The culprit of chronic complications of diabetes-from glucose to insulin resistance

Abstract

The prevalence of diabetes and its complications has been increasing exponentially worldwide, especially in China with approximately one-quarter of the global diabetes population. And constitute a major public health problem (Diabetes in China part 1, 2024). As hyperglycemia is the distinguishing feature of diabetes, and also supposed to be the most important risk factor for long-term complications in diabetes by evidence from clinical trials and longitudinal population-based studies (Buse JB et al., 2020), controversy over the target level of glucose control in diabetes lasted more than a decade. The two earliest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) in 1970 and the University Group Diabetes Program (UGDP) study in 1998 did not reveal a reduction of cardiovascular endpoints through improved metabolic control(C L Meinertet al.,  1970; UK Prospective Diabetes Study (UKPDS) Group,1998). Therefore, the effect of improved glucose control on coronary complications in this population remains questionable. After 2006, three randomized control trials (ACCORD, ADVANCE, Veterans Affairs Diabetes), assessed the impact on cardiovascular events of intensive glucose-lowering therapy (Gerstein HCet al., 2008; Goff DC Jr et al., 2007; Patel A et al., 2008; Robins et al., 2007). None of these studies was able to demonstrate a significant reduction of cardiovascular outcomes in the intensive group (with a HbA1c target of less than 6.0%) as compared to the standard group (with a HbA1c target of 7.0% to 7.9%). Unexpectedly, the ACCORD study was terminated early because of a higher mortality in the intensively group. In contrast, in ACCORD, the study with the most ambitious goal (HbA1c < 6%), the overall and cardiovascular mortality was greater in the intensive group. Meanwhile, in the ADVANCE trial, the mortality and the incidence of cardiovascular events were not statistically different between the two treatment groups. Notably, Veterans Affairs Diabetes study showed that the effect of better glucose control on cardiovascular complications disappeared with duration of the disease and that the risk of cardiovascular events increased in patients with severe hypoglycemic events (Robins et al., 2007). The hypoglycemic risk was finally increased in the intensive group, which may contribute to reduce the positive impact of better glucose control on cardiovascular complications. Therefore, Prof. BYRON J. HOOGWERF, an investigator in the ACCORD trial, once asked” Is glucose a culprit, or does it just run in bad company?”. Glycemic profiles could not fully explain the presence/absence and severity of chronic complications of diabetes.

Diabetes shared a common feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. As early as in the prediabetes, insulin levels began to increase leading to chronic hyperinsulinemia, hyperglycemia-induced β-cell failure, and eventually to type 2 diabetes (Kahn SE, 2003). As the sole hypoglycemic hormone in the body, insulin is an important anabolic hormone and a pivotal regulator of to transform nutrient from production to storage when our body faced nutrient scarcity. In adipose tissue or skeletal muscle and other key storage and consumption sites, insulin can promote carbohydrate uptake. As a result, carbohydrates and proteins are stored as lipids. However, in modern society, western diet, stress, and sedentary lifestyles disrupt the balance and might cause insulin resistance and the subsequent various metabolic abnormalities in proteins, lipids, and carbohydrates (Lee SH et al., 2022). Hyperinsulinemia is considered as the pathogenic driver of many modern diseases, including cardiovascular disease and even cancer (Chiefari E et al., 2021). Many studies indicated that insulin resistance contributes to cardiovascular disease (CVD) risk in patients with diabetes. In patients with diabetes, insulin resistance is associated with a cluster of cardiometabolic risk factors that contribute to the increased risk of cardiovascular disease (Antonino& Ralph A, 2019).

The presence of insulin resistance was traditionally regarded as a pathogenic character of type 2 diabetes, however, evidence from clinical practice and public studies indicated it might be common in type 1 diabetes, both in youth and adults. Results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study revealed that 36% of patients with type 1 diabetes showed evidence of insulin resistance.[13-14] In type 1 diabetes, insulin resistance has been reported as an additional risk factor for CVD and all-cause mortality (Sun R et al., 2024).And in routine clinical practice, we constantly encounter patients with type 1 diabetes or even the specific types of diabetes exhibiting severe insulin resistance. For example, the most common type of monogenic diabetes is maturity-onset diabetes of the young (MODY). In one of our MODY 3 patients, which should be characterized as young-onset hyperglycemia, evidence of residual pancreatic function, and lack of beta cell autoimmunity or insulin resistance. Insulin resistance was obvious and the glucose levels were difficult to maintain normal.

In conclusion, the treatment of diabetes should be focused on the therapeutic strategies for insulin resistance, which include lifestyle modifications and weight loss. Moreover, the insulin-sensitizing antidiabetic drugs, such as thiazolidinediones, has been shown to reduce cardiovascular events and retard the atherosclerotic process in high-risk patients with diabetes (Antonino& Ralph, 2019). Although glucagon-like peptide-1 (GLP-1) stimulates insulin secretion by β-cells to improve hyperglycemia, they might reduce insulin resistance by weight loss. And the newly launched dual GIP/GLP-1 receptor co-agonist, for example, Tirzepatide, has already been found to improve insulin sensitivity and insulin secretory responses (Nauck & D'Alessio, 2022). Although we have known about diabetes for hundreds of years, we still need more efforts to explore the treatment and prevention of this sweet burden.