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    • gpr40 agonist The sensitivity analyses were restricted to me

    2018-10-23

    The sensitivity analyses were restricted to men that had remained alive and cancer-free after 10years of follow-up. The results were similar to those obtained when the entire 40-year follow-up was included (Table 3). Alternatively, studying the change from fasting gpr40 agonist to the level at 10min showed a higher risk of all-site cancer among men with a rapid decline (above the median change) than among men with a slower decline (below the median change) in glucose levels (Model III, HR: 1.4, 95% CI: 1.2–1.8). The risk was similarly elevated, when considering either the absolute or the relative change from fasting to 10-min glucose levels (data not shown). Lastly, the KG was not associated with all-site cancer risk, either in the univariate or in the multivariate Cox regression analysis (Table 3).
    Discussion In this prospective study of initially healthy, middle-aged men, we examined the association between plasma glucose levels at 10min (first phase) and at 10–60min (second phase), after an intravenous glucose infusion, and the risk of cancer in a 40-year follow-up. We found that low levels of plasma glucose at 10min were associated with a higher incidence of cancer. In contrast, the risk of cancer was not associated with the slope of plasma glucose elimination in the 10–60min period after infusion. Furthermore, the risk of cancer was not associated with the fasting glucose level or with any of the glucose levels at 20, 30, 40, 50, and 60min. The strong negative association we found between the 10-min plasma glucose and the risk of cancer may appear contradictory to previous prospective studies on cancer incidence and OGTT responses. In those studies, a higher risk was associated with higher levels of plasma glucose at 2-h post-loading (Jee et al., 2005; Huang et al., 2014; Rapp et al., 2006). However, we studied a quite different aspect of glucose metabolism, which manifests itself in the first minutes after an intravenous glucose load, namely the efficiency of first phase glucose disposal. The low 10-min glucose level after an intravenous glucose load was most likely due to an effective first-phase glucose-induced insulin secretion (GIIS) response from β cells, which led to an effective insulin-stimulated elimination of plasma glucose. In principle, increased glucose disposal at 10min could also be due to increased general insulin sensitivity, or increased general insulin independent glucose uptake by various GLUTs. However, it was less likely that high insulin sensitivity, or high insulin independent glucose uptake, could be responsible for this first phase effect, because neither the fasting glucose nor the glucose disappearance rate was found to be associated with cancer risk. Therefore, we focused on specific mechanisms associated with the first phase GIIS. The key proteins in the first phase GIIS include the facilitated glucose transporters (GLUT 1 and GLUT 2) and hexokinase, which are responsible for pancreatic glucose sensing and the immediate release of predocked insulin granules (Seino et al., 2015). These proteins are also rate limiting for the uptake and utilization of glucose in tumors. Cancer cells generally have enhanced glucose utilization and a metabolic shift towards aerobic glycolysis, which generate sustained metabolic changes that favor tumor growth and progression, and require a constant supply of high glucose (Jang et al., 2013). Thus, more efficient glucose uptake may be particularly advantageous for cancer cells. Low 10-min plasma glucose levels were associated with a higher incidence of cancer, considering all cancer sites combined. Our site-specific analyses could not exclude the possibility that similar mechanisms may apply to all the cancer sites studied. Nevertheless, some cancer sites appeared to be more strongly associated with the rates of plasma glucose absorption, such as digestive organs and the colon. Those findings were consistent with data that showed that GLUT 1 or GLUT 2 levels were relatively high in cancer cells at those sites (Barron et al., 2016). In light of the argument that it is critical for cancer cells to obtain glucose, it is notable that GLUT 1 polymorphisms have been linked to cancers in the lung (Fan et al., 2016), liver (Amann et al., 2011), and kidney (Page et al., 2005).