Factors Affecting Insulin Resistance and Its Relation to Vitamin D Status and Clinical Nutritional Parameters in Dialysis Patients: A Single-center Indian Study

Introduction

Despite new advances in the treatment of chronic kidney disease (CKD), it remains an important public health challenge.[1] CKD is a major risk factor for cardiovascular disease, which is the leading cause of mortality in these patients. Cardiac mortality in dialysis patients is more than 10-fold greater than that of the general population.[2] The excess cardiovascular mortality in patients with CKD is not fully explained by traditional risk factors such as hypertension, hypercholesterolemia, and smoking. One of the factors which were neglected in earlier studies was insulin resistance (IR) in CKD. IR which is a central pathogenic mechanism in metabolic syndrome and recognized in CKD patients has been directly associated with increased cardiovascular mortality in many studies.[34]

IR can be physiologic (e.g., in pregnancy) or pathologic as in CKD and it is linked to protein energy wasting and malnutrition in dialysis patients.[56] Hyperinsulinemic-euglycemic clamp is the gold standard for IR determination because it provides a direct measure of whole-body sensitivity to insulin. Other is oral glucose tolerance test primarily measuring glucose tolerance, which reflects both IR and beta-cell function. However, due to the complexity of these methodologies, more practical methods such as homeostatic model assessment (HOMA) and the quantitative insulin sensitivity check index are widely used in clinical studies.[7]

The role of Vitamin D deficiency in several pathological conditions has been the focus of several investigations in the last few years.[8] The complexity of the biological role of Vitamin D metabolism makes it difficult to clearly delineate the role of Vitamin D cascade in this complex pathophysiology of IR. In CKD, Vitamin D status has been related to IR; however, very limited information is available on dialysis patients and factors affecting IR. We designed this study to assess the IR in dialysis patients and its relation with Vitamin D status.

Materials and Methods

Results

Characteristics of dialysis patients

A total of 55 diabetic and nondiabetic patients on dialysis were included in our study. Their demographic and laboratory profile are shown in Table 1. Forty-one (74.55%) patients were male. The mean age was 37.44 ± 14.96 years, height was 166.24 ± 8.66 cm, body weight was 52.81 ± 10.21 kg, LBW was 44.81 ± 7.81 kg, body fat percentage was 14.6 ± 8.80, body fat weight was 8 ± 6.15 kg, fat weight–to-LBW ratio was 0.18 ± 0.14, LBW index was 16.13 ± 2, and BMI was 19.06 ± 3.16. The cause of end-stage renal disease was chronic glomerulonephritis in 15 patients (27.27%), hypertension in seven patients (12.73%), diabetic nephropathy in seven patients (12.73%), polycystic kidney disease in two patients (3.64%), and unknown in 24 (43.64%). The estimated glomerular filtration rate by Cockcroft–Gault formula was 7.82 ± 3.04 ml/min/1.73 m².

Table 1 Baseline characteristics of the patients

As per SGA, all patients have some degree of malnutrition. Six patients had mild degree of malnutrition (10.9%), 46 patients had moderate degree of malnutrition (83.64%), and three patients had severe degree of malnutrition (5.46%). As per BMI, thirty patients were <19 kg/m² (54.55%), 23 patients were between 19 and 25 kg/m² (41.82%), and two were >25 kg/m² (3.64%). Of 55 patients, 42 were on HD (73.36%) and 13 patients were on PD (23.64%).

Relationship of insulin resistance with Vitamin D and other measured parameters

Age, hemoglobin level, serum albumin, and serum uric acid had positive correlation with IR; however, only uric acid level had significant association (r = 0.303, 95% confidence interval [CI] 0.021–0.534, P = 0.025) [Table 2]. Duration of dialysis, serum ALP, parathyroid hormone, and Vitamin D level had negative correlation; however, only Vitamin D level < 20 ngm/ml had significantly higher IR (3.743 ± 4.367) compared to those with Vitamin D level >20 ngm/ml (1.673 ± 1.473 (P = 0.018) as shown in Figure 1a.

Table 2 Association of homeostasis model assessment-insulin resistance index with different parameters

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Figure 1

Homeostatic model assessment-insulin resistance index (a) mean homeostatic model assessment-insulin resistance index was 3.743 ± 4.367 and 1.673 ± 1.473 in patients with Vitamin D level <20 ngm/ml and >20 ngm/ml, respectively (P = 0.018). (b) Insulin resistance was compared in peritoneal dialysis and hemodialysis. Mean homeostatic model assessment-insulin resistance index was 3.270 ± 2.486 and 3.101 ± 4.223 in peritoneal dialysis and hemodialysis, respectively (P = 0.277)

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Relationship between insulin resistance and nutrition parameters

Of all the measured nutritional parameters as detailed in Table 3, lean BMI (r = 0.375, 95% CI: 0.099–0.669, P = 0.005), MAC (r = 0.377, 95% CI: 0.115–0.586, P = 0.004), MAMC (r = 0.380 95% CI: 0.121–0.579, P = 0.004), and BMI (r = 0.451, 95% CI: 0.231–0.717, P = 0.001) had significant positive association with IR. Body fat percentage did not had strong correlation in our study; however, body fat weight had achieved significant association with IR (r = 0.275, 95% CI: 0.038–0.531, P = 0.041).

