Cardiovascular disease is the leading cause of morbidity and mortality in patients with Type II (non-insulin-dependent) diabetes mellitus accounting for up to 75 % of deaths [1]. Although insulin and insulin resistance have been considered major factors in the pathogenesis of cardiovascular disease [2,3], given the close links between the insulin-like growth factor-system and insulin action we examined the potential role of the insulin-like growth factor-system in the pathogenesis of macrovascular disease. Diabetologia (2001) Abstract Aims/hypothesis. Insulin resistance/hyperinsulinaemia is implicated in the development of cardiovascular disease and diabetes but its role and causal pathways are not clear. We tested the hypothesis that the insulin-like growth factor system is independently associated with cardiovascular risk within susceptible populations based on previous reports of the links between low circulating insulin-like growth factor binding protein-1 concentrations and increased macrovascular disease in Type II (non-insulin-dependent) diabetes mellitus. Methods. In a population-based study 272 subjects (142 subjects of European and 130 Pakistani of origin) underwent a 75 g oral glucose tolerance test and standardised anthropometry. Fasting concentrations of insulin-like growth factor binding protein-1 (IG-FBP-1), insulin-like growth factor-I (IGF-I), insulinlike growth factor-II (IGF-II), intact insulin and lipids were measured and were related to 2-h glucose tolerance test status. Insulin sensitivity was calculated using the homeostasis model assessment (HOMA). Results. Insulin-like growth factor binding protein-1 was significantly lower in subjects with impaired glucose tolerance when compared with normal glucose tolerance in both ethnic groups (Europeans F = 6.7, p = 0.002 and Pakistanis F = 4.4, p = 0.01). Multiple linear regression modelling showed that insulin-like growth factor binding protein-1 was independently associated with 2-h glucose (b = 0.16, p = 0.009) and logistic regression indicated a 40 % reduction in risk of impaired glucose tolerance for every 2.7 ng/ml increase in the insulin-like growth factor binding protein-1 concentration [odds ratio 0.6 (CI = 0.49±0.71), p = 0.001)]. In addition, insulin-like growth factor binding protein-1 was significantly correlated negatively with several established cardiovascular factors, and positively with insulin sensitivity. Conclusion/interpretation. Insulin-like growth factor binding protein-1 is closely related to risk factors for diabetes and cardiovascular disease in people of European and Pakistani origin. It has potential use as a marker of (hepatic) insulin resistance in clinical intervention studies and further implicates the insulin-like growth factor system in the development of macrovascular disease. [Diabetologia (2001) 44: 333±339]

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The observation that long-lived and relatively healthy animals can be obtained by simple genetic manipulation prompts the search for chemical compounds that have similar effects. Since aging is the most important risk factor for many socially and economically important diseases, the discovery of a wide range of chemical modulators of aging in model organisms could prompt new strategies for attacking age-related disease such as diabetes, cancer and neurodegenerative disorders (Collins et al., 2006;Floyd, 2006;Gill, 2006;Hefti and Bales, 2006). Resistance to multiple types of stress is a common trait in long-lived genetic variants of a number of species; therefore we have tested compounds that act as stress response mimetics. We have focused on compounds with antioxidant properties and identified those that confer thermal stress resistance in the nematode Caenorhabditis elegans. Some of these compounds (lipoic acid, propyl gallate, trolox and taxifolin) also extend the normal lifespan of this simple invertebrate, consistent with the general model that enhanced stress resistance slows aging.

The lifespan of Caenorhabditis elegans can be extended by the administration of synthetic superoxide dismutase/ catalase mimetics (SCMs) without any effects on development or fertility. Here we demonstrate that the mimetics, Euk-134 and Euk-8, confer resistance to the oxidative stress-inducing agent, paraquat and to thermal stress. The protective effects of the compounds are apparent with treatments either during development or during adulthood and are independent of an insulin/IGF-I-like signalling pathway also known to affect thermal and oxidative stress resistance. Worms exposed to the compounds do not induce a cellular stress response and no detrimental effects are observed.

The insulin-like growth factor (IGF) system, comprising insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), and their binding proteins (IGFBPs), is linked to cell growth, the development of cardiovascular disease, and several cancers. Little is known about its epidemiology. The authors studied relations of the IGF system to anthropometric and metabolic variables in three population-based ethnic groups in Manchester, England, in 1994-1998 with differing disease risks: African Caribbean (n = 193), Pakistani (n = 130), and local Europeans(n = 142). Standardized anthropometry, glucose tolerance tests, and serum assays were performed. Body mass indices (BMIs) were high in all groups. IGF-I levels were highest in normoglycemic African Caribbeans and declined with age (r = -0.28). IGF-II levels were greatest in Europeans. IGFBP-1 concentrations increased with age in Pakistanis (r = 0.20) and Europeans (r = 0.29), but not in African Caribbeans (r = 0.06), and were inversely related to BMI (r = -0.37). Age- and sex-adjusted IGFBP-1 was inversely related to fasting insulin and proinsulin in all groups; participants with newly detected diabetes were relatively insulinopenic but had higher IGFBP-1 concentrations. Nonesterified (free) fatty acid (NEFA) concentrations increased with declining glucose tolerance. In multiple regression analysis, IGFBP-1 was independently and negatively related to fasting insulin, BMI, and African-Caribbean compared with European ethnicity but positively related to age, fasting glucose, and NEFA. IGF-I was inversely related only to age, NEFA, and Pakistani ethnicity. IGF-II showed a strong ethnic difference but was unrelated to other variables. These data indicate considerable potential for exploring disease-IGF system relations in population samples.