Insulin Resistance In Chronic Kidney Disease Research Articles

Insulin Resistance and Insulin Handling in Chronic Kidney Disease.

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of IR in patients with CKD, and recent type 2 diabetic trials with implications for improved cardiovascular outcomes in CKD. © 2023 American Physiological Society. Compr Physiol 13:5069-5076, 2023.

Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease.

Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.

Role and Treatment of Insulin Resistance in Patients with Chronic Kidney Disease: A Review

Patients with chronic kidney disease (CKD) and dialysis have higher mortality than those without, and cardiovascular disease (CVD) is the main cause of death. As CVD is caused by several mechanisms, insulin resistance plays an important role in CVD. This review summarizes the importance and mechanism of insulin resistance in CKD and discusses the current evidence regarding insulin resistance in patients with CKD and dialysis. Insulin resistance has been reported to influence endothelial dysfunction, plaque formation, hypertension, and dyslipidemia. A recent study also reported an association between insulin resistance and cognitive dysfunction, non-alcoholic fatty liver disease, polycystic ovary syndrome, and malignancy. Insulin resistance increases as renal function decrease in patients with CKD and dialysis. Several mechanisms increase insulin resistance in patients with CKD, such as chronic inflammation, oxidative stress, obesity, and mineral bone disorder. There is the possibility that insulin resistance is the potential future target of treatment in patients with CKD.

Insulin Resistance in Chronic Kidney Disease: Is There a Distinct Role of Vitamin D?

Background: Chronic kidney disease (CKD) is associated with significant morbidity and mortality. Many factors including inflammation, oxidative stress, and vitamin D deficiency contribute to insulin resistance (IR). Vitamin D requires attention because of the kidney’s involvement in vitamin D metabolism, the high prevalence of vitamin D deficiency in CKD, and the effect of vitamin D that may cover multiple factors contributing to IR in CKD, as inflammation. Aim: To Identify the role of vitamin D deficiency in diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients. Patients and Methods: The study was performed as a cross-sectional study including 84 patients with T2DM admitted in Suez Canal University Hospitals. Results: In diabetics with normal kidney function 64.3% of patients had sufficient level of vitamin D, while 14.3% of patients had vitamin D deficiency. In diabetics with late nephropathy 46.4% of patients had vitamin D deficiency with significant relationship between the progress of DN and vitamin D level (p value ≤ 0.05). Conclusion:vitamin D deficiency is strongly associated with DN.

Peripheral Insulin Resistance Is Associated with Copeptin in Patients with Chronic Kidney Disease.

Insulin resistance is associated with cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels) have been associated with an increased incidence and progression of CKD, and with incident diabetes mellitus. The purpose of our study was to examine the relationship between insulin resistance, copeptin, and CKD. We performed a cross-sectional study to investigate if insulin resistance was associated with higher copeptin levels in nondiabetic patients with stage 3-4 CKD versus controls. We measured plasma copeptin levels and used data from 52 patients with stage 3-4 CKD and 85 controls (eGFR ≥60 ml/min per 1.73 m2) enrolled in the Insulin Resistance in Chronic Kidney Disease (IRCKD) study. We then used a multivariable linear-regression model to assess the independent relationship between peripheral or hepatic insulin resistance and copeptin across levels of eGFR. We found that in patients with CKD (eGFR of 30-60 ml/min per 1.73 m2), but not in controls, peripheral insulin resistance was significantly correlated with higher levels of log copeptin (r=-0.21, P=0.04). In patients with CKD, when adjusted for age, sex, BMI, serum osmolality, log IL6, and log leptin/adiponectin ratio, each 1 SD decrease in insulin sensitivity was associated with a 39% increase in serum copeptin levels. The relationship between hepatic insulin resistance, copeptin, and eGFR is similar between controls and patients with reduced eGFR. Peripheral insulin resistance is associated with elevated copeptin levels in nondiabetic patients with stage 3-4 CKD. Further research into how the interaction between peripheral insulin resistance and elevated vasopressin affects CKD progression could be of interest.

New insights into muscle function in chronic kidney disease and metabolic acidosis.

