Review: Greater Focus on Targeting Insulin Resistance in Patients With CKD May Be Needed

Based on current evidence, several mechanisms can contribute to rises in insulin resistance in patients with chronic kidney disease (CKD), suggesting that providers may need to more prioritize insulin resistance as a target of treatment in the future, according to a literature review.

The review, published in Nutrients, summarized the importance and mechanism of insulin resistance in cardiovascular disease, which is a main cause of death among patients with type 2 diabetes and CKD, and discussed the published evidence regarding insulin resistance in patients with CKD.

Insulin resistance is a major cause of cardiovascular disease and is characterized by a balance between calorie intake and consumption. Although insulin resistance is affected by genetics, lifestyle factors including dietary habits and daily exercise can also impact insulin resistance through hypertrophy of fat cells, ultrafiltration of inflammatory cells into adipose tissue, and inappropriate secretion of adipokines. Patients with CKD have a higher insulin resistance status than those without the disease because the disease can lead to chronic inflammation, uremic toxins, and vitamin D deficiency.

Investigators believe that insulin resistance could be improved by CKD-mineral bone disorder (MBD), such as phosphate binder and vitamin D. Although the mechanism of insulin resistance has been uncovered in recent studies, the detailed mechanism of it are unknown and whether vitamin D can improve insulin resistance is still under investigation.

Insulin largely targets the liver, skeletal muscle, and fat cells. The main causes of insulin resistance in patients are obesity and overnutrition, which can throw adipocytokines, lipotoxicity, and chronic inflammation out of balance.

Reports have shown that resistance to insulin typically manifests in patients with stage 1 CKD. However, patients with stage 3 or 4 CKD have shown to have high values from the homeostasis model assessment of insulin resistance (HOMA-IR), and the primary determinant of insulin resistance was body mass index (BMI). Among those undergoing dialysis treatment, HOMA-IR was also high and was correlated with inflammatory markers.

The authors of the review listed some of the theories for kidney dysfunction and insulin resistance upregulation, including that uremic toxins may increase insulin resistance and that uremic toxins may induce reactive oxygen species production, which are known to cause insulin resistance.

Weight loss and pharmacological therapy are the 2 main approaches to treatment of insulin resistance. For those with severe obesity, classified as having a BMI of 35 kg/m2 or higher, they are recommended to reduce their weight by 5% to 10% with a calorie intake of 20 to 25 kcal or less per standard daily body weight and regular exercise. Thiazolidine improved insulin resistance by inhibiting receptors that regulate fatty cells. However, the drug should be used with caution because there are concerns about using it for fracture, bladder cancer, and fluid retention.

For patients with CKD-MBD, paricalcitol can decrease serum parathyroid hormone levels but there are no significant differences in insulin resistance between the drug and placebo. Additionally, interventional studies have shown that activated vitamin D analogs can improve insulin resistance.

The review has some limitations, including that clinical evidence of insulin resistance is lacking, and that little data exists on how insulin resistance impacts fracture and malignancy. The authors said that more well-designed studies are required to investigate the impact of insulin resistance and subsequent treatment in the CKD population is needed.

Reference

Makashima A, Kato K Ohkido I, Yokoo T. Role and treatment of insulin resistance in patients with chronic kidney disease: A review. Nutrients. 2021;13:4349. doi: 10.3390/nu13124349