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Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes
Diabetes Research and Clinical Practice 77S (2007) S247–S251 www.elsevier.com/locate/diabres
Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes Mi Jin Kim a,*, Kwang Ha Yoo b, Ji Hoon Kim a, Young Tak Seo a, Byung Wook Ha a, Jang Hyun Kho c, Young Goo Shin c, Choon Hee Chung c a Department of Internal Medicine, Hong-ik Hospital, Seoul, Korea Department of Internal Medicine, College of Medicine, Konkuk University, Seoul, Korea c Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Korea b
Accepted 29 January 2007 Available online 27 April 2007
Abstract Pinitol (3-O-methyl-D-chiro-inositol) was identified in putative insulin mediator fractions that have hypoglycemic activity, and appears to mimic the act effects of insulin by acting downstream in the insulin signaling pathway. We evaluated the effect of pinitol therapy in type 2 diabetic patients who were poorly controlled with hypoglycemic drugs, such as sulfonylurea, metformin and/or insulin. Twenty type 2 diabetic patients were enrolled in our study. Fasting glucose, fasting c-peptide, total cholesterol, triglyceride, and HDL- and LDL-cholesterol were checked before and after a 12-week pinitol treatment (20 mg kg1 day1). All subjects continued their current medications during the study. Adipocytokines, such as adiponectin, leptin, free fatty acids, and c-reactive protein (CRP) were checked before and after pinitol treatment. After pinitol treatment, fasting glucose, post-prandial glucose levels, and hemoglobin A1c were significantly decreased (P < 0.05). Fasting serum adiponectin, leptin, free fatty acid, and CRP levels did not change after pinitol treatment. In the unresponsive group, serum c-peptide levels were higher than in the responsive group. Twelve weeks of pinitol treatment altered glucose metabolism, but not lipid profiles or adipocytokine levels, in type 2 diabetic patients. Additional research is needed to define the physiological and potential therapeutic effects of pinitol administration. # 2007 Published by Elsevier Ireland Ltd. Keywords: Diabetes mellitus; Pinitol; Adipocytokine
1. Introduction Inositol phosphoglycans are potentially important post-receptor mediators of insulin action [1,2]. Pinitol (3-O-methyl-D-chiro-inositol) was identified in putative insulin mediator fractions that had hypoglycemic * Corresponding author at: Division of Endocrinology, Department of Internal Medicine, Hong-ik Hospital, Shin-jeong 5 Dong, Yancheon-gu, Seoul 158-738, Korea. Tel.: +82 2 2600 0437; fax: +82 2 2600 0400. E-mail address: [email protected] (M.J. Kim). 0168-8227/$ – see front matter # 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.diabres.2007.01.066
activity, and appears to mimic the effects of insulin by acting downstream in the insulin signaling pathway [3]. Pinitol has been shown to lower the blood glucose concentration in diabetic rats and in normal rats given glucose [4]. This isomer also increased the rate of glucose disappearance in insulin-resistant and hyperinsulinemic monkeys [4,5], which suggests that it might improve glucose metabolism in addition to recover insulin resistance. However, it has been reported that pinitol administration dose not alter glucose metabolism nor improve insulin sensitivity [6]. We evaluated the effect of pinitol therapy on glucose metabolism and
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adipocytokines in type 2 diabetic patients who did not respond adequately to hypoglycemic drugs, such as sulfonylurea, metformin and/or insulin. 2. Materials and methods 2.1. Subjects and biochemical data This study included twenty type 2 diabetic patients (6 men and 14 women) who were poorly controlled with hypoglycemic drugs such as sulfonylurea, metformin and/or insulin. Poorly controlled hyperglycemic status was defined as recent fasting plasma glucose concentration 7.8 mmol/L or HbA1c 7.5%. All the subject’s heights and weights were recorded, and their adiposity was checked by a bioelectrical method (Inbody 2.0, Biospace1). The body mass index (BMI) was defined as weight(kg)/height(m2). The total cholesterol, HDLcholesterol, LDL-cholesterol, triglyceride, fasting plasma glucose, post-prandial glucose, fasting plasma c-peptide and HbA1c levels were checked after 10 h of fasting. Twenty-four hour urine albumin and protein excretion were checked. The above data were rechecked after pinitol treatment. Adipocytokines such as adiponectin, leptin, free fatty acid (FFA) and c-reactive protein (CRP) were checked after 10 h of fasting. Studies were performed at the Konkuk University School of Medicine in Seoul. The institutional review boards at each site approved the protocol and informed consent was obtained from each participant. 2.2. Materials and methods Pinitol containing 40–60% (w/w) chiroinositol was prepared from soybeans(AMICOGEN, Korea). Subjects consumed 20 mg kg1 day1 of pinitol for 12 weeks. All subjects also maintained their current medication for the 12 weeks of pinitol treatment. No patient had a history of allergy to soy protein or soy products. Subjects were encouraged to maintain their daily habits. Adverse reactions were checked at every visit. 2.3. Plasma adipocytokines measurement The plasma adiponectin levels and leptin levels were measured by radioimmunoassay using the Human Adiponectin RIA kit and the Human Leptin RIA kit, respectively (LINCO Research, Inc., USA). FFA levels were measured by an enzyme-linked immunosorbent assay using the Sicdia NEFAZYME kit (EIKEN, Japan). And plasma CRP levels were measured by an immonoturbidometry method using a creactive protein kit (Denka, Seiken, Japan).
