The metabolic score of insulin resistance is positively correlated with bone mineral density in postmenopausal patients with type 2 diabetes mellitus – Scientific Reports

This study provides new findings on the relationship between METS-IR, and BMD and OP in postmenopausal patients with T2DM. The METS-IR in the OP group was significantly lower than in the non-OP group. After adjusting the confounding factors, each unit of increased METS-IR value was associated with increased lumbar vertebrae, femoral neck, and hip BMD 0.006 g/cm³, 0.005 g/cm³, and 0.005 g/cm³, respectively (all P < 0.05). When METS-IR < 44.5, each unit of increased METS-IR value was associated with a decreased OP risk of 12%; When METS-IR ≥ 44.5, there was no significant correlation between METS-IR and the risk of OP. In addition, METS-IR has a certain predictive value for the risk of OP in postmenopausal patients with T2DM. In summary, it is helpful to measure and calculate METS-IR as an objective index to evaluate the risk of OP in the diagnosis and treatment of postmenopausal patients with T2DM.

Early diagnosis and risk assessment of OP in postmenopausal patients with T2DM is essential. In recent years, with the improvement of people’s living standards and the change in living habits, the prevalence of OP in T2DM patients has increased yearly. Especially in postmenopausal women, due to the decrease of estrogen in the body, osteoclasts’ inhibition, bone resorption enhanced, and massive bone loss led to the prevalence of OP significantly increasing¹⁸. At present, the clinical diagnosis of OP is mainly through dual-energy X-ray absorptiometry. The risk of OP can be evaluated by bone turnover markers, HDL-C, and BMI. Dual-energy X-ray is relatively expensive, has radiation and can only reflect the static, and local BMD of the patient¹⁹. Moreover, it is easy to underestimate the fracture risk in T2DM patients simply considering BMD alone²⁰. Detecting bone turnover markers takes a long time, and many primary healthcare facilities lack relevant detection equipment. Using laboratory indexes such as HDL-C and BMI²¹ alone to predict the risk of OP has low sensitivity and specificity. Therefore, it is crucial to explore a more simple, economical, and accurate method to predict the risk of OP in postmenopausal T2DM.

IR is a state in which insulin is ineffective in peripheral tissues, leading to hyperinsulinemia and impaired lipid and glucose homeostasis. Among various methods for evaluating IR, the gold standard is the euglycemic–hyperinsulinemic clamp technique²², but this invasive method is unsuitable for the large-scale population. Some non-insulin indicators, such as TyG and METS-IR, combined with various serum biochemical indicators to evaluate IR, have attracted more and more attention. TyG is calculated from TG and FPG¹⁵, and METS-IR is calculated from HDL-C, TG, FPG, and BMI¹³. It is stated that these parameters are a non-insulin-based alternative to insulin-based methods to quantify peripheral insulin sensitivity. These indicators are easy to measure and calculate, so they are widely used in epidemiological studies and compared with traditional IR indicators. Cho et al.’s study²³ of 1145 middle-aged people in Korea found that individuals with a high TyG correlation index are likelier to experience coronary artery calcification. Compared with HOMA-IR, TyG correlation index can better predict the progression of coronary artery calcification. In a study of 4,986 Korean adults, Lee et al.²⁴ found that the TyG index has a better predictive power for NAFLD compared with HOMA-IR. A large cross-sectional study of 21,082 participants by Chen et al.²⁵ found that the increase in METS-IR index was associated with a higher incidence of asthma and an earlier age of first asthma in American adults. Han et al.²⁶ found a positive correlation between METS-IR and serum ferritin in a cross-sectional study of 4182 American women. This correlation was evident among participants ≥ 40 years old. Yoon et al.²⁷ found that METS-IR was highly correlated with metabolic syndrome and cardiac metabolic risk, and METS-IR had better predictive value for ischemic heart disease than metabolic syndrome. Similarly, many studies have confirmed the correlation between IR and BMD, but the results are inconsistent, and we have not found any research on METS-IR and BMD. A cross-sectional study of postmenopausal women in Tunisia by Cherif et al.²⁸ found that HOMA-IR was positively correlated with BMD of the left femur and total hip. Yoon et al.²⁹ found that the TyG index negatively correlated with femoral neck BMD in non-diabetic men and postmenopausal women over 50 in a cohort study of 4810 non-diabetic Koreans. Zhou et al.¹² found that the increase in HOMA-IR level was related to the increase of hip BMD in 7,170 American adults, but no causal relationship was found between IR and BMD in a Mendelian randomized study of European adults. In addition, numerous studies^30,31,32,33 have proved that the indexes used to calculate METS-IR are significantly correlated with BMD. Therefore, this study collected serological indicators of postmenopausal patients with T2DM and evaluated the correlation between METS-IR and OP for the first time. The results showed that there was a significant positive correlation between METS-IR and BMD, and METS-IR was the protective factor of OP in postmenopausal patients with T2DM. However, we found that TyG and HOMA-IR had no significant correlation with BMD and OP.

