile of metabolic-syndrome features.

In contrast to macrovascular changes, diabetic microvascular complications (including retinopathy[27], neuropathy and nephropathy[28]) are mainly linked to hyperglycemia[29]. Intensive blood-glucose control decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes[30]. Our finding of higher rates of microvascular complications in T allele patients with diabetes is consistent with specific dysfunction of insulin production in the beta cell present with the TCF7L2 polymorphism[4], perhaps leading to greater exposure to hyperglycemia-mediated damage. The prevailing biochemical theories on how diabetes leads to microvascular disease[31] includes several glucose-related pathways that contribute to endothelial damage and dysfunction.

In evaluating these results, it is important to note that the data are cross-sectional, and could perhaps have been affected by differential survival of high-risk participants. In theory, the lower risk lipid profile of T allele carriers may be due to a markedly higher mortality rate in T carriers who had had metabolic syndrome features plus the T allele-associated diabetes risk, and therefore did not survive past 65 years of age. However, there was no significant association between T allele status and age in this study (linear sex adjusted regression β = 0.031, p = 0.963) and there was also less dyslipidemia in the general population, excluding those with diabetes or IFG, making a differential mortality scenario less likely. A second limitation is our relatively crude measure of beta-cell function; more accurate measurements are obtained from oral glucose tolerance tests, but these were not performed in InCHIANTI. In addition, the numbers of patients with diabetes with major complications are limited, and although the findings presented are consistent with previous knowledge of the mechanisms of diabetes-related complications, replication of these findings in independent populations is clearly needed. Two-thirds of those with diabetes were receiving some form of treatment, and prior treatment may have influenced diabetes-specific estimates, although rates of treatment were not significantly different by SNP status. As treated patients with diabetes are likely to have more severe disease and complications than untreated patients, simple exclusion or adjustment for treatment would be misleading. The presence of many of the associations in the general population sample and the combined diabetes and IFG groups, in which the effect of treatment would be diluted, suggests that these findings are robust.

If these findings are confirmed in other populations and in prospective cohort studies, the presentation of T allele carriers as having lower risk of metabolic syndrome but greater risk of microvascular complications would have obvious clinical implications. The desegregation of type 2 diabetes into subtypes with different patterns of risk suggests that treatment approaches, especially to lipid reduction and closeness of glycemic control, could be more closely tailored to genetic subtype.

The TCF7L2 polymorphism is associated with beta-cell dysfunction but also a more protective lipid risk profile in the general elderly population. TCF7L2 minor allele carrier patients with diabetes are less likely to have metabolic syndrome features, but may be at higher risk from more microvascular complications, including renal impairment and (vascular) dementia. If replicated, these findings may have implications for developing treatment approaches tailored to the balance of risks in the different genotype groups.