PINITOL DOES NOT AFFECT GLUCOSE LEVELS, INSULIN RESISTANCE AND THE ADIPOCYTOKINE IN PREDIABETIC INDIVIDUALS - A PRELIMINARY STUDY

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1 CURRENT TOPICS IN NUTRACEUTICAL RESEARCH Vol. 10, No. 2, pp , 2012 ISSN print, Copyright 2012 by New Century Health Publishers, LLC All rights of reproduction in any form reserved PINITOL DOES NOT AFFECT GLUCOSE LEVELS, INSULIN RESISTANCE AND THE ADIPOCYTOKINE IN PREDIABETIC INDIVIDUALS - A PRELIMINARY STUDY 1 H. J. Kim, 2 I. S. Lee, 1 J. M. Kim, 1 H. Jung, 1 Y. E. Kang, 1 T. K. Kim, 3 J. M. Lee, 3 K. S. Park and 1 B. J. Ku (HJK and ISL made equal contributions). 1 Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea; 2 Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea; and 3 Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea [Received March 21, 2012; Accepted May 16, 2012] [Communicated by Prof. Chandan Prasad] ABSTRACT: Pinitol is thought to improve insulin resistance. We performed this study to evaluate the effects of pinitol on the glucose level, insulin resistance and the adipocytokine levels in prediabetic individuals. A total of 23 subjects with pre-diabetes were enrolled. The subjects were randomized to receive pinitol (n=12) or a placebo (n=10) for 12 weeks. The clinical and laboratory parameters were assessed for all the participants. There was no significant difference in the mean change with regard to the levels of glucose, HbA1c, insulin and HOMA-IR between the pinitol and control groups at the end of 12 weeks treatment. The mean increment of the adiponectin level was significantly higher in the pinitol group than that in the control group. There was also no difference in the mean change in the level of leptin and RBP-4 between the two groups. The twelve week treatment with pinitol was effective in increasing the adiponectin level, but it had no effect on the glucose level, insulin resistance and the levels of other adipocytokines in the subjects with pre-diabetes. KEYWORDS: Adipocytokines, Insulin Resistance, Pinitol, Prediabetic State. Corresponding Author: Bon Jeong Ku, Department of Internal Medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, Korea; Fax: ; bonjeong@cnu.ac.kr INTRODUCTOIN Pre-diabetes is a state between normal glucose tolerance and diabetes mellitus, and includes impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or both (American Diabetes Association, 2010, Aroda and Ratner, 2008). According to a previous study, insulin resistance is increased in the prediabetic stage (Nathan et al. 2007). The clinical importance of pre-diabetes is reflected by the increased risk of diabetes mellitus and cardiovascular disease (CVD) (Aroda and Ratner, 2008, Nathan et al. 2007). Diabetes mellitus eventually develops in up to 70% of the pre-diabetic subjects. The risk of cardiovascular mortality for individuals with pre-diabetes increases 2.47 fold compared to that for individuals with normal glucose tolerance (Rijkelijkhuizen et al. 2007). Some intervention studies have been conducted to estimate the role of prevention on the progression of diabetes or CVD events in pre-diabetic subjects (Knowler, 2002). Pinitol is a natural component of plants (Streeter, 2001), and it is thought to mediate insulin s action and improve insulin resistance. Pinitol is converted to D-chiroinositol (DCI) in the body after ingestion, and it may be a component of inositol phosphoglycans (IPGs). IPGs are potentially important post-receptor mediators of insulin s action (Jones and Varela-Nieto, 1998). Many studies have been conducted to evaluate the effect of pinitol in animals or patients with diabetes mellitus (Huang et al. 1993; Fonteles et al. 2000; Kim et al. 2007; Kim et al. 2012; Ortmeyer et al. 1995; Davis et al. 2000). We discovered that pinitol improved glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (Kim et al. 2012). However, another study showed that insulin sensitivity did not increase after pinitol treatment in obese individuals with type 2 diabetes mellitus (Davis et al. 2000). Most of the previous studies focused on subjects with diabetes mellitus and there are still no reports that have evaluated the effect of pinitol in subjects with pre-diabetes. In this study, we estimate the role of pinitol on the glucose level, insulin resistance and the adipocytokine levels in subjects with prediabetes.