: Sarcopenia, defined as decreased muscle mass or function, is prevalent in chronic kidney disease (CKD) increasing the risk of mobility impairment and frailty. CKD leads to metabolic acidosis (MA) and retention of uremic toxins contributing to insulin resistance and impaired muscle mitochondrial energetics. Here we focus on the central role of muscle mitochondrial metabolism in muscle function. : Mitochondrial dysfunction underlies muscle wasting and poor physical endurance in CKD. Uremic toxins accumulate in muscle disrupting mitochondrial respiration and enzymes. Changes in mitochondrial quantity, quality, and oxidative capacity contribute to mobility impairment in CKD. Major determinants of muscle mitochondrial function are kidney function, inflammation, and oxidative stress. In CKD, MA is the major determinant of muscle mitochondrial function. Metabolomics reveals defects in pathways linked to mitochondrial energy metabolism and acid-base homeostasis underlying insulin resistance in CKD. : Decreased mitochondrial capacity and quality control can impair muscle function contributing to decreased physical endurance. MA augments insulin resistance perpetuating the catabolic state underlying muscle wasting in CKD. Further studies are needed to investigate if targeting of MA improves muscle mitochondrial function and insulin resistance translating into meaningful improvements in physical endurance.

Association of FGF19, FGF21 and FGF23 with carbohydrate metabolism parameters and insulin resistance in patients with chronic kidney disease.

Insulin resistance (IR) is characterised by increased gluconeogenesis in the liver and the resistance of peripheral receptors to insulin. Several factors, including IR, type 2 diabetes, new-onset diabetes after transplant (NODAT) and secondary parathyroidism, are related to chronic kidney disease (CKD). These factors are associated with higher mortality due to the increased risk of cardiovascular complications. Many factors have been identified as potential markers of IR in CKD. These factors include fibroblast growth factors (FGFs), a subfamily of endocrine polypeptides. In this study, we examined the association of FGF19, FGF21 and FGF23 with selected parameters related to carbohydrate metabolism and insulin resistance in non diabetic patients with predialysis CKD and in non diabetic patients after renal transplantation. The study included 108 non diabetic subjects: 40 patients with predialysis CKD, 45 patients with CKD who had undergone renal transplantation, and 23 healthy subjects (control group). In patients who had undergone renal transplantation, concentrations of FGF23 were increased compared to the control group and patients with predialysis CKD. The highest and lowest FGF19 concentrations were observed in CKD patients and in patients who had undergone kidney transplantation, respectively. This difference was statistically significant. Leptin concentrations were higher in CKD patients compared to the control group and patients who had undergone kidney transplantation. There were no statistically significant differences in adiponectin concentrations, lean body mass or fat tissue mass between the studied groups. HOMA-IR and insulin levels were significantly increased in CKD patients and in patients who had undergone renal transplantation in comparison to the control group. The results of the study suggest the involvement of FGF in carbohydrate metabolism and insulin resistance in patients with predialysis CKD, as well as a correlation with kidney function.

Gut Microbiota In Chronic Kidney Disease

Abstract In health, the relationship between gut microflora and the host is of a mutualistic kind. Microbiota offers many benefits to the host, including harvesting energy, regulating host immunity, and the synthesis of vitamins. Alteration in gut microflora can lead to homeostasis disruption and development of various diseases. Dysbiosis is commonly observed in chronic kidney disease (CKD). Nutrient processing by gut microbiota results in the production of some uremic toxins, and these accumulate in CKD causing deleterious effects. Increased permeability of the intestinal barrier, which is also seen in CKD contributes to the development of the uremic state. These factors are associated with chronic inflammation and oxidative stress and therefore are involved in CKD-related complications, including disease progression, cardiovascular disease, anemia, mineral-metabolism, and insulin resistance. This review describes connections between altered gut microflora and development of CKD and its complications, as well as possible therapeutic options. 1. Microbiota – short characteristic. 2. Mechanisms leading to alterations in gut microbiota and their effects on intestinal barrier permeability. 3. Causes of chronic kidney disease progression related to gut microbiota alterations. 4. Complications of chronic kidney disease related to gut microbiota alterations. 4.1. Cardiovascular disease. 4.2. Anemia. 4.3. Bone metabolism disorders. 4.4. Insulin resistance in CKD. 5. Therapeutic options. 6. Summary

Chronic kidney disease attenuates the plasma metabolome response to insulin

Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.

