Comparison of the Effects of Uremia and Metabolic Disorders on the Development of Insulin Resistance

Objective: The aim of the present study was to show the important effectof a uremic environmenton the development of insulin resistance and if insulin resistance might be reversible with the treatment of metabolic disordersin patients with hypothyroid. Materials and Methods: Patients with stage 2, stage 3, and stage 4 chronic renal disease and dialysis treatment and patients with hypothyroid with normal renal function and thyroxine replacement treatment were included in the study. Patients with some metabolic disorders, such as obesity, dyslipidemia, anemia, and severe vitamin Ddeficiency, were excluded from the study. Insulin, fasting blood glucose, and thyroid function levels were measured. Homeostatic model assessments of insulin resistance (HOMA-IR) values were calculated. Results: The mean age, body mass index, and distribution of gender were found to be similar in the patient groups. No statistical significance was found in HOMA-IR values between the patient groups. The important effects of chronic kidney disease and hemodialysis replacement treatment were determined to the development of insulin resistance. Conclusion: A uremic environment might be affected by the development of insulin resistance as in the development of metabolic disorders, such asthyroid dysfunction and glucose and lipid metabolism disorders. Understanding of the molecular mechanism and effects of uremic toxins can contribute to the development of new treatment targets.


INTRODUCTION
Insulin resistance is an important and common health problem.Insulin resistance and hyperinsulinemia can cause the development of type 2 diabetes mellitus and coronary heartdiseases.Additionally, metabolic defects and metabolic disorders might contribute to thedevelopment of insulin resistance (1).
It is known that the presence of insulin resistance can cause endothelial dysfunction, arteriole changes, and inflammation (2).Therefore, insulin resistance can contribute to the increase risk of atherosclerosis and coronary heart disease.The existence of insulin resistance can be provenby a decrease ofinsulin sensitivity of the tissues.Insulin resistance accompanies many diseases, such as obesity, metabolic syndrome, chronic kidney disease, and thyroid dysfunction (3,4).Currently, the pathogenesis of insulin resistance is unclear for some diseases.Forexample, insulin resistance might be detected in people with normal weight and without metabolic disorders, and this condition has been explained by greater storedbody fat, but it is unclear (5).
It is known that insulin resistance increases inevery stage of chronic kidney diseaseand dialysis replacement treatments (6).The existence of insulin resistance is associated with in flammatory response, oxidative stress, metabolic acidosis, anemia, malnutrition, excess angio-Cite this article as: Akalın N, Uran MA, Uçar M, Özkan H, Kıraç Utku İ.Comparison of theEffects of Uremia and Metabolic Disorders on the Development of Insulin Resistance.Turk J Nephrol 2019; 28(1): 12-6 tensin II, and disorders of vitamin D metabolismin chronic kidney diseases (7).However, it is shown that physical inactivity and dietaryand genetic factors might play an important role to the development of insulin resistancein patients with chronic kidney disease (4).Additionally, lowlevels of Akt phosphorylation are determined in the presence of insulin resistance, and it is shown that this condition might lead to the development of insulin-related metabolicdefects, such as disorders of metabolism of glucose, lipids, and muscle proteins (8).
Currently, it is shown that thyroid dysfunctions are associated with insulin resistance, dyslipidemia, metabolic syndrome, and ischemic heart diseases (9).However, metabolic disorders might be reversible with suitable treatment (10).The ratio of insulin resistance is controversial in patients with hypothyroid and hyperthyroid.However, it is suggested that thyroid dysfunctions can cause the development of disorders of glucose tolerance or fasting glucose and insulin resistance (11).
We aimed to show the effects of uremic environment and uremic toxins on the development of insulin resistance.In addition, we tried to show the importance of metabolic control on the development of insulin resistance, and insulin resistance might be reversible with proper treatment.Therefore, we compared the ratio of insulin resistance inpatients with chronic renal disease and hypothyroid because they were patients with high risk for the development of insulin resistance.