2 112 The pinitol dose not effect in prediabetic patients MATERIALS AND METHODS From November 2007 to January 2009, 23 subjects from Eulji Medical Center who were diagnosed with IFG, IGT or both by oral glucose tolerance test according to the American Diabetes Association criteria (American Diabetes Association, 2010) participated in this study. The patients who had a diabetes mellitus, renal dysfunction or hepatic dysfunction, and those who were pregnant or had a past history of drug or alcohol abuse were excluded. The Institutional Review Board of Eulji Medical Center approved the study s protocol. Pinitol (3-O-Methyl-chiro-inositol) was purchased from Solgent (Daejeon, Korea). This study was a double-blind, randomized, placebo-controlled study. Participants were randomized to receive pinitol or a matching placebo. From 23 enrolled subjects, 22 subjects finished the study. One subject from the control group withdrew consent. All the remaining subjects were administered 1200mg (400mg three times a day) of pinitol (n=12) or a placebo (n=10) for 12 weeks. Extensive clinical and laboratory screening was conducted for all the participants. All the participants gave their written informed consent before entering the study. A medical history and a physical examination from each participant were obtained by personal interview. Blood pressure was measured on the right arm after at least 10 minutes of rest with the subject in a sitting position and using a standard mercury manometer. Height and weight were measured when the subjects were wearing light clothing and no shoes. The body mass index (BMI) was calculated as weight (kg) divided by the square of the height (m 2 ). Blood samples were collected before and after the 12-week treatment for measurements of HbA1c, glucose, insulin, c-peptide, adipocytokines and the blood chemistry levels. Complete blood counts were obtained using a Coulter counter (Coulter Electronics, Hialeah, FL, USA). Triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol were measured enzymatically using a chemistry analyzer (Hitachi 747, Tokyo, Japan). Plasma glucose was measured by the glucose oxidase method. Plasma HbA1c was measured by the high performance liquid chromatography method (BIO- RAD, Hercules, California, USA). Plasma insulin (Roche, Germany) was measured by radioimmunoassay. Adiponectin, leptin and retinol binding protein 4(RBP4) were measured by radioimmunoassay (LINCO Research, Inc., St. Charles, MO, USA). Intra-assay coefficient of variation was ranged % for insulin, % for adiponectin, less than 8.3% for leptin, and less than 5% for RBP4. The homeostasis model assessment (HOMA) of insulin resistance was determined by the formula: HOMA-IR = [insulin (mu/l) glucose (mmol/l)]/22.5. Continuous variables were expressed as the mean ± standard deviation (SD). Statistical analysis was performed using a commercially available program called the Statistical Package for the Social Sciences (SPSS Ò ) (version 18.0; Chicago, IL, USA) for Windows Ò. Comparisons between groups were performed using unpaired t-tests. A P value less than 0.05 was considered statistically significant. RESULTS The baseline clinical and laboratory profiles of control and pinitol groups The baseline clinical and laboratory profiles of control and pinitol groups are listed in Table 1. The body mass index was larger in the control group than that in the pinitol group (p=0.0450). The high density lipoprotein (HDL) cholesterol level was higher in the control group than that in the pinitol group (p=0.0172). The other variables were not different between the two groups. TABLE 1. The baseline clinical and laboratory profiles of control and pinitol groups. The data are presented as means±sds. AST: aspartate aminotransferase, ALT: alanine transaminase, HDL: high density lipoprotein, LDL: low density lipoprotein, HbA1c: glycosylated hemoglobin, PP2; 2 hour glucose after 75-gram glucose load, HOMA-IR: homeostasis model assessment-insulin resistance, RBP4: retinol binding protein 4. Control Pinitol Measurements P-value (n = 10) (n = 12) Gender (Male:Female) 6:4 10: Age (year) 47.2 ± ± Height(m) 1.63 ± ± Weight(kg) 64.8 ± ± Body mass index(kg/m 2 ) 24.1 ± ± AST 31.2 ± ± ALT 35.4 ± ± Triglyceride 93.7 ± ± HDL cholesterol 59.7 ± ± LDL cholesterol 115 ± ± Hemoglobin 14.8 ± ± HbA1c (%) 6.01 ± ± Glucose, fasting(mg/dl) 108 ± ± Glucose, PP2 (mg/dl) 173 ± ± Insulin, fasting (IU/L) 6.34 ± ± Insulin, PP2 (IU/L) 41.1 ± ± HOMA-IR 1.68 ± ± Adiponectin (μg/ml) 8.93 ± ± Leptin (ng/ml) 5.02 ± ± RBP4 (mg/dl) 47.6 ± ±