Chronic Kidney Disease-Induced Insulin Resistance: Current State of the Field

Insulin resistance is an early complication of chronic kidney disease (CKD) associated with worsening cardiovascular outcomes. This review will evaluate mechanisms responsible for CKD-induced insulin resistance and therapies currently available. Recent mechanisms have been identified including SIRPα and specific E3 ubiquitin ligases causing insulin resistance in CKD. The hallmark finding in these mechanisms is degradation of the insulin receptor substrate 1 (IRS1) which impairs intracellular insulin signaling and ultimately metabolism. The mechanisms responsible for insulin resistance in CKD include inflammation, oxidative stress, elevations in aldosterone, angiotensin II, uremic toxins, and metabolic acidosis. Potential treatments currently available for CKD-induced insulin resistance include lifestyle modification and metformin. Potential future treatments may include glucagon-like peptide agonists, SGLT2 inhibitors, and thiazolidinediones. Investigations into molecular mechanisms responsible for insulin resistance in CKD may provide new therapeutic targets while current therapies may prevent the catabolic sequelae of CKD and ameliorate its cardiovascular consequences.

Fibroblast growth factor-23 is a strong predictor of insulin resistance among chronic kidney disease patients

Insulin resistance (IR) is very common among chronic kidney disease (CKD) patients. Disturbance in mineral and bone metabolism (MBD) seems to play a role in the pathogenesis of insulin resistance. Fibroblast growth factor-23 (FGF23) is evolving as the most important link between MBD and many pathologic sequences of CKD. The aim was to evaluate IR in pre-dialysis CKD patients looking for a possible association to mineral metabolism among CKD patients. A total of 100 stage 3–5 CKD patients were selected beside 20 normal control subjects. Homeostatic model assessment of insulin resistance (HOMA-IR) was used to assess IR in selected cases. Both groups were compared for fasting blood glucose (FBG), fasting blood insulin (FBI), HOMA-IR, estimated glomerular filtration rate (eGFR), serum calcium (Ca), phosphorus (P), 25 hydroxy vitamin D (25 OH vit D), parathormone (PTH), and uric acid (UA). Correlation study between HOMA_IR and different studied parameters was performed. HOMA-IR is significantly higher in CKD (8.87 ± 3.48 vs. 3.97 ± 0.34 in CKD vs. control, respectively, p < .001). In addition CKD patients have significantly higher FGF23 (235 ± 22.96 vs. 139 ± 12.3 pg/mL, p < .001), PTH (76.9 ± 15.27 vs. 47.9 ± 2.52 pg/mL, p < .001), P (4.3 ± 0.67 vs. 3.6 ± 0.23 mg/dL, p < .001), and UA (5 ± 1.22 vs. 4.85 ± 0.48 mg/dL, p < .001) and significantly lower Ca (8.2 ± 0.3 vs. 8.9 ± 0.33 mg/dL, p < .001), and 25 (OH) vit D (17 ± 5.63 vs. 37 ± 3.43 ng/mL, p < .001). Stepwise linear regression analysis revealed that BMI, GFR, Ca, P, and FGF23 were the only significant predictors of HOMA IR. Increased IR in CKD is a consequence of the uremic status and is intimately associated with disturbed phosphate metabolism and FGF23. Further studies are needed to look for an underlying mechanism.

