We found that CMI, a novel metabolic index that expresses both dyslipidemias and accurately reflects central obesity status, was significantly and independently associated with the risk of developing microalbuminuria in Chinese patients with type 2 diabetes. The findings reveal the potential of CMI as a screening marker for microalbuminuria in patients with T2DM, demonstrating that CMI is a crucial independent determinant of early diabetic nephropathy and has important implications for exploring potential areas of research targeting CMI in the future, especially for delaying the progression of diabetic nephropathy and reducing the risk of developing end-stage renal disease. Patients with T2DM are often associated with dyslipidemia and central obesity. Previous studies have shown that individuals with abnormal lipid metabolism and obesity have worse metabolic profiles and poorer renal outcomes . In patients with early-stage chronic kidney disease, dyslipidemia is mainly characterized by atherogenic dyslipidemia: high TG levels, low HDL-C levels, and increased concentrations of small, dense, low-density lipoprotein (sdLDL) particles . Cao et al.  showed that high TG levels are an essential risk factor for kidney damage, and the adjusted risk of any renal event associated with increased TG levels remains high. sd-LDL is a vital lipid indicator in diabetic dyslipidemia , and TG/HDL-C is thought to reflect the level of "sd-LDL" particles. Because of the combination of TG and HDL-C levels, TG/HDL-C is valuable in differentiating microalbuminuria. Wen et al.  found that elevated TG/HDL-C was significantly associated with microalbuminuria excretion in Chinese patients with type 2 diabetes. A study of Japanese diabetic patients showed a significant decrease in LDL particle size and a considerable increase in the TG/HDL-C ratio in patients with nephropathy than subjects without nephropathy . As our hypothesis in general, TG/HDL-C performed better in predicting proteinuria/chronic kidney disease compared to non-HDL-C/HDL-C, TG, and HDL-C .
Obesity is considered to be an essential risk factor for the development of renal damage in T2DM. Data from the Framingham Heart Study, which included more than 2600 patients without chronic kidney disease at baseline, showed that obese patients were at increased risk of developing stage 3 chronic kidney disease ((BMI ≧ 30 kg/m2)) compared to non-obese subjects . Several independent studies have shown that anthropometric measures representing central obesity are superior to general obesity indicators in predicting the development of microalbuminuria in T2DM [22-25]. As tools for detecting central obesity, BMI and WC have a clear relationship with the excretion of microalbuminuria. Still, neither can distinguish between SAT and VAT, especially for Asians, as they are not suitable for diagnosing early diabetic nephropathy because Asians are more prone to visceral fat accumulation and insulin resistance [26, 27]. KB et al. found that
individuals with chronic kidney disease had higher WC and WHtR; however, only WHtR showed a relationship with reduced eGFR and albuminuria excretion, possibly due to different criteria for WC values in individuals of different heights. WHtR corrects WC for height and better reflects abdominal obesity in people of other races, ages, and genders [28-30].
Cardiometabolic index (CMI) is a new index calculated from TG/HDL-C and WHtR, which was proposed by Ichiro Wakabayashi in 2015 . It can better reflect the status of diabetes mellitus and the progression of atherosclerosis [31-32]. As a new indicator of visceral adipose tissue distribution and dysfunction, CMI has been closely associated with various diseases since its introduction [33-35]. In T2DM, considering that insulin resistance, inflammatory response, and abnormal lipid metabolism are inextricably linked to microalbuminuria production, we speculate that CMI is associated with microalbuminuria excretion and may serve as a novel screening index for early diabetic nephropathy. This paper is the first to explore the predictive value of CMI and other lipid and obesity indicators for the development of microalbuminuria in diabetic patients in a Chinese type 2 diabetic population.
We included CMI and LAP as categorical variables in our analysis and found that both had a more significant effect on early kidney damage in women compared to men, but the impact of LAP appeared to be more powerful. After excluding the impact of confounding factors, the risk of developing microalbuminuria in men with T2DM increased significantly with increasing quartiles of CMI, independent of LAP. In a cross-sectional study of 5398 healthy Koreans over 20 years of age, in general, the urinary albumin/creatinine ratio increased with increasing CMI levels, and that CMI was associated with increased glucose and urinary albumin/creatinine ratio increased were independently correlated . Wang et al. also concluded that CMI reflects the visceral fat area and the pathological process leading to impaired renal function and can be used as a screening marker for CKD . Our study confirmed that the risk of developing microalbuminuria increased proportionally with changes in CMI quartiles, and CMI showed a strong correlation with microalbuminuria excretion in T2DM. Although the ORs for the risk of developing CMI were weaker than LAP, considering that LAP does not include HDL-C, an essential indicator of dyslipidemia, in its calculations for analysis, and that people of different heights should have other WC criteria, it neglects the role of height. It, therefore, has limited value as a test indicator for combined microalbuminuria in patients with T2DM .
To distinguish the predictive value of CMI from lipid and obesity indicators as screening markers for diabetic microalbuminuria, we analyzed T2DM patients of both sexes separately using ROC curves. We found that CMI had the most significant AUC value in female patients. Although its discriminatory power was not significantly greater than LAP, it had a more comprehensive diagnostic significance considering that CMI covered both HDL-C and height-specific indicators. Surprisingly, CMI and LAP showed better predictive effects in women, but both TG/HDL-C and WHtR had larger AUC values than WC. This cause may be related to the smaller number of our subjects. Similarly, the AUC value of CMI was still the largest in male patients; however, the sensitivity of CMI was only 68%, and the specificity was even lower at 54.00%. Compared to men, CMI is much more sensitive than LAP in women, so CMI values are more valuable for diagnosing microalbumin excretion in women with T2DM. In conclusion, CMI has a robust discriminatory ability and high sensitivity and can be an economic screening index for screening people with T2DM combined with microalbuminuria.
Our study found that CMI and LAP are of clinical value as new metabolic indicators in assessing the risk of developing microalbuminuria in type 2 diabetes and differ by gender. The deleterious effect of CMI on early diabetic nephropathy was more significant in women compared to men. Our findings are consistent with previous clinical studies in which abnormal lipid metabolism and central obesity triggered microalbuminuria excretion, particularly in female patients with T2DM. A study based on the Korean National Health and Nutrition Examination Survey found that obese female patients were more likely to develop microalbuminuria and that impaired fasting glucose and high triglycerides were significant correlates of microalbuminuria . The interaction of increased glucose exposure with abnormal lipid metabolism associated with central obesity may be one of the leading causes of vascular endothelial dysfunction and microalbuminuria excretion in a 5398 Korean general population . Based on a retrospective observational study of renal injury in elderly participants in a Chinese community, researchers hypothesized that female patients with high TG and high WC levels were significantly associated with microalbuminuria excretion. In conjunction with our findings, we showed that the statistical effect of visceral fat distribution on microalbuminuria excretion in female T2DM patients manifested itself as a significant effect of CMI and LAP. The reason for this outcome may be the dysregulation of macrophage and adipocyte secretion in patients with T2DM, which produces a variety of hormones and pro-inflammatory factors, leading to a low inflammatory response, insulin resistance, dyslipidemia, and/or increased synthesis of vasoactive and fibrogenic substances [42-46]. Their complex interactions may negatively affect the vascular endothelium and impair renal function, thus causing the production of microalbuminuria. In addition, considering that most of the female patients we included were postmenopausal women with decreased sex hormones, the beneficial effects of estrogen on the kidney were inevitably lost. Estrogen is thought to reduce proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis [47-49]. Possible mechanisms are: (i) in diabetic patients, (estradiol) E2 attenuates glomerulosclerosis and tubulointerstitial fibrosis by reducing type I and type IV collagen synthesis, increasing matrix metalloproteinase expression, and inhibiting apoptosis [50-52]; (ii) E2 reduces the angiotensin type II1 receptor expression, transforming growth factor-β and endothelin-1 and regulating vascular dysfunction; (iii) E2 has also been shown to upregulate nitric oxide synthase activity and vascular endothelial growth factor expression in glomeruli and improve vascular permeability, thereby potentially reducing the loss of glomerular function in progressive chronic kidney disease, including diabetic nephropathy [53-56].
This study still has some limitations: (1) This study is a cross-sectional study, and this study can only provide evidence about the strong correlation between CMI and LAP and microalbuminuria. Still, it cannot further elucidate the causal relationship between CMI, LAP, and microalbuminuria in patients with T2DM, which needs to be further verified by a large follow-up study. (2) The sample size was small and limited by the region, and data we only collected from some patients in southwest China with a single ethnicity, so more studies are needed to investigate whether the findings apply to different regions or ethnic groups. (3) There are too many confounding factors affecting microalbuminuria excretion, and the effects of confounding factors were not eliminated when conducting the analysis, which may produce some data bias.