baseline; and non-responder, HbA1c >11.5% of fasting blood glucose >14.0 mmol/L during the study course and <15% decrease in HbA1c levels and/or <20% decrease in fasting blood glucose levels after 12 weeks of pinitol treatment as compared with baseline. 2.5. Statistical analysis All data were expressed as the mean S.D. The SPSS 10.0 (Chicago, USA) programs were used for the statistical analyses. Differences between before and after pinitol treatment were assessed by unpaired Student’s t-test. And differences in clinical characteristics between the responsive group and unresponsive group were analyzed by the same method as above. A significance level of 5% was chosen for all the tests (P-value <0.05).
3. Results 3.1. Clinical data and basic parameters The mean age of the subjects was 56 years and the mean duration of diabetes was 9.8 7.2 years. Most of the patients had been prescribed glimepride and four patients had been prescribed insulin (Table 1). 3.2. Basic parameters changes after pinitol administration Fasting plasma glucose, post-prandial glucose and HbA1c levels were significantly reduced after 12 weeks of pinitol administration (Table 2, Fig. 1). 3.3. Biochemical differences between the responsive group and unresponsive group The unresponsive group had higher serum c-peptide levels than the responsive group (Table 3). Table 1 Clinical characteristics and current medication of patients Number Number Age (year) Sex (male/female) DM duration (year) Current medication
20 56.8 10.8 6/14 4 (20%)
2.4. Definition of responsive and unresponsive group Responders and non-responders to the pinitol administration were defined as follows: responder, >15% decrease in HbA1c levels and/or >20% decrease in fasting blood glucose levels after 12 weeks pinitol administration as compared with
Mean S.D.
10 (50%) 2 (10%) 4 (20%)
9.8 7.2 glimepride + metformin + a-glucosidase inhibitor glimepride + metformin glimepride insulin and/or glimepride, metformin, a-glucosidase inhibitor
M.J. Kim et al. / Diabetes Research and Clinical Practice 77S (2007) S247–S251 Table 2 Clinical and biochemical changes before and after pinitol treatment Pre-treatment Post-treatment P-value Weight (kg) 65.3 9.4 65.7 9.4 26.3 2.7 26.2 3.2 BMI (kg/m2) Fat content (kg) 20.1 5.0 20.9 4.6 Muscle content (kg) 42.6 8.2 42.3 8.3 FPG (mmol/L) 11.1 2.1 9.4 2.8 PP2hrG (mmol/L) 16.5 4.7 12.9 4.1 HbA1c (%) 9.8 1.6 8.3 1.1 C-peptide (nmol/L) 0.8 0.5 0.6 0.3 Total cholesterol (mmol/L) 5.2 0.9 5.3 1.5 Triglyceride (mmol/L) 4.8 3.5 4.0 2.5 HDL-cholesterol (mmol/L) 1.3 0.3 1.4 0.3 LDL-cholesterol (mmol/L) 3.0 0.8 3.5 1.3 GOT (IU/L) 26.6 18.6 25.5 12.3 GPT (IU/L) 33.2 28.2 34.7 27.8 24 h urinary protein 292.5 369.9 114.2 51.2 (mg/day) 24 h urinary albumin 63.9 167.4 32.9 71.1 (mg/min)
NS NS NS NS 0.03 0.02 0.008 NS NS NS NS NS NS NS NS NS
Data is expressed as the mean S.D.; FPG: fasting plasma glucose concentration; PP2hrG: post-prandial 2 h glucose concentration.