MATERIALS AND METHODS
The present study was performed in the Nephrology and Internal Medicine Clinic of Bakirkoy Training and Research Hospital.The study was approved by the ethics committee of Bakirkoy Dr. Sadi Konuk Training and Research Hospital (grant no: 758).Informed consent was obtained from all patients.
Thirty patients with chronic renal disease, 42 patients with hemodialysis treatment and patients with hypothyroid with thyroxine replacement treatment were included in the prospec-tive study.Decline in glomerular filtration rate was defined as chronic renal disease,and glomerular filtration category of 60-89 mL/min/1.73m 2 was classified as stage 2, 30-59 mL/ min/1.73m 2 as stage 3, and 15-29 mL/min/1.73m 2 as stage 4 chronic renal diseases (12).Gender, age, weight, and height of allpatients were recorded.The mean age, body mass index (BMI), and distribution of gender were calculated.Patient history was collected for the study.Patients with diabetes mellitus,obesity (BMI>29.90-kg/m 2 ), metabolic syndrome (hypertriglyceridemia associated with abdominal obesity,decreased serum high-density lipoprotein cholesterol, high blood pressure, and high fastingglucose levels), severe anemia, nutrition disorders (vomiting, nausea, and weightloss), uncontrolled secondary hyperparathyroidism (parathyroid hormone levels >150pg/mL), and thyroid dysfunction,such as subclinical hypothyroid, hypothyroid, and hyperthyroid,were excluded from the study.Patients with collagen tissue disease, such as rheumatoid arthritis and psoriatic arthritis, or drug treatments, such as carbamazepine, valproic acid, coumadin, lithium, and cortisone, were also excluded from the study.
The mean urine output was measured <50-100 cc/day in all patients with hemodialysisreplacement treatment, and urine output was not evaluated.Dialysis adequacy was provided for patients with dialysis replacement treatment.Kt/V ≥1.40 and urea reduction ratio≥70.00%were considered as dialysis adequacy.Glomerular filtration rates of patients with chronic kidney disease were calculated by the Modification of Diet in Renal Diseaseformula as glomerular filtration rate = 186×serum creatinine -1.154 ×Age -0.203 ×Gender×Race.BMIwas evaluated for all patients.BMI valueswere calculated using the formula: BMI=body weight (kg)/height (m 2 ).
Venous blood samples were collected and were transferred to the laboratoryprovided with suitable conditions.Thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), and free thyroxine (free T4) levels were measured, and the existenceof thyroid dysfunction was evaluated.Insulin and blood glucose Significance was evaluated at the levels of p<0.01 and p<0.05.

RESULTS
Patients were divided into three groups as patients with hemodialysis replacementtreatment, chronic renal disease, and hypothyroid with thyroxinereplacement treatment.Demographic features of patients with chronic renal disease andhypothyroid disease and dialysis treatment are shown Table 1.
Each of the stages of chronic renal diseaseswas evaluated for patients with chronic renal disease, and 6.66% (n=2), 13.33% (n=4), and 80.01% (n=24) of patients with chronic renal disease were detectedat stage 2, stage 3, and stage 4 chronic renaldiseases, respectively.Distributions of gender were evaluated forthe hemodialysis and hypothyroid patient groups, and 25 (59.52%)male and 17 (40.48%)female patients were determinedin thehemodialysis patient group, where as 25 (62.50%)male and 15 (37.50%) female patientswere determinedin the hypothyroid patient group.A statistically significant difference was found in thedistribution of gender, but the ratio of male patients was found to be higher than that offemale patients-  between the patient groups (p=0.002)(Table 1).No statistically significant difference was determined in the mean ages and BMIs between the patient groups (p=0.520 and p=0.723, respectively) (Table 1).
No statistically significant difference was found in the mean fasting blood glucose and insulin levels and HOMA-IR values (p=0.104,p=0.252, and p=0.190, respectively) (Table 2).
The effects of parameters (age, gender, BMI, fasting blood glucose, and insulin) were evaluated to the development of insulin resistance, and no statistically significant difference was determined (p=0.193,p=0.062, p=0.258, and p=0.208, respectively) (Table 4).A statistically significant difference was found between the effects of insulin levels on the development of insulin resistance (p=0.001)(Table 4).
The effects of the disease groups were determined to the development of insulinresistance (dialysis patient group: p=0.001, chronic renal disease group: p=0.047, and hypothyroid patient group: p=0.006) (Table 5).

