The question is whether bedtime insulin, one of the standard therapy regimens of type 2 diabetes, can be more atherogenic than daytime insulin. There is no study to answer this question. However, pharmacokinetics of drugs and physiopathology of type 2 diabetes are considered, we can assume that daytime OAD plus bedtime insulin therapy might be more atherogenic than daytime insulin plus bedtime OAD therapy. The rationale for combination therapy is based on the assumption that, if evening insulin lowers the fasting glucose concentration to normal, then daytime oral agents wilt be more effective in controlling postprandial hyperglycemia. However, exogenous insulin administration is not a convenient way to inhibit hepatic glucose production which determines fasting plasma glucose because in post absorptive period, hepatic glucose production is determined by high glucagon and low insulin levels. In postprandial period, beta cell-originated insulin inhibits glucagon synthesis by paracrine effect and also inhibits hepatic glucose production by using half of its concentration that administered to portal system. Since half of insulin that found in portal system is exposed to hepatic clearance to inhibit hepatic glucose production, portal insulin concentration is 2-4-folds higher than peripheral insulin concentration. But, exogenous insulin neither inhibits glucagon synthesis via paracrine effect, nor reaches desired portal concentrations because it has a short half-life and in opposition to physiologic states it is not administered to the portal system. On the contrary, its peripheral concentration is higher than portal one. Thus, exogenous insulin that is used to inhibit hepatic glucose production requires higher concentrations than physiologic: values. Eventually, peripheral hyperinsulinemic state which is a risk factor of CVD is created iatrogenically. Bearing in mind that PI3K pathway, working synchronously with the diurnal rhythm of other metabolic hormones, is more active during daytime especially in postprandial period when aminoacids and glucose exist in the environment, and that decreased insulin response in PI3K pathway in diabetics, we may propose iatrogenically created hyperinsutinemia can cause more atherogenic effects via MAN pathway. For that reason, using OAD instead of bedtime insulin may be a more convenient way to inhibit hepatic glucose production. Thus, glucagon synthesis inhibition can be achieved via paracrine effect of OAD-induced insulin secretion, as well as required portal insulin concentration can be reached by the direct secretion of insulin to the portal system. Moreover, Lower peripheral hyperinsutinemia state can be provided. (C) 2006 Elsevier Ltd. All rights reserved.