PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online)
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Physiol. Res. 60: 149-155, 2011
Insulin Resistance and Vitamin D Deficiency in Patients With Chronic
Kidney Disease Stage 2-3
K. ŠTEFÍKOVÁ1, V. SPUSTOVÁ1, Z. KRIVOŠÍKOVÁ1, A. OKŠA1, K. GAZDÍKOVÁ1,
V. FEDELEŠOVÁ1, R. DZÚRIK1
1Department of Clinical and Experimental Pharmacotherapy, Slovak Medical University,
Received May 4, 2009
Accepted July 14, 2010
On-line October 15, 2010
Vitamin D status and the relationship between serum 25(OH)
vitamin D concentrations and the components of insulin
resistance were examined in 120 patients with chronic kidney
disease stage 2 and 3. Insulin sensitivity/resistance was
calculated by the quantitative insulin sensitivity check index
(QUICKI). In this analysis, the prevalence of insulin resistance
was 42 %. Only 17 % of patients had serum 25(OH) vitamin D
concentration in the recommended range (≥30 ng/ml), 42 %
suffered from vitamin D insufficiency and 41 % had moderate
vitamin D deficiency. Insulin resistance significantly correlated
with serum 25(OH)D and 1,25(OH)2D concentrations, renal
function and protein excretion rate. Our results support the
increasing evidence that vitamin D deficiency may be one of the
factors participating in the development of insulin resistance
already in the early stages of chronic kidney disease.
Chronic kidney disease • Insulin resistance • 25(OH) vitamin D •
1,25(OH)2 vitamin D • Proteinuria
Kornélia Štefíková, Department of Clinical and Experimental
Pharmacotherapy, Slovak Medical University, Limbová 12, 833 03
Bratislava 37, Slovakia. Fax: (+421-2) 59370 598. E-mail:
insulin resistance (Fliser et al. 1998, Kato et al. 2000, Chen
et al. 2003) which plays an important role in the
Chronic kidney disease (CKD) is associated with
pathogenesis of cardiovascular diseases. Insulin resistance
is a risk factor of metabolic syndrome (Tuttle 2005).
According to WHO classsification, microalbuminuria is
also a clinical criterion for the metabolic syndrome (Chen
et al. 2004, Grundy et al. 2004). Analysis of a subsample
of NHANES III (National Health and Nutrition
Examination Survey) participants revealed a strong,
positive, and significant relationship between the insulin
resistance and a risk for CKD (Chen et al. 2003). Vitamin
D deficiency has long been considered as a risk factor for
glucose intolerance (Boucher et al. 1995, Chiu et al. 2004,
Foroughi et al. 2008). An inverse correlation between
serum concentration of vitamin D and insulin resistance
was found in NHANES III participants (Ford et al. 2002,
Chonchol and Scragg, 2007). There is an increasing
evidence that vitamin D metabolism affects insulin
resistance. Previous studies reported reduced serum
25(OH) vitamin D concentration in patients with CKD
(Ishimura et al. 1999, Gonzales et al. 2004, Chonchol and
Scragg, 2007), although the relationship between vitamin
D status and insulin resistance has not been examined.
Therefore, the aim of our study was to evaluate
the relation of insulin sensitivity/resistance to vitamin D
status in CKD patients with mild to moderate decrease in
Subjects and Methods
One hundred and twenty patients with CKD,
71 women and 49 men, aged 22-83 years, (mean age
64±10 years) were included into the examination. The
patient diagnoses are summarized in Table 1. Patients with
150 Štefíková et al.
diabetes mellitus type 2 (DM) treatead with any insulin
therapy were excluded, but 19 diabetic patients on
sulfonylurea treatment or diet were included. Hypertension
was present in 97 patients (81 %) and was predominantly
treated with angiotensin converting enzyme inhibitors or
angiotensin II receptor blockers. Dyslipidemia was treated
by statins or fibrates in 49 patients (41 %). The therapy of
hypertension, diabetes and dyslipidemia was not changed
at least two months before the examination. Chronic
kidney disease was defined according to K/DOQI
guidelines (K/DOQI, 2002). Glomerular filtration rate
(GFR) was assessed by the abbreviated modification of
MDRD equation (http://www.kidney.org/, Okša et al.
2008) and patients with stable GFR of 0.50-1.49 ml/s
(CKD stage 2-3) were eligible for enrollment. Proteinuria
was determined in the 24 hour urine collection by a routine
method. Patients with an acute impairment of renal
function, nephrotic proteinuria,
derangements of mineral metabolism were excluded before
enrolment to the study. Vitamin D, calcitriol or any over-
the-counter vitamin D preparations had to be cancelled at
least 2 months before examination.
Table 1. Patient renal diagnoses.