DISCUSSION
Insulin resistance indicates endogenous insulin secretion disorders.It affects endothelial vasodilatation and leads to endothelial dysfunction, arteriole changes, and initiation inflammation (13).The risk of insulin resistance increases inthyroid dysfunction and every stage of chronic renal diseases.
Hypothyroidism is detected in the ratio of 1.00%-10.00%forthe adult population (14).It is associated with glucose and insulin metabolism disorders.It can cause a defect in insulin secretion in response to glucose and alterations in peripheral glucose metabolism, there by leading to the development of insulin resistance (15).Currently, it is known that thyroid replacement treatments can restore insulin-mediated glucose uptake; therefore, glucose and insulin metabolism disorders might be corrected (17,18).
Uremia causes postreceptor insulin-signaling defectsin chronic kidney diseases andhemodialysis treatments.Additionally, metabolic disorders, such as metabolic acidosis, vitamin D deficiency, anemia, accumulation of nitrogenous compounds, and adipokine, contribute to the impairment of various insulin-signaling molecules in chronic kidney diseases.For example, it appears that the activity of phosphatidylinositol 3-kinase is reducedin the presence of insulin resistance (19).
We compared insulin resistance ratio and effects of chronic renal disease, dialysis treatment, and thyroid dysfunction on the development of insulin resistance.No statistically significant dif-ference was determined in insulin resistance ratio between the disease groups.However, a more important relationship was found between insulin resistance with hemodialysis treatment.This condition might be explained by influences of uremia in patients with hemodialysis treatment.It is known that uremia and uremic toxins are removed with dialysis treatments.Nevertheless, patients with hemodialysis treatment are exposed to uremic toxins because hemodialysis treatments are usually used 3 days/week.Thyroid dysfunctions affect glucose and insulin metabolism, but results of many studies suggested that glucose metabolism disorders, hyperinsulinism, and insulin resistance can be corrected with thyroid dysfunction treatments (19,20).Patients with hypothyroid were treated regularly in our study.We thought that thyroxine replacement treatment might contribute to the correction of glucose and insulin metabolism defects, and there by, insulin resistance ratio might be reduced.However, the effects of BMI and distributions of gender and age were not determined to the development of insulin resistance, but a significant relationship was found between insulin levels with insulin resistance ratio.Many studies have shown that metabolic disorders, such as obesity, anemia, vitamin D deficiency, and lifestyle (e.g., sedentary lifestyle), body fat storage, race, and genetic factors might have an effect on the development of insulin resistance.Patients in our study had a normal weight, but it is known that insulin resistance can appear in patients with normal weight (20,21).Therefore, wethought that our results might be affected by the features of the patient groups, such as body fat storage ratio, and the drug treatments.Since they were metabolically controlled, they had no severe anemia, vitamin D deficiency, dyslipidemia, and thyroid dysfunction.
Our results suggested that the presence of the relationship between insulin resistance with thyroid dysfunction and different stages of chronic renal diseases and insulin resistance might be corrected with treatment of metabolic disorders.
In summary, we have shown that the existence of insulin resistance in different stages of chronic renal diseases and thyroid dysfunction and ratio of insulin resistance might be reduced with suitable treatment of metabolic disorders.In addition, the more important effects of hemodialysis treatment were detected in insulin resistance ratio, and we thought that this condition might be explained by influences of uremic environment and uremic toxins.
Currently, the pathogenesis of insulin resistance is unclear for many diseases.Understanding of the pathogenesis of insulin resistance andthe effects of the molecular actions of uremic toxins might contribute to the development of new treatments and new treatment targets.

Study Limitations
Insulin resistance is especially associated with metabolic disorders and metabolic defects, and it accompanies many diseases.However, the molecular mechanism and pathogenesis of insulin resistance are unclear.
We tried to show the importance of uremic toxins and uremic environment on the development of insulin resistance, andthe effects of the different disease groups were compared with insulin resistance ratio.All patients in our study were regularly treated.However, the more important effects of hemodialysis treatment were detected to insulin resistance ratio.This condition might be explained by influences of uremic environment and uremic toxins.However, measurementsof uremic toxins, such as the accumulation of nitrogenous compounds, were not made, and the relationship between insulin resistance with uremic toxins and the effects of drug treatment were not investigatedin our study.We thought that this condition can be a limitation to the results of our study.

CONCLUSION
Insulin resistance is an important health problem because it leads to the development ofchronic inflammation, atherosclerosis, and coronary heart diseases, and thereby, it can increase morbidity and mortality risks.We think that understanding of the pathogenesis of insulin resistance and the effects of uremic environment canbe contribute to the development of new treatments and decrease morbidity and mortality risks.

Table 1 .
Turk J Nephrol 2019; 28(1): 12-6 Akalın et al.Effects of Uremia on Insulin Resistance 13 Demographic features of thepatient groups *p<0.01.BMI: body mass index levels were measured after fasting for 12 hin all patients, and homeostatic model assessment of insulin resistance (HOMA-IR) values were calculated.HOMA-IR index was calculated as HOMA-IR=fasting blood glucose (mg/dL)×fasting insulin level (mU/mL)/405.HOMA-IR val-ues>2.50wereacceptedas thepresence of insulin resistance.Statistical AnalysisThe Number Cruncher Statistical System 2007&PASS (Power Analysis and Sample Size) 2008 statistical software (UT, USA) program was used for statistical analysis.Student's t-test was used for group comparisons of parameters with normal distribution, and Mann-Whitney U test was used for group comparisons of parameters without normal distribution.Mann-Whitney U test was used to determine the group causing the difference.Pearson's chi-square test was used for comparison of qualitative data.Linear regression analysis was usedin multivariate evaluations of affected parameters on HOMA-IR and insulin values.

Table 2 .
Comparison of insulin resistance in the patient groups

Table 3 .
Evaluation of HOMA-IR in the patient groups

Table 4 .
Evaluation of the effect of parameters on HOMA-IR values *p<0.01.