These contradictory results may be due to different study populations or different assessment methods of IR. Based on the population of this study (postmenopausal patients with T2DM) and the IR assessment method (METS-IR), we believe that the possible mechanism of METS-IR affecting BMD and OP is as follows. Firstly, IR promotes insulin secretion, and hyperinsulinemia leads to an increase in BMD. Insulin can promote osteoblast proliferation, inhibit osteoclast activity, and act as an anabolic agent in bones³⁴. In the state of IR, insulin secretion increases to compensate for the resistance of skeletal muscle, adipose tissue, and liver to insulin, which leads to hyperinsulinemia. Therefore, IR can promote insulin secretion and further increase bone mass. In addition, the synergistic effect of excessive insulin and other synthetic metabolic hormones (parathyroid hormone, insulin-like growth factor) can also lead to BMD increase^7,35. Secondly, IR may further affect bone metabolism by affecting inflammatory response and estrogen levels. Wang et al.³⁶ speculated that the relationship between IR and OP may not be linear and have a threshold effect. Our results confirm this view. In postmenopausal women with T2DM, when METS-IR < 44.5, the higher the IR, the lower the risk of OP. When METS-IR ≥ 44.5, the higher the IR, the greater the risk of OP. The reason may be that with the development of diabetes, the increase of pro-inflammatory cytokines and oxidative stress and the decrease of estrogen level has adverse effects on bone health, eliminating the protective effect of IR on the bone^37,38. Finally, previous studies on IR and BMD mostly used TyG and HOMA-IR as evaluation indicators^12,23,24. Our results showed that the BMD of lumbar vertebrae, femoral neck, and hip increased with the increasing TyG, HOMA-IR, and METS-IR in postmenopausal patients with T2DM. However, the association between TyG, HOMA-IR, and BMD lost significance after adjusting BMI. Napoli et al.³⁹ found similar results in a prospective study of 2398 non-diabetic elderly. We think that compared with METS-IR, TyG, and HOMA-IR ignore the effects of BMI and other lipid types on bone metabolism. METS-IR is more comprehensive in evaluating metabolic status and is recognized as an effective index for IR estimation in the Chinese population^40,41,42,43. Some chronic disease studies have also confirmed this view^13,27,44.

The main advantage of this study is that METS-IR is used for the first time to evaluate the correlation of BMD and OP risk in postmenopausal patients with T2DM, which opens a new direction for the study of the correlation between IR and OP. To a certain extent, it can provide a breakthrough point for expanding OP-related predictive biological indicators and the screening, prevention, and treatment of OP in primary healthcare facilities. Despite the efforts made in this study, there are still some limitations. Firstly, this was a single-center cross-sectional study in which the sample size was small and the METS-IR was not repeatedly evaluated. The effectiveness of METS-IR changes over time in predicting OP risk was not obtained in postmenopausal patients with T2DM. Secondly, the population of this study is Chinese postmenopausal T2DM patients, and there are geographical and ethnic restrictions. The study results cannot be applied to healthy people or other races. Finally, the use of hypoglycemic drugs in inpatients was not collected in this study, so we cannot rule out the bias of hypoglycemic drugs on our results by affecting lipid metabolism. Therefore, large-scale, multicenter, high-level evidence-based research is still needed to confirm the relationship between METS-IR and OP in different populations.