Diagnosis n %
Atherosclerotic / ischemic
Polycystic kidney disease
Combination of ≥ 2 diagnoses*
* In 8/30 combined diagnoses, diabetic nephropathy was
Insulin resistance was calculated by the
Quantitative Insulin Sensitivity Check Index (QUICKI)
(Katz et al. 2000) from fasting glucose and insulin
concentrations. Each subject was classified as either insulin
sensitive (IS) or insulin resistant (IR) based on the
QUICKI index above or below 0.356, respectively. Body
mass index (BMI) was calculated as weight in kilograms
divided by the square of height in meters. Serum
concentrations of 25-hydroxyvitamin D (25(OH)D) and
Diagnostic System, UK) were analysed by RIA methods.
Intact PTH (Immunotech,
(Immunotech, Czech Republic) were evaluated by IRMA
The Ethics Committee of the Slovak Medical
University approved the study, and all participants gave
their written informed consent.
The statistical software SPSS (release 13.0) was
used for analysis. After testing for normality of data
distribution, the data of three patients groups divided
according to insulin sensitivity/resistance and DM were
tested by Kruskal-Wallis test. Two groups of patient
divided according to GFR were tested by Mann-Whitney
test. Spearman’s correlation analysis between QUICKI on
one hand and age, BMI, GFR, 25(OH)D and 1,25(OH)2D,
PTH, blood pressure on other hand was done in pooled
patient data only. All data are presented as median and
inter quartile range unless otherwise stated. Differences at
a P-value<0.05 were considered significant.
Patients were divided into three groups according
to QUICKI index. Fourty seven patients were insulin
sensitive with the average QUICKI value of 0.377 (39 %),
50 patients were insulin resistant with the average QUICKI
value of 0.321 (42 %) and 23 patients suffered from
diabetes mellitus type II with the average QUICKI value
0.304 (19 %) (Table 2). In addition to QUICKI, significant
differences in fasting plasma glucose and insulin
concentrations, as components for the calculation of
QUICKI were detected among individual groups. Insulin
resistant and DM patients had significantly higher BMI in
comparison with IS group. Glomerular filtration rate was
significantly lower in IR and DM patients. Insulin sensitive
and IR patients had an urinary protein excretion in the
range of microalbuminuria and diabetic patients in the
range of proteinuria. Median
concentration was in the range of vitamin D insufficiency
in all three groups. The serum concentration of
1,25(OH)2D significantly decreased with diminution of
insulin sensitivity. The serum PTH concentration was in
the normal range in the all three groups. Median systolic
blood pressure was 130 (120-140) mmHg and median
diastolic blood pressure was 80 (78-85) mmHg, with
nonsignificant decrease in IR and DM groups.
D (1,25(OH)2D) (Immuno
France) and insuline
Insulin Resistance and Vitamin D Deficiency in Kidney Disease 151
Table 2. Characteristics in patients grouped by insulin sensitivity and diabetes mellitus according to insulin sensitivity.
Blood glucose (mmol/l)
Proteinuria (g/24 h)
Blood pressure (mmHg)
All values are medians and interquartile ranges unless otherwise indicated. * values are mean ± SD; ° Kruskal Wallis test; NS – not
significant; IS – insulin sensitivity; IR – insulin resistance; DM – diabetes mellitus type II
25(OH) vitamin D
Serum 25(OH)D concentrations were distributed
in log-normal fashion (Fig. 1). Vitamin D
insufficiency/deficiency was evaluated according to
K/DOQI guidelines (K/DOQI, 2003). Only 20 patients
(17 %) had serum 25(OH)D concentration in the
recommended range (≥30 ng/ml), 51 patients (42 %)
suffered from vitamin D insufficiency (16-30 ng/ml) and
49 patients (41 %) from moderete vitamin D deficiency
(5-15 ng/ml). Nobody had severe vitamin D deficiency
(<5 ng/ml) (Fig. 2).
To evaluate the differences of individual
parameters according to renal function, patients were
devided into two groups, CKD stage 2 (n=45, 46 %) and
CKD stage 3 (n=52, 54 %) (Table 3). Patients with
diabetes mellitus were excluded. Urinary protein
excretion was in the range of microalbuminuria in both
groups. Patients with CKD stage 3 were older, had
significantly higher plasma fasting glucose and insulin
concentrations and higher insulin resistance. The serum
concentrations of 25(OH)D and 1,25(OH)2D were
significantly lower in patients with CKD stage 3. In spite
of lower vitamin D concentrations, median PTH levels
were in the normal range, though at the upper normal
limit in CKD stage 3 group. Patients with lower renal
function had significantly higher systolic blood pressure
without differences in diastolic blood pressure.