Table 3 Association of anthropometry and subjective global assessment with homeostasis model assessment-insulin resistance index

The mean HOMA-IR index in mild, moderate, and severe grade malnutrition by SGA was 2.54 ± 1.55, 3.27 ± 4.17, and 2.39 ± 2.05, respectively (P = 0.861). The IR between male and female was 3.12 ± 3.69 and 2.44 ± 2.55, respectively (P = 0.528). HOMA-IR index in HD and PD patients was 3.101 ± 4.223 (P = 0.277) [Figure 1b]. Diabetic patients who were on dialysis had IR similar with that of nondiabetic patients on dialysis in our study (2.774 ± 1.800 vs. 3.194 ± 4.087, P = 0.647).

Discussion

We studied dialysis patients and majority were male; however, the IR was not different in either gender in our study group (P = 0.528). The mean Vitamin D level was 15.91 ± 7.98 ng/ml and majority were Vitamin D deficient. In our study, the prevalence values of Vitamin D deficiency <10 ng/ml, <20 ng/ml, and <30 ng/ml levels were 23.64%, 70.91%, and 96.36%, respectively. Studies have reported 70%–80% prevalence of Vitamin D deficiency in CKD patients which worsens with deteriorating renal function.[1314] The mode of dialysis did not affect IR in dialysis patients in our study (P = 0.277). In an earlier study, both HD and PD had shown similar improvement in IR after initiation of dialysis.[15]

The Vitamin D and IR had nonsignificant negative correlation; however, in subgroup analysis, patients with Vitamin D level <20 ng/ml had significantly high IR compared to those with Vitamin D level >20 ng/ml [Figure 1a]. There is also experimental evidence that Vitamin D is related to IR, a condition frequently observed in patients with progressive renal disease.[16] Earlier study by Chonchol and Scragg also support our finding and had shown that renal dysfunction and Vitamin D have independent inverse associations with IR.[17]

Another important association of IR is with serum uric acid level which has been considered as a potential risk factor in the development and progression of CKD.[18] IR has significant positive correlation with serum uric acid (r = 0.303 95% CI: 0.021–0.534, P = 0.025). This is not new in metabolic syndrome patients. However, in our study, this association reflects significance of uric acid in dialysis patients also.

One of the most important predictive factors for survival on dialysis is the presence of malnutrition.[1920] Moreover, most of the patients in our study were malnourished. The mean BMI was 19.055 ± 3.161 kg/m² and more than 50% patientshave BMI <19 kg/m². As measured by SGA, around 80% patients had moderate grade malnutrition. Out of the measured parameters, BMI, MAC, MAMC, and body fat content had significant positive correlation with IR [Figure 2 and Table 2]. This means that muscle mass and body fat have significant associations with IR in dialysis patients. Other studies also have reported significant positive correlation of BMI and body fat with IR.[2122]

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Figure 2

Insulin resistance and nutrition (a) homeostatic model assessment-insulin resistance index increases as body mass index increases (P < 0.001). (b) Insulin resistance (homeostatic model assessment-insulin resistance) increases with increase in mid-arm muscle circumference (P = 0.004)

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Although the exact mechanism for IR in CKD remains unclear, a postreceptor defect in the insulin-receptor signaling pathway in skeletal muscle is the likely primary abnormality.[23] Siew et al. have highlighted that IR is an important determinant of protein breakdown in CKD.[24] It appears that in CKD patients requiring dialysis, skeletal muscle is the primary tissue which is responsible for IR. In our study, IR increases with skeletal muscle mass; however, in sarcopenic patients, other factors such as metabolic acidosis, inflammation, and oxidative stress might be the main contributors of IR.

There are many limiting factors in our study. First, inflammatory state of the patient which is an important mechanism of IR in CKD has not mean measured and needs a well-controlled study. Second, visceral fat which has been reported in some studies to be related with IR has not been measured in our study. Third, dual-energy X-ray absorptiometry or bioimpedance was not used in our study. Finally, IR was quantified using the surrogate index of HOMA, and these findings need to be confirmed using euglycemic clamp technique.

Conclusion

Serum uric acid and Vitamin D level <20 ng/ml significantly influence the insulin sensitivity in dialysis patients. Anthropometric measures which indicate body muscle mass are more strongly correlated with IR in dialysis patients. It appears that the milieu in CKD is different, where IR is less likely depended on underlying causes and mode of dialysis. However, IR is a potentially modifiable cardiovascular risk factor and more studies are required in the future regarding intervention for preventing IR and its effect on cardiovascular morbidity.