3.4. Plasma adipocytokine changes after pinitol administration The plasma adiponectin, leptin, FFA and CRP levels were not significantly different between before and after pinitol administration (Table 4). 4. Discussion Defective metabolism of D-chiro-inositol may be one of the causes of impaired insulin action and insulin resistance in type 2 diabetes. Inositol phosphoglycans are generated from membrane glycosylphosphatidyli-
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Table 3 Clinical and biochemical differences between the responsive and unresponsive group Responsive
Unresponsive P-value
Number (n) 15 5 Age (year) 57.6 11.9 54.2 6.5 DM duration (year) 9.9 8.3 9.4 2.6 Height (cm) 156.8 8.2 159.2 10.3 Weight (kg) 65.3 9.8 65.2 8.6 26.6 3.0 25.6 1.0 BMI (kg/m2) Fat content (kg) 20.8 5.5 17.9 2.4 Muscle content (kg) 41.9 7.8 44.8 9.9 FPG (mmol/L) 10.6 2.1 12.5 1.6 PP2hrG (mmol/L) 16.4 5.3 16.7 2.3 HbA1c (%) 10.0 1.6 9.0 1.3 C-peptide (nmol/L) 0.6 0.3 1.4 0.9 Total cholesterol (mmol/L) 5.2 1.0 5.2 0.7 Triglyceride (mmol/L) 4.9 3.5 4.4 3.8 HDL-cholesterol (mmol/L) 1.3 0.3 1.3 0.3 LDL-cholesterol (mmol/L) 2.9 0.9 3.1 0.3 GOT (IU/L) 28.2 21.1 21.8 6.6 GPT (IU/L) 36.1 32.1 24.4 6.9
NS NS NS NS NS NS NS NS NS NS 0.04 NS NS NS NS NS NS
Data is expressed as the mean S.D.; FPG: fasting plasma glucose concentration; PP2hrG: post-prandial 2 h glucose concentration.
nositol (GPI) phospholipids and/or GPI proteins as a result of insulin receptor binding [7,8]. Although inositol phosphoglycans have been shown to have insulin-like effects, their precise role in the insulinsignaling pathway is still unknown [9]. Reduced chiroinositol levels were associated with insulin resistance in animal studies [4,9] and with type 2 diabetes [10,11]. Nestler et al. demonstrated increased insulin action and recovery of insulin resistance in women with polycystic ovary syndrome treated with D-chiro-inositol [12]. This study showed that 12 weeks of pinitol administration significantly reduced plasma fasting glucose, post-prandial glucose and HbA1c levels. Fasting cpeptide levels were reduced after pinitol treatment, but not significantly. The observed reduction in fasting cpeptide levels may indicate a recovery of insulin resistance, but this cannot be confirmed because the decrease was not statistically. DeFronzo et al. reported that the hyperinsulinemic euglycemic clamp technique is
Table 4 Adipocytokine levels before and after pinitol treatment Pre-treatment
Fig. 1. Fasting glucose, post-prandial glucose and HbA1c changes between pre-and post-pinitol treatments. Data is expressed as the mean S.D; FPG: fasting plasma glucose concentration; PP2hrG: post-prandial 2 h glucose concentration.
Post-treatment P-value
Adiponectin (mg/mL) 6.1 3.3 6.0 2.9 Leptin (ng/mL) 7.5 6.2 8.6 5.8 Free Fatty Acid (mEq/L) 486.9 374.4 421.7 288.4 CRP (mg/dL) 0.2 0.4 0.3 0.4 Data is expressed as the mean S.D.
NS NS NS NS
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currently regarded as the gold standard for measuring insulin sensitivity [13]. However, this method requires highly trained personnel. QUICK (quantitative insulin sensitivity check index) and HOMAIR are also known as reliable indices of insulin sensitivity [14]. In our study, we did not perform a hyperinsulinemic euglycemic clamp study. Because of the insulin therapy status of patients, we were not able to perform QUICK or HOMAIR. To get an accurate measure of the effect of pinitol treatment on insulin resistance, we will need to perform a hyperinsulinemic euglycemic clamp study or an insulin tolerance test (ITT). After 12 weeks of pinitol treatment, HbA1c levels were significantly reduced (9.8 1.6% ! 8.3 1.1%). The mechanism by which pinitol lowers glucose may involve metabolism of inisitol phosphoglycan and enhanced insulin action on peripheral target tissues. Its action is similar to that of thiazolidinedion (TZD), the ‘‘insulin sensitizer’’. Treatment with TZD improves insulin-stimulated (i.e., muscle) glucose uptake [15,16]. TZD reduces triglyceride levels and FFA, and increases the total cholesterol and HDL-cholesterol levels [16]. After pinitol treatment, the lipid profile showed a change similar to that seen with TZD treatment, but the difference was not significant. Adverse reactions to TZD that occurred with a greater frequency than in the placebo group included edema and fluid retention [16]. Weight gain is more augmented with a sulfonylurea drug combination. During pinitol treatment, no patients complained of edema or weight gain. After pinitol treatment, 15 (75%) patients had decreased fasting glucose or HbA1c levels. Only fasting c-peptide levels showed a significant difference between the responsive and unresponsive group. Fasting glucose, post-prandial glucose levels, weight, age, diabetes duration and lipid levels did not differ between the responsive and unresponsive group. We presume that high fasting c-peptide levels represent increased insulin resistance status. The glucose-lowering effect of pinitol is more effective in the low c-peptide level group, indicating higher effectiveness in patients with low insulin resistance. Fat composition did not affect the difference between responsive and unresponsive group. Adiponectin is a 244-amino acid protein, with high structural homologies to collagen VIII, X and the complement C1q [17–20], as well as TNF-a [21]. Plasma adiponectin levels are lower in obese Caucasians [22] and Japanese with type 2 diabetes [23]. Berg et al. showed that TZD treatment increased plasma adiponectin concentrations and improved insulin resistance in db/db mice [24]. Leptin inhibits insulin secretion in b-cells and induces insulin resistance [25,26]. FFA is also an adipocytokine derived
from adipose tissue, and high levels of FFA are associated with insulin resistance [27]. After pinitol administration, plasma adiponectin, leptin, FFA and CRP levels were not changed. Plasma adiponectin, leptin, FFA and CRP levels were affected by body fat amounts, age, gender, and glucose status. This suggests that it is important to specifically address pinitol effects on adipocytokines. Our stuffy had some limitation. In the future, we must design a double-blinded placebo study to determine the exact effects of pinitol on glucose lowering. The glucose lowering effects of pinitol cannot be explained by pinitol treatment alone. Second, we will need to use objective methods, such as a hyperglycemic clamp study or insulin tolerance test, to prove insulin sensitization. Pinitol combination treatment may improve glucose metabolism in hyperglycemic patients independently of insulin or sulfonylurea drug treatment. Even so, additional research is needed to clarify the physiological and potential therapeutic effects of pinitol administration. References [1] K.L. Kelly, J.M. Mato, I. Merida, L. Jarrett, Glucose transport and antilipolysis are differentially regulated by the polar head group of an insulin-sensitive glycophospholipid, Proc. Natl. Acad. Sci. U.S.A. 84 (1987) 6404–6407. [2] J. Larner, G. Allan, C. Kessler, P. Reamer, R. Gunn, L. Cuang, Phosphoinositol glycan derived mediators and insulin resistance: prospects for diagnosis and therapy, J. Basic Clin. Physiol. Pharmacol. 9 (1988) 127–137. [3] M.C. Fonteles, L.C. Huang, J. Larner, Infusion of pH 2.0 D-chiroinositol glycan insulin putative mediator normalizes plasma glucose in streptozotocin diabetic rats at a dose equivalent to insulin without inducing hypoglycemia, Diabetologia 39 (1996) 731–734. [4] H.K. Ortmeyer, L.C. Huang, L. Zhang, B.C. Hansen, L. Larner, Chiroinositol deficiency and insulin resistance. II. Acute effects of D-chiroinositol administration in streptozotocin-diabetic rats, normal rats given a glucose load, and spontaneously insulinresistance rhesus monkeys, Endocrinology 132 (1993) 646–651. [5] H.K. Ortmeyer, J. Larner, B.C. Hansen, Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys, Obes. Res. 3 (1995) S605–S608. [6] A. Davis, M. Christiansen, J.F. Horowitz, S. Klein, M.K. Hellerstein, R.E. Ostlund Jr., Effect of pinitol treatment on insulin action in subjects with insulin resistance, Diabetes Care 23 (2000) 1000–1005. [7] G. Romero, J. Larner, Insulin mediators and the mechanism of insulin action, Adv. Pharmacol. 24 (1993) 21–50. [8] M.G. Low, A.R. Saltiel, Structural and functional roles of glycosylphosphatidylinositol in membrane, Science 239 (1988) 268–275. [9] J. Larner, L.C. Huang, C.F. Schwartz, A.S. Oswald, T.Y. Shen, M. Kinter, et al., Rat liver insulin mediator which stimulates
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Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes Mi Jin Kim a,*, Kwang Ha Yoo b, Ji Hoon Kim a, Young Tak Seo a, Byung Wook Ha a, Jang Hyun Kho c, Young Goo Shin c, Choon Hee Chung c a Department of Internal Medicine, Hong-ik Hospital, Seoul, Korea Department of Internal Medicine, College of Medicine, Konkuk University, Seoul, Korea c Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Korea b
Accepted 29 January 2007 Available online 27 April 2007
Abstract Pinitol (3-O-methyl-D-chiro-inositol) was identified in putative insulin mediator fractions that have hypoglycemic activity, and appears to mimic the act effects of insulin by acting downstream in the insulin signaling pathway. We evaluated the effect of pinitol therapy in type 2 diabetic patients who were poorly controlled with hypoglycemic drugs, such as sulfonylurea, metformin and/or insulin. Twenty type 2 diabetic patients were enrolled in our study. Fasting glucose, fasting c-peptide, total cholesterol, triglyceride, and HDL- and LDL-cholesterol were checked before and after a 12-week pinitol treatment (20 mg kg1 day1). All subjects continued their current medications during the study. Adipocytokines, such as adiponectin, leptin, free fatty acids, and c-reactive protein (CRP) were checked before and after pinitol treatment. After pinitol treatment, fasting glucose, post-prandial glucose levels, and hemoglobin A1c were significantly decreased (P < 0.05). Fasting serum adiponectin, leptin, free fatty acid, and CRP levels did not change after pinitol treatment. In the unresponsive group, serum c-peptide levels were higher than in the responsive group. Twelve weeks of pinitol treatment altered glucose metabolism, but not lipid profiles or adipocytokine levels, in type 2 diabetic patients. Additional research is needed to define the physiological and potential therapeutic effects of pinitol administration. # 2007 Published by Elsevier Ireland Ltd. Keywords: Diabetes mellitus; Pinitol; Adipocytokine
1. Introduction Inositol phosphoglycans are potentially important post-receptor mediators of insulin action [1,2]. Pinitol (3-O-methyl-D-chiro-inositol) was identified in putative insulin mediator fractions that had hypoglycemic * Corresponding author at: Division of Endocrinology, Department of Internal Medicine, Hong-ik Hospital, Shin-jeong 5 Dong, Yancheon-gu, Seoul 158-738, Korea. Tel.: +82 2 2600 0437; fax: +82 2 2600 0400. E-mail address: [email protected] (M.J. Kim). 0168-8227/$ – see front matter # 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.diabres.2007.01.066
activity, and appears to mimic the effects of insulin by acting downstream in the insulin signaling pathway [3]. Pinitol has been shown to lower the blood glucose concentration in diabetic rats and in normal rats given glucose [4]. This isomer also increased the rate of glucose disappearance in insulin-resistant and hyperinsulinemic monkeys [4,5], which suggests that it might improve glucose metabolism in addition to recover insulin resistance. However, it has been reported that pinitol administration dose not alter glucose metabolism nor improve insulin sensitivity [6]. We evaluated the effect of pinitol therapy on glucose metabolism and
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adipocytokines in type 2 diabetic patients who did not respond adequately to hypoglycemic drugs, such as sulfonylurea, metformin and/or insulin. 2. Materials and methods 2.1. Subjects and biochemical data This study included twenty type 2 diabetic patients (6 men and 14 women) who were poorly controlled with hypoglycemic drugs such as sulfonylurea, metformin and/or insulin. Poorly controlled hyperglycemic status was defined as recent fasting plasma glucose concentration 7.8 mmol/L or HbA1c 7.5%. All the subject’s heights and weights were recorded, and their adiposity was checked by a bioelectrical method (Inbody 2.0, Biospace1). The body mass index (BMI) was defined as weight(kg)/height(m2). The total cholesterol, HDLcholesterol, LDL-cholesterol, triglyceride, fasting plasma glucose, post-prandial glucose, fasting plasma c-peptide and HbA1c levels were checked after 10 h of fasting. Twenty-four hour urine albumin and protein excretion were checked. The above data were rechecked after pinitol treatment. Adipocytokines such as adiponectin, leptin, free fatty acid (FFA) and c-reactive protein (CRP) were checked after 10 h of fasting. Studies were performed at the Konkuk University School of Medicine in Seoul. The institutional review boards at each site approved the protocol and informed consent was obtained from each participant. 2.2. Materials and methods Pinitol containing 40–60% (w/w) chiroinositol was prepared from soybeans(AMICOGEN, Korea). Subjects consumed 20 mg kg1 day1 of pinitol for 12 weeks. All subjects also maintained their current medication for the 12 weeks of pinitol treatment. No patient had a history of allergy to soy protein or soy products. Subjects were encouraged to maintain their daily habits. Adverse reactions were checked at every visit. 2.3. Plasma adipocytokines measurement The plasma adiponectin levels and leptin levels were measured by radioimmunoassay using the Human Adiponectin RIA kit and the Human Leptin RIA kit, respectively (LINCO Research, Inc., USA). FFA levels were measured by an enzyme-linked immunosorbent assay using the Sicdia NEFAZYME kit (EIKEN, Japan). And plasma CRP levels were measured by an immonoturbidometry method using a creactive protein kit (Denka, Seiken, Japan).
baseline; and non-responder, HbA1c >11.5% of fasting blood glucose >14.0 mmol/L during the study course and <15% decrease in HbA1c levels and/or <20% decrease in fasting blood glucose levels after 12 weeks of pinitol treatment as compared with baseline. 2.5. Statistical analysis All data were expressed as the mean S.D. The SPSS 10.0 (Chicago, USA) programs were used for the statistical analyses. Differences between before and after pinitol treatment were assessed by unpaired Student’s t-test. And differences in clinical characteristics between the responsive group and unresponsive group were analyzed by the same method as above. A significance level of 5% was chosen for all the tests (P-value <0.05).
3. Results 3.1. Clinical data and basic parameters The mean age of the subjects was 56 years and the mean duration of diabetes was 9.8 7.2 years. Most of the patients had been prescribed glimepride and four patients had been prescribed insulin (Table 1). 3.2. Basic parameters changes after pinitol administration Fasting plasma glucose, post-prandial glucose and HbA1c levels were significantly reduced after 12 weeks of pinitol administration (Table 2, Fig. 1). 3.3. Biochemical differences between the responsive group and unresponsive group The unresponsive group had higher serum c-peptide levels than the responsive group (Table 3). Table 1 Clinical characteristics and current medication of patients Number Number Age (year) Sex (male/female) DM duration (year) Current medication
20 56.8 10.8 6/14 4 (20%)
2.4. Definition of responsive and unresponsive group Responders and non-responders to the pinitol administration were defined as follows: responder, >15% decrease in HbA1c levels and/or >20% decrease in fasting blood glucose levels after 12 weeks pinitol administration as compared with
Mean S.D.
10 (50%) 2 (10%) 4 (20%)
9.8 7.2 glimepride + metformin + a-glucosidase inhibitor glimepