B-CRF : metabolic and endocrine complications
B-CRF : nutritional complications
D- Metabolic syndrome and obesity
Clinical Correlates of Insulin Sensitivity and Its Association with
Mortality among Men with CKD Stages 3 and 4
Hong Xu*,†, Xiaoyan Huang*,‡, Johan Ärnlöv§‖, Tommy Cederholm¶, Peter Stenvinkel*, Bengt
Lindholm*, Ulf Risérus¶, Juan Jesús Carrero**,*
+ Author Affiliations
1.
*
2.
†
3.
‡
4.
§
5.
¶
6.
‖
7.
**
Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science,
Intervention and Technology, Karolinska Institutet, Stockholm, Sweden;
Department of Nephrology, Peking Union Medical College Hospital, Chinese
Academy of Medical Science, Beijing, China;
Division of Nephrology, Peking University Shenzhen Hospital, Peking University,
Shenzhen, China;
Department of Public Health and Caring Sciences, Section of Geriatrics, and
Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism,
Uppsala University, Uppsala, Sweden;
School of Health and Social Studies, Dalarna University, Falun, Sweden; and
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Correspondence:
Dr. Juan Jesús Carrero, Divisions of Renal Medicine and Baxter Novum, Karolinska
University Hospital at Huddinge K56, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
Email: juan.jesus.carrero@ki.se
ABSTRACT
Background and objectives
Insulin resistance participates in the pathogenesis of multiple metabolic and cardiovascular
diseases. CKD patients have impaired insulin sensitivity, but the clinical correlates and
outcome associations of impaired insulin sensitivity in this vulnerable population are not well
defined.
Design, setting, participants, & measurements
The prospective cohort study was from the third examination cycle of the Uppsala
Longitudinal Study of Adult Men, a population-based survey of elderly men ages 70–71
years; insulin sensitivity was assessed by glucose disposal rate as measured with
euglycemic clamps. Inclusion criterion was eGFR<60 ml/min per 1.73 m2 (n=543). Exclusion
criteria were incomplete data on euglycemic clamp and diabetes (n=97), leaving 446 men
with CKD stages 3 and 4 (eGFR median=51.9 ml/min per 1.73 m2; range=20.2–59.5 ml/min
per 1.73 m2).
Results
The mean of glucose disposal rate was 5.4±1.9 mg/kg per minute. In multivariable analysis,
the independent clinical correlates of glucose disposal rate were eGFR (slope, 0.02; 95%
confidence interval, 0.01 to 0.04), hypertension (−0.48; 95% confidence interval, −0.86 to
−0.11), hyperlipidemia (−0.51; 95% confidence interval, −0.84 to −0.18), and body mass
index (−0.32; 95% confidence interval, −0.37 to −0.27). During follow-up (median=10.0
years; interquartile range=8.7–11.0 years), 149 participants died. In Cox regression models,
glucose disposal rate was not associated with all-cause or cardiovascular mortality.
Multiplicative interactions (P<0.05) were observed between glucose disposal rate and
physical activity or smoking in total mortality association. After subsequent stratification,
glucose disposal rate was an independent correlate of all-cause mortality in smokers
(adjusted hazard ratio, 0.72; 95% confidence interval, 0.54 to 0.96 per 1 mg/kg per minute
glucose disposal rate increase) and physically inactive individuals (hazard ratio, 0.77; 95%
confidence interval, 0.61 to 0.97) but not their counterparts.
Conclusion
eGFR, together with various components of the metabolic syndrome, contributed to explain
the variance of insulin sensitivity in men with CKD stages 3 and 4. Insulin sensitivity was
associated with a lower mortality risk in individuals who smoked and individuals who were
physically inactive.
COMMENTS
Insulin resistance (IR) is defined as reduced sensitivity of target organs to the biologic effects
of insulin. IR plays an important role in the pathogenesis of multiple metabolic diseases and
cardiovascular diseases (CVDs), and it is associated with increased risk of cardiovascular
events and premature mortality in diverse community-based populations
Multiple mechanisms may explain a potentially causal link in this association, including
promotion of endothelial dysfunction, oxidative stress, inflammation, and other cardiovascular
risk factors (obesity, hypertension, and dyslipidemia) that are parts of the metabolic
syndrome .
IR is common in patients with ESRD, and possibly, it is also common in moderate to severe
stages of CKD
These studies use surrogate indices of IR, like the homeostasis model assessment–IR
(HOMA-IR) (Wallace TM, Levy JC, Matthews DR: Use and abuse of HOMA modeling.
Diabetes Care 27: 1487–1495, 2004), and its validity in the context of uremic retention is not
yet fully established . The objectives of this study were to investigate the clinical and
biochemical characteristics associated with IR (or its reciprocal IS) in a large cohort of
nondiabetic men with CKD stages 3 and 4 as well as establish plausible associations with
mortality. They assessed IS by the gold standard—the hyperinsulinemic euglycemic clamp
technique ( DeFronzo RA, Tobin JD, Andres R : Glucose clamp technique: A method for
quantifying insulin secretion and resistance. Am J Physiol 237: E214–E223, 1979).
This study has two main findings. First, reduced eGFR and various features of the metabolic
syndrome were independently associated with impaired IS in nondiabetic elderly men with
CKD stages 3 and 4. Second, although IS per se did not associate with total and
cardiovascular mortality in this population, IS was a predictor of mortality in CKD individual
strata with unhealthy but modifiable lifestyles . On the basis of these results, the authors
speculate that increased physical activity and smoking cessation can be preventive
strategies to improve IS in the CKD population, potentially attenuating the negative impact of
reduced IS on clinical outcomes.
Pr. Jacques CHANARD
Professor of Nephrology