Vitamin D receptor activation by paricalcitol and insulin resistance in CKD

The nature of the link (causal vs non-causal) between low 1,25-OH vitamin D and insulin resistance (IR) in patients with chronic kidney disease (CKD) remains elusive. We have now made a post hoc analysis of the effect of vitamin D receptor activation by paricalcitol on IR in the complete dataset of a double-blind, randomized, placebo controlled trial, the Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY). Eighty-eight patients with stage 3-4 CKD were randomized (1:1) to receive 2μg/day paricalcitol or matching placebo for 12 weeks. IR was measured by five IR indices: the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), the McAuley index, the HOMA corrected for adiponectin (HOMA-AD) and the Leptin-adiponectin ratio (LAR). As compared to placebo, paricalcitol produced the expected small rise in serum calcium (+0.07mmol/L, P=0.01) and phosphate (+0.08mmol/L, P=0.034) and the expected parathyroid hormone suppression (-96pg/ml, P<0.001). However, the drug largely failed to affect the five indices of IR which remained unchanged both in the active and the placebo arm (paricalcitol vs placebo, P ranging from 0.25 to 0.62) and no effect modification of paricalcitol on IR by vitamin D or other parameters was registered. Paricalcitol treatment for 12 weeks does not improve IR in patients with stage 3-4 CKD. Low vitamin D receptor activation is not a causal factor for IR in the CKD population.

P-Cresyl glucuronide is a major metabolite of p-cresol in mouse: in contrast to p-cresyl sulphate, p-cresyl glucuronide fails to promote insulin resistance.

The role of uraemic toxins in insulin resistance associated with chronic kidney disease (CKD) is gaining interest. p-Cresol has been defined as the intestinally generated precursor of the prototype protein-bound uraemic toxins p-cresyl sulphate (p-CS) as the main metabolite and, at a markedly lower concentration in humans, p-cresyl glucuronide (p-CG). The objective of the present study was to evaluate the metabolism of p-cresol in mice and to decipher the potential role of both conjugates of p-cresol on glucose metabolism. p-CS and p-CG were measured by high performance liquid chromatography-fluorescence in serum from control, 5/6 nephrectomized mice and mice injected intraperitoneously with either p-cresol or p-CG. The insulin sensitivity in vivo was estimated by insulin tolerance test. The insulin pathway in the presence of p-cresol, p-CG and/or p-CS was further evaluated in vitro on C2C12 muscle cells by measuring insulin-stimulated glucose uptake and the insulin signalling pathway (protein kinase B, PKB/Akt) by western blot. In contrast to in humans, where p-CS is the main metabolite of p-cresol, in CKD mice both conjugates accumulated, and after chronic p-cresol administration with equivalent concentrations but a substantial difference in protein binding (96% for p-CS and <6% for p-CG). p-CG exhibited no effect on insulin sensitivity in vivo or in vitro and no synergistic inhibiting effect in combination with p-CS. The relative proportion of the two p-cresol conjugates, i.e. p-CS and p-CG, is similar in mouse, in contrast to humans, pinpointing major inter-species differences in endogenous metabolism. Biologically, the sulpho- (i.e. p-CS) but not the glucuro- (i.e. p-CG) conjugate promotes insulin resistance in CKD.

Insulin resistance in predialytic, nondiabetic, chronic kidney disease patients: A hospital-based study in Eastern Uttar Pradesh, India.

Most investigations have focused on patients with end-stage renal disease (ESRD). More recently, due to increased recognition of the high prevalence of moderate-to-severe chronic kidney disease (CKD), attention has been redirected to this patient population to identify risk factors associated with hospitalization, death, and progression to ESRD. The objective of this study was to examine the degree and determinants of insulin resistance (IR) in predialytic, nondiabetic, CKD patients. Our study is a hospital-based cross-sectional study. The participants were aged 18 years and above with CKD due to any cause, were all nondiabetic patients, and the mean serum creatinine was 1.41-5 mg/dL. Anthropometric parameters included body weight, height, and skinfold thickness. Homeostasis model assessment of IR (HOMA-IR) score was 2.5 ± 1.2 in CKD patients and 1.9 ± 0.7 in controls. In the unadjusted analysis, there was a significant (P <0.05) correlation between HOMA-IR and body mass index (BMI), waist circumference, cholesterol, and triglyceride (TG) levels. Upon adjusting for age and sex, total body fat (BF), globulin, TG, and C-reactive protein were having positive, significant (P <0.05) correlation with HOMA-IR. In multivariate regression models, BMI and total BF% were significant (P <0.05) predictors of IR in patients with CKD but not in controls. BF% and BMI are indicators of IR in CKD as in non-CKD population.

Insulin resistance in chronic kidney disease: a systematic review.

Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

PS 08-11 THE EFFECT OF MINERALOCORTICOID ANTAGONIST ON RENAL INSULIN RESISTANCE AND THE PROGRESSION OF RENAL FAILURE IN NON-DIABETIC CKD PATIENTS

Objective: Insulin resistance (IR) is evident in Chronic Kidney Disease (CKD ) even in non-diabetic patient, although the clinical relevances remain to be determined. We reported that aldosterone increase in CKD is contributed to IR in CKD and MR antagonist, spironolactone ameliorated IR in CKD in three months treatment. We follow our CKD cohort for five years and explored the relevance of IR in the progression of CKD. We also performed procebo-controlled clinical trial using mineralocorticoid receptor antagonist eplerenone and examined its effects on the progression of CKD. Design and Method: Between 2007 and 2008, consecutive 197 patients with CKD were enrolled and followed these patients for five years. Risk factors for the progression of CKD evaluated by the rate of eGFR decline was determined by multiple regression analysis. We recruited the patients with hyperaldosterone and IR patients (N = 48) and treated them with eprelenone (N = 22) and placebo (N = 26) for three years and evaluated its effect on eGFR decline. Results: In CKD patients, HOMA-IR levels were negatively associated with eGFR levels. Plasma aldosterone concentration was determined as an independent risk factor for HOMA-IR levels. After three years follow-up, baseline HOMA-IR levels was significantly associated with eGFR decline and selected as a independent risk factor. We classified quartile groups depending on the baseline HOMA-IR levels and found out the 3rd and 4th quartile groups were significantly higher decline in eGFR. Finally, eplereneone ameliorated eGFR decline of non-diabetic CKD patients with high HOMA-IR and high plasm aldosterone levels(eplerenone; eGFR 51.0 ± 3.7→50.4 ± 3.4 ml/min, placebo; eGFR 55.6 ± 5.1→53.1 ± 4.7 ml/min). Conclusions: IR is a risk factor of the progression of CKD and mineralocorticoid receptor antagonist will provide a novel strategy against the progression of CKD through the amelioration of IR.

Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

Insulin resistance in chronic kidney disease: a step closer to effective evaluation and treatment.

Accurate measurements are needed to target insulin resistance in CKD. Among older men with and without moderate CKD, Jia and colleagues compared insulin resistance estimated from glucose and insulin concentrations obtained while fasting or during an oral glucose tolerance test to insulin resistance measured by the gold standard hyperinsulinemic euglycemic clamp and tested associations of each with mortality. These findings move forward the study of insulin resistance in CKD and generate new questions for future work.

Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1(-/-) mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Insulin resistance is associated with Fibroblast Growth Factor-23 in stage 3–5 chronic kidney disease patients

AimTo determine the associations between insulin resistance, fibroblast growth factor 23 (FGF-23), and coronary artery calcification (CAC) in chronic kidney disease (CKD) patients. IntroductionFGF-23 is associated with atherosclerosis and cardiovascular disease, but its association with insulin resistance in CKD has not been explored. SubjectsCross sectional study of 72 stage 3–5 CKD patients receiving care in Ontario, Canada. Materials and MethodsInsulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR), FGF-23 was measured by carboxyl terminal enzyme linked immunoassay (ctFGF-23) and CAC was measured by multi-slice computed tomography. ResultsMedian HOMA-IR was 2.19μU/ml (interquartile range 1.19 to 3.94). Patients with HOMA-IR>2.2 had greater ctFGF-23 (179.7 vs 109.6; P=0.03), and 40% higher log CAC scores (2.09±0.87 vs 1.58±1.26; P=0.049). Multivariable linear regression adjusted for 1,25 dihydroxyvitamin D, kidney function, and parathyroid hormone revealed insulin resistance was a risk factor for greater log ctFGF-23 levels (log HOMA IR β=0.37; 95% confidence interval 0.14 to 0.59; P=0.002). ConclusionsInsulin resistant CKD patients demonstrated higher FGF-23 levels, and increased CAC, while PO4 levels remained normal, suggesting a potential link between insulin resistance and PO4 homeostasis in CKD.