insulin resistance increase the risk of stone formation

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. I I I IOriginal Articles

INSULIN RESISTANCE AND URINARY STONE FORMATION IN METABOLIC SYNDROME

IBA

ET AL.

Insulin resistance increases the risk ofurinary stone formation in a rat model of

metabolic syndrome

Akinori Iba, Yasuo Kohjimoto, Takashi Mori, Tomomi Kuramoto,Satoshi Nishizawa, Reona Fujii, Yoshihito Nanpo, Nagahide Matsumura,Yasuyo Shintani, Takeshi Inagaki and Isao Hara

Department of Urology, Wakayama Medical University, Wakayama, Japan

Accepted for publication 10 November 2009

4 weeks. Ten-week-old male OLETF and LETO

rats were divided into three groups of nineeach and treated with vehicle or oral

administration of 3 or 10 mg/kg/daypioglitazone, an agent that improves insulinresistance. After 4 weeks, body weight andserum and urinary biochemistry were

determined.

RESULTS

The OLETF rats had significantly lower

urinary pH and citrate excretion, and higherurinary uric acid and calcium excretion, than

the LETO rats, with increases in body weight,serum triglyceride, glucose and insulin. Theadministration of pioglitazone to the OLETF

rats for 4 weeks significantly increased

urinary pH dose-dependently. There was no

change in the urinary excretion of citrate,uric acid, calcium, oxalate or magnesium.

CONCLUSION

These results indicate that metabolic

syndrome causes the changes in urinaryconstituents, leading to increased risk ofboth uric acid and calcium stone formation.

Improvement in insulin resistance, a centralcause of metabolic syndrome, might preventuric acid stone formation by raising urinary

pH.

KEYWORDS

urinary stone disease, metabolic syndrome,

insulin resistance, rat, pioglitazone

OBJECTIVE

To investigate the association between

metabolic syndrome and urinary stonedisease, and whether insulin resistanceassociated with adiposity affects the risk ofurinary stone formation, using a rat model of

metabolic syndrome.

MATERIALS AND METHODS

Four-week-old male Otsuka Long-EvansTokushima Fatty (OLETF, a model of human

type 2 diabetes and metabolic syndrome)rats, and Long-Evans Tokushima (LETO, a

non-diabetic control) rats (10 each) weregiven a standardized diet and free access towater. Body weight and serum and urinary

biochemistry were determined every

INTRODUCTION

The prevalence of kidney stones has beenincreasing in several countries, in parallel

with the growing epidemics of obesityand type 2 diabetes [14]. In large

epidemiological studies, an increasedprevalence of kidney stones was reportedin patients with obesity [5], type 2 diabetes[6] and hypertension [7]. These medical

conditions are now collectively referred to asmetabolic syndrome, which has receivedmuch attention in recent years as a risk

factor for developing cardiovascular diseases[8]. In the present study, we investigated theassociation between metabolic syndrome and

urinary stone disease, and whether insulinresistance, a central cause of metabolicsyndrome, affects the risk of urinary stone

formation, using a rat model of metabolic

syndrome [9].

MATERIALS AND METHODS

Male Otsuka Long-Evans Tokushima Fatty(OLETF, a model of human type 2 diabetes andmetabolic syndrome) rats, and Long-EvansTokushima (LETO, a non-diabetic control) rats,

aged 4 weeks, were kindly provided by OtsukaPharmaceuticals, Japan. OLETF rats, whichwere developed from a strain of Long-Evans

rat by selective breeding, are a useful model ofhuman type 2 diabetes and metabolicsyndrome [9]. They spontaneously develop

visceral adiposity and insulin resistance at anearly age and later have hyperglycaemia,hyperlipidaemia and hypertension. Both sets

of rats were maintained according to the

ethical guidelines of our institution, and theCommittee on Animal Investigations of theWakayama Medical University approved the

experimental protocols.

In protocol 1, 4-week-old male OLETF andLETO rats (10 each) were given standardizeddiet and free access to water, and weighedevery 4 weeks. A fasting blood sample was

obtained every 4 weeks for analysis ofglucose, insulin, triglyceride and totalcholesterol. A 24-h urine sample was

collected every 4 weeks to analyse the risk ofstone disease, including pH, calcium, oxalate,citrate, magnesium and uric acid levels.

In protocol 2, 10-week-old male OLETF andLETO rats were divided into three groups of

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nine each and treated with vehicle or oral

administration of 3 or 10 mg/kg/daypioglitazone (Takeda Chemical Industry Co.,Japan), an agent that improves insulin

resistance. After 4 weeks, body weight and

serum and urinary biochemistry were

determined.

Serum glucose levels were measured using

the glucose oxidase method, and serum

insulin concentrations by radioimmunoassay

using a double-antibody method, with acommercially available radioimmunoassay kit(Morinaga, Japan). Serum triglyceride and

total cholesterol levels were measured by an

FIG. 1. Time courses of body weight (

A

) and fasting serum levels of triglyceride (

B

), glucose (

C

) and insulin (

D

)

in OLETF (red line) and LETO (blue line) rats (10 each). Values are the mean (

SD

). *

P


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enzymatic colorimetric method usingcommercially available kits. The homeostasismodel assessment ratio (HOMA-R), an index

of insulin resistance, was calculated as:(fasting immunoreactive insulin level

fasting glucose)/405 [10]. Two successive

24-h urine samples were collected in 50 mLcentrifuge tubes; the first was collected inliquid paraffin and used for the measurement

of pH, calcium, magnesium, and uric acid; thesecond was collected in concentrated HCl andused for the oxalate and citrate measurement

via capillary electrophoresis.

All results are shown as the mean (

SD

); groups

were compared using Students t

-test andDunnetts multiple comparison test; in allstatistical analyses P

insulin resistance increase the risk of stone formation

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