3 The pinitol dose not effect in prediabetic patients 113 The mean changes in the level of glucose, HbA1c, insulin and HOMA-IR The mean changes (end of treatment baseline) in the level of glucose, HbA1c, insulin and HOMA-IR are listed in Table 2. The mean changes in the level of fasting glucose were -2.0 mg/dl in the control group and mg/dl in the pinitol group. The mean changes in the level of glucose at 2 hours after a 75 gram glucose load (PP2) were mg/dl in the control group and mg/dl in the pinitol group. There was no significant difference between the two groups. The mean changes of the HbA1c level were -0.11% in the control group and -0.09% in the pinitol group. There was no difference between the two groups. The mean changes in the level of fasting insulin and PP2 insulin were IU/L and IU/L, respectively, in the control group. The mean changes in the level of fasting insulin and PP2 insulin were 1.64 IU/L and 5.02 IU/L, respectively, in the pinitol group. There was no significant difference between the two groups. The mean changes of HOMA-IR were in the control group and 0.47 in the pinitol group. There was no difference between the two groups. The negative results of this study may be due to large SDs and lack of sufficient power. TABLE 2. The mean changes of the parameters of glucose control and level of adipocytokines after 12 weeks treatment. The data are presented as means±sds. HbA1c: glycosylated hemoglobin, PP2; 2 hour glucose after 75-gram glucose load, HOMA-IR: homeostasis model assessment-insulin resistance, RBP4: retinol binding protein 4. Control Pinitol Measurements P-value (n = 10) (n = 12) Glucose, fasting(mg/dl) -2.0 ± ± Glucose, PP2 (mg/dl) ± ± HbA1c (%) ± ± Insulin, fasting (IU/L) ± ± Insulin, PP2 (IU/L) ± ± HOMA-IR ± ± Adiponectin (μg/ml) ± ± Leptin (ng/ml) 1.06 ± ± RBP4 (mg/dl) ± ± The mean changes in the level of adipocytokines The mean changes in the level of adipocytokines are listed in Table 2. The mean changes in the level of adiponectin were μg/ml and 0.53 μg/ml in the pinitol group and the control group, respectively. The mean changes of the adiponectin level were significantly higher in the pinitol group than that in the control group (p=0.006). The mean changes in the level of leptin were 1.06 ng/ml in the control group and 0.59 ng/ml in the pinitol group. There was no significant difference between the two groups. The mean changes of the RBP4 level were mg/dl in the control group and mg/dl in the pinitol group. There was no significant difference between the two groups. These results may be due to large SDs and lack of sufficient power. Safety No notable safety findings (physical examination, vital signs and laboratory tests) were reported. Minor adverse events such as indigestion, dyspepsia, flu-like symptoms and palpitation were reported in both groups. None of the events were related with drug treatment. DISCUSSION According to previous studies, pinitol is a potential insulin sensitizer. Pinitol improved the glucose tolerance and insulin sensitivity in streptozotocin diabetic rats (Fonteles et al. 2000), hyperinsulinemic rhesus monkeys (Ortmeyer et al. 1995) and humans with type 2 diabetes (Kim et al. 2007; Kim et al. 2012) or polycystic ovarian syndrome (Baillargeon et al. 2004). Therefore, we expected that pinitol can improve insulin sensitivity and finally prevent diabetes mellitus or CVD in subjects with pre-diabetes. Yet after 12 weeks treatment, we couldn t find any difference of mean change in the level of glucose, insulin and insulin resistance between the pinitol and control groups (Table 2). Most of the previous studies were conducted on subjects with diabetes mellitus. To the best of our knowledge, this is the first study conducted on subjects in pre-diabetic state. We think that the difference characteristics of subjects, such as glucose tolerance, affected the discrepancy of our results and those of the previous studies. Twelve weeks treatment with pinitol was enough time to improve glucose level and insulin sensitivity in individuals with type 2 diabetes (Kim et al. 2007; Kim et al. 2012). However, for the subjects with pre-diabetes, 12 weeks may not be enough time to detect changes in the glucose level and insulin sensitivity. Initial difference of BMI might affect these negative data (Table 1). Although we randomized subjects, there is significant difference in BMI between control and pinitol group. The reason maybe small number of subjects and one subject with highest BMI. Adipokines are cytokine that are secreted from adipose tissue. In the previous studies, changes in the adipokine level were related to insulin resistance and several metabolic disorders (Hajer et al. 2008). Hypoadiponectinemia causes insulin resistance and an increment of adiponectin reflects improvement of insulin sensitivity (Hara et al. 2006; Matsubara et al. 2002). In this study, the changes of serum adiponectin were significantly higher in the pinitol group than that in the control group after 12 weeks of treatment. This means that pinitol could improve insulin sensitivity in subjects with pre-diabetes. The index of insulin sensitivity

