Many studies support the notion that CVD is related to insulin resistance [10–12]. However, results from different studies are controversial. In the 8.6 years’ follow-up of the Prospective Study of Pravastatin in the Elderly (PROSPER), higher HOMA-IR was not associated with all-cause and CHD mortality or fatal/non-fatal CVD . There is a paucity of evidence whether a higher post-load insulin response which induced by insulin resistance is a risk factor for CVD mortality in people with normal glucose status and impaired glucose tolerance.
In the present study, we found that non-diabetic Chinese people with higher insulin AUC in response to standard glucose challenge, an indicator of higher insulin demands for maintaining glucose metabolism, had significantly higher rates of all-cause and CVD mortality during the subsequent 30 years. Multiple regression analysis further confirmed that baseline insulin AUC significantly predicted these risks. A more interesting finding was that the predictive effect of insulin AUC on mortality was coexisted with a significant association between death and 2-hour post load glucose levels of the participants after controlling for the influence of traditional risk factors. It indicated that a higher post-load insulin response in this non-diabetes participants contributed to increased risk of mortality independent of other cardiovascular risk factors. This finding highlighted that a strategy only focusing on blood sugar control but ignoring role of the higher post-load insulin response may not reduce the overall risks of death. Therefore, to identify those non-diabetes subjects with higher post-load insulin response should be included in the strategies of lowing all-cause and CVD mortality. Accordingly, to eliminate these clustered risk factors, a package plan to deal with them in a coordinated and balanced manner is warrened.
Higher post-load insulin response was a manifestation of hyperinsulinemia. Why hyperinsulinemia increased the risk of death in the non-diabetes population? Clinically, an easily accepted reason is that the hyperinsulinemia in the non-diabetes subjects triggered and speed-up the onset of diabetes, and then the development to diabetes exacerbated the high risk of any death, especially CVD death. Findings in basic research also provided some insights into understanding the complexity between hyperinsulinemia and CVD risk. Chronic hyperinsulinemia causes coronary vasoconstriction by increasing the release of endothelin-1 and sympathetic nerve activity and by reducing endothelial response to vasodilators . It is also associated with several dysregulations of coagulation and fibrinolysis . Nolan et al proposed a more convincing concept of insulin mediated metabolic stress for conditions related to insulin resistance . It was the insulin resistance had conferred protection against the nutrient overload and metabolic stress by limiting glucose flux into the cell. However, the iatrogenic hyperinsulinemia to override insulin resistance may also override the defence mechanism because the tissues will no longer gain protection from excess nutrient entry. Recently, this idea was supported by Stephan M’s team, wherein they stated that too high systemic insulin levels are detrimental for body functions . For non-diabetes, the higher post-load insulin response for maintaining normal blood glucose level may cause insulin-induced metabolic stress in target organs, thereby increasing the risk of death. This means that higher post-load insulin response is harmful to the body even in the non-diabetes population and should therefore be avoided. Most people with IGT and higher insulin response in the present study have deterioration of diabetes during the 30-year follow-up period. Therefore, findings in this non-diabetes population, especially both higher post load 2h glucose and higher insulin response were significantly associated with the increased risk of all-cause death, may also have some implications for people with diabetes.
Type 2 diabetes with poor glycaemic control is often characterised by high blood glucose and low insulin levels and severe insulin resistance. The optimum and timely use of high-dose insulin response of the body may significantly improve the glucose control, but at the same time it had to pay the expense of hyperinsulinemia, which may lead to insulin-induced metabolic stress in the heart. It was reported that over-nutrition-induced metabolic stress is harmful to the heart (18–21). Like iatrogenic hyperinsulinemia, the higher post-load insulin response in patients with type 2 diabetes may lead to insulin-induced metabolic stress in the heart (metabolic cardiomyopathy), followed by increased risk of cardiac failure and arrhythmias (22–24). Unfortunately, hyperinsulinemia is almost inevitable for better glucose control because more than 80% of type 2 diabetes patients are resistant to insulin. Even worse, it is possible that this insulin resistance and hyperinsulinemia status may exist for lifetime. Thus, in the real-word clinical practice, how to balance the benefits of better blood glucose control and adverse effects of exogenic hyperinsulinemia in patients with type 2 diabetes has become a big challenge.
For alleviating higher insulin response, both lifestyle modification and using medications, such as GLP1 receptor agonists or metformin, should not be ignored. The present data showed that the baseline insulin AUC sequentially increased with the increase in BMI across the four groups, suggesting that insulin-induced harm is more likely to occur in overweight/obese people. Therefore, losing weight and improving insulin sensitivity are good ways to avoid higher insulin response and prevent the development of diabetes.
Our study has several strengths. First, a standard OGTT was conducted at baseline; thus, plasma insulin AUC over 2 hours could be calculated. Second, very few people migrated away from the city, with a minimum rate of loss to follow-up. Third, the participants were followed up for 30 years, which was an optimal duration for patients to develop life-threatening complications such as CVD and stroke.
The limitations of the study should also be acknowledged. The sample size was relatively small. Furthermore, we had no systemic data of medications for the treatment of hypertension and hyperlipidaemia over the 30-year follow-up period; therefore, we are unable to evaluate the impact of these factors on the risk of mortality in the study population. High-quality research using real-world data may provide more information on this aspect.
In conclusion, together with an increase in post-load hyperglycaemia, a higher insulin response to glucose challenge significantly predicted the long-term risk of all-cause and CVD mortality in the Chinese non-diabetes population. Our findings suggest that identifying people with higher insulin response and taking appropriate measures to reduce an individual’s insulin response to eliminate hyperinsulinemia may help in reducing all-cause and CVD mortality.