Correlations between QUICKI index, serum 25(OH)D
concentration and other variables
Insulin resistance evaluated by the QUICKI
index significantly correlated with serum 25(OH)D and
152 Štefíková et al.
1,25(OH)2D concentrations, GFR and protein excretion
rate (Table 4). Expected negative and highly significant
correlations were found between QUICKI, BMI and
systolic blood pressure. In addition to correlation of
serum 25(OH)D concentration with QUICKI, it
correlated with fasting insulin concentration, but not with
fasting glucose concentration. Significant possitive
correlation was found between serum 25(OH)D and
1,25(OH)2D concentrations, renal function and negative
correlation with systolic blood pressure. No significant
correlation was determined between serum 25(OH)D
concentration and proteinuria.
Insulin resistance and renal function
The principal finding in the present study is the
demonstration that CKD is accompanied by insulin
resistance even in stages 2 and 3. Our study identified a
strong and significant relationship between QUICKI,
renal function and proteinuria. Several large studies
examined the association between insulin resistance and
risk of chronic kidney disease (Fliser et al. 1998, Chen et
al. 2003). Hoechner and colleagues (2002) found that
persons with 3 or more symptoms of the metabolic
sydrome had 2.3-fold higher odds for microalbuminuria
than persons with no symptoms. Chen and colleagues
(2003) reported that insulin resistance estimated by
homeostasis model assessment was associated with
increased risk for chronic kidney disease in nondiabetic
participants. Our results are in accordance with these
observations and supports the notion that kidney disease
is associated with insulin resistance, hyperinsulinemia
and hyperglycemia, and that insulin resistance might be
an important factor in the cause of chronic kidney
Vitamin D, insulin resistance and renal function
Serum concentrations of 25(OH)D are the
measure of the vitamin D body stores. The most well-
known role of vitamin D is the regulation of calcium
absorption and bone metabolism. It is becoming clear that
this hormone has pleiotropic effects (Dusso et al. 2005)
with possible roles in the pathogenesis of cancer,
cardiovascular disease, multiple sclerosis (Holick 2004),
and type I diabetes (Holick 2004). Recent epidemiological
evidence (Boucher 1998, Chiu et al. 2004, Ford et al.
2005) also points to a potential association of vitamin D
insufficiency with type 2 diabetes. Among these, vitamin
D seems to be implicated in the development and
progression of chronic renal disease and the risk of insulin
resistance and diabetes (Chonchol and Scragg 2007,
Remuzzi 2007, Mehrotra et al. 2008) In this study we have
demonstrated a high prevalence
insufficiency/deficiency in patients with the mild and
moderate CKD. Hypovitaminosis
correlated with the renal function and insulin resistance
evaluated by QUICKI index.
of vitamin D
Fig. 1. Distribution of 25(OH)D serum concentration among
Fig. 2. Prevalence of vitamin D insufficiency/deficiency according
Insulin Resistance and Vitamin D Deficiency in Kidney Disease 153
Table 3. Characteristics in patients grouped by renal function without diabetics.
evidence that vitamin D deficiency may affect also non-
calcemic vitamin D functions, i.e. insulin resistance.
More experimental and clinical data are required to
elucidate pathophysiological mechanisms of non-
calcemic vitamin D functions.
In conclusion, our results support the increasing
Conflict of Interest
There is no conflict of interest.
This work was supported by the Slovak Research and
Development Agency under the contract No. APVT-21-
CKD stage 2
CKD stage 3
Blood glucose (mmol/l)
Serum creatinine (µmol/l)
Proteinuria (g/24 h)
1,25(OH)2 D (pg/ml)
Blood pressure (mmHg)
All values are medians and interquartile ranges unless otherwise indicated. * values are mean ± SD; NS – not significant; ° Mann-
Whitney test; CKD – chronic kidney disease
Table 4. Spearman’s correlations between serum 25(OH)D, QUICKI and other variables.
r p values r p values
Protein exretion rate (g/24 h)
Systolic blood pressure (mmHg)
Blood glucose (mmol/l)
r – correlation coefficient; NS – not significant
154 Štefíková et al.
BOUCHER BJ, MANNAN N, NOOMAN K, HALES CN, EVANS SJ: Glucose intolerance and impairment of insulin
secretion in relation to vitamin D deficiency in east London Asians. Diabetologia 38: 1239-1245, 1995.
BOUCHER BJ: Inadequate vitamin D status: does it contribute to the disorders comprising syndrom "X"? Br J Nutr 79:
CHEN J, MUNTNER P, HAMM LL, FONESCA V, BATUMAN V, WHELTON PK, HE J: Insulin resistance and risk
of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 14: 469-477, 2003.