4 114 The pinitol dose not effect in prediabetic patients such as HOMA-IR was not changed in our study. We thought that the change of adiponectin may occur prior to a change of insulin sensitivity. We think that if we treat with pinitol for a longer time than was done in this study, then the insulin sensitivity will change in the subjects with pre-diabetes. Leptin is one of the adipokines, and the serum level of leptin was correlated with insulin resistance and metabolic syndrome in several previous studies (Shankar and Xiao; 2010, Meier and Gressner, 2004). RBP4 is also one of the adipokines and the serum level of RBP4 was shown to be related to insulin resistance in previous studies (Esteve et al. 2009). In this study, the changes of serum leptin and RBP4 were not different between the two groups. Twelve weeks treatment with pinitol had no effect on the serum leptin and RBP4 concentration in the subjects with pre-diabetes. In conclusion, we demonstrated that a 12-week treatment with pinitol in the subjects with pre-diabetes had an effect on the serum level of adiponectin, but no effect on the serum levels of glucose and insulin, the insulin resistance and the serum levels of leptin and RBP4. This study has some limitations. The number of enrolled subjects was small. The period of drug treatment was just 12 weeks and this was not time enough to estimate the changes of insulin resistance and the serum level of adipokines in the subjects with pre-diabetes. Further studies are required to overcome these limitations. CONFLICTS OF INTEREST The authors have no potential conflicts of interest relevant to this article to report. REFERENCES American Diabetes Association. (2010). Diagnosis and classification of diabetes mellitus. Diabetes Care 33:S Aroda V.R., Ratner R. (2008). Approach to the patient with prediabetes. The Journal of Clinical Endocrinology and Metabolism 93: Baillargeon J.P., Iuorno M.J., Jakubowicz D.J., Apridonidze T., He N., Nestler J.E. (2004). Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism 89: Davis A., Christiansen M., Horowitz J.F., Klein S., Hellerstein M.K., Ostlund R.E. Jr. (2000). Effect of pinitol treatment on insulin action in subjects with insulin resistance. Diabetes Care 23: Esteve E., Ricart W., Fernández-Real J.M. (2009). Adipocytokines and insulin resistance: the possible role of lipocalin-2, retinol binding protein-4, and adiponectin. Diabetes Care 32:S Fonteles M.C., Almeida M.Q., Larner J. (2000). Antihyperglycemic effects of 3-O-methyl-D-chiro-inositol and D-chiro-inositol associated with manganese in streptozotocin diabetic rats. Hormone and Metabolic Research 32: Hajer G.R., van Haeften T.W., Visseren F.L. (2008). Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. European Heart Journal 29: Hara K., Horikoshi M., Yamauchi T., Yago H., Miyazaki O., Ebinuma H., Imai Y., Nagai R., Kadowaki T. (2006). Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 29: Huang L.C., Fonteles M.C., Houston D.B., Zhang C., Larner J. (1993). Chiroinositol deficiency and insulin resistance. III. Acute glycogenic and hypoglycemic effects of two inositol phosphoglycan insulin mediators in normal and streptozotocindiabetic rats in vivo. Endocrinology 132: Jones D.R., Varela-Nieto I. (1998). The role of glycosylphosphatidylinositol in signal transduction. The International Journal of Biochemistry and Cell Biology 30: Kim H.J., Park K.S., Lee S.K., Min K.W., Han K.A., Kim Y.K., Ku B.J. (2012). Effects of Pinitol on Glycemic Control, Insulin Resistance and Adipocytokine Levels in Patients with Type 2 Diabetes Mellitus. Annals of Nutrition and Metabolism 60:1-5. Kim M.J., Yoo K.H., Kim J.H., Seo Y.T., Ha B.W., Kho J.H., Shin Y.G., Chung C.H. (2007). Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes. Diabetes Research and Clinical Practice 77:S Knowler W.C., Barrett-Connor E., Fowler S.E., Hamman R.F., Lachin J.M., Walker E.A., Nathan D.M.: Diabetes Prevention Program Research Group. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine 346: Matsubara M., Maruoka S., Katayose S. (2002). Decreased plasma adiponectin concentrations in women with dyslipidemia. The Journal of Clinical Endocrinology and Metabolism 87: Meier U., Gressner A.M.(2004). Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clinical Chemistry 50: Nathan D.M., Davidson M.B., DeFronzo R.A., Heine R.J., Henry R.R., Pratley R., Zinman B.: American Diabetes Association. (2007). Impaired fasting glucose and impaired

5 The pinitol dose not effect in prediabetic patients 115 glucose tolerance: implications for care. Diabetes Care 30: Ortmeyer H.K., Larner J., Hansen B.C. (1995). Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys. Obesity Research 3:605S-608S. Rijkelijkhuizen J.M., Nijpels G., Heine R.J., Bouter L.M., Stehouwer C.D., Dekker J.M. (2007). High risk of cardiovascular mortality in individuals with impaired fasting glucose is explained by conversion to diabetes: the Hoorn study. Diabetes Care 30: Shankar A., Xiao J.(2010). Positive relationship between plasma leptin level and hypertension. Hypertension 56: Streeter J.G. (2001). Simple partial purification of D-pinitol from soybean leaves. Crop Science 41:

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