CHEN J, MUNTNER P, HAMM LL, JONES DW, BATUMAN V, FONESCA V, WHELTON PK, HE J: The
metabolic syndrome and chronic kidney disease in U.S. adults. Ann Int Med 140: 167-174, 2004.
CHIU KC, CHU A, GO VL, SAAD MF: Hypovitaminosis D is associated with insulin resistance and beta cell
dysfunction. Am J Clin Nutr 79: 820-825, 2004.
CHONCHOL M, SCRAGG R: 25-hydroxyvitamin D, insulin resistance, and kidney function in the Third National
Health and Nutrition Examination Survey. Kidney Int 71: 134-139, 2007.
DUSSO AS, BROWN AJ, SLATOPOLSKY E: Vitamin D. Am J Renal Physiol 289: F8-F28, 2005.
FLISER D, PACINI G, ENGELLEITER R, KAUTZKY-WILLER A, PRAGER R, FRANEK E, RITZ E: Insulin
resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int 53:
FORD ES, GILES WH, DIETZ WH: Prevalence of the metabolic syndrome among US adults: findings form the third
National Health and Nutrition Examination Survey. JAMA 287: 356-359, 2002.
FORD ES, AJANI UA, MCGUIRE LC, LIU S: Concentrations of serum vitamin D and the metabolic syndrome among
US adults. Diabet Care 28: 1228-1230, 2005.
FOROUGHI NG, LUAN J, COOPER A, BOUCHER BJ, WAREHAM N: Baseline serum 25-hydroxy vitamin D is
predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective
Study 1990-2000. Diabetes 57: 2619-2625, 2008.
GONZALES EA, SACHCEVA A, OLIVER DA, MARTIN KJ: Vitamin D insufficiency and deficiency in chronic
kidney disease. A single center observational study. Am J Nephrol 24: 503-510, 2004.
GRUNDY SM, BREWER HB Jr, CLEEMAN JI, SMITH SC Jr, LENFANT C; American Heart Association; National
Heart, Lung, and Blood Institute: Definition of metabolic syndrome: Report of the National Heart, Lung, and
Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation
109: 433-438, 2004.
HOEHNER CM, GREENLUND KJ, RITH-NAJARIAN S, CASPER ML, MCCLELLAN WM: Association of the
insulin resistance syndrome and microalbuminuria among nondiabeteic native Americans. The Inter-Tribal
Heart Project. J Am Soc Nephrol 13: 1626-1634, 2002.
HOLICK MF: Sunlight and vitamin D for health and prevention of autoimmune diseases, cancers, and cardiovascular
disease. Am J Clin Nutr 80 (6 suppl): 1678S-1688S, 2004.
HOLICK MF: Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis.
Am J Clin Nutr 79: 362-371, 2004.
ISHIMURA E, NISHIZAWA Y, INABA M, MATSUMOTO N, EMOTO M, KAVAGISHI T, SHOJI S, OKUNO S,
KIM M, MIKI T, MORII H: Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-
hydroxyvitamin D in nondialyzed patients with chronic renal failure. Kidney Int 55: 1019-1027, 1999.
K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J
Kidney Dis 39 (2 Suppl 1): S1-S266, 2002.
K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42
(4 Suppl 3): S1-S201, 2003.
KATO Y, HAYASHI M, OHNO Y, SUZAWA T, SASAKI T, SARUTA T: Mild renal dysfunction is associated with
insulin resistance in chronic glomerulonephritis. Clin Nephrol 54: 366-373, 2000.
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KATZ A, NAMBI SS, MATHER K, BARON AD, FOLLMANN DA, SULLIVAN G, QUON MJ: Quantitative insulin
sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin
Endocrinol Metab 85: 2402-2410, 2000.
MEHROTRA R, KERMAH D, BUDOFF M, SALUSKY IB, MAO SS, GAO YL, TAKASU J, ADLER S, NORRIS K:
Hypovitaminosis D in chronic kidney disease. Clin J Am Soc Nephrol 3: 1144-1151, 2008.
OKŠA A, SPUSTOVÁ V, KRIVOŠÍKOVÁ Z, GAZDÍKOVÁ K, FEDELEŠOVÁ V, LAJDOVÁ I, ŠTEFÍKOVÁ K,
BERNASOVSKÁ G, ŽILINSKÁ Z, DZÚRIK R: Effect of long-term cholecalciferol supplementation on
mineral metabolism and calciotropic hormones chronic kidney disease. Kidney Blood Press Res 31: 322-329,
REMUZZI A: Vitamin D, insulin resistance, and renal disease. Kidney Int 71: 96-98, 2007.
TUTTLE KR: Renal manifestations of the metabolic syndrome. Nephrol Dial Transplant 20: 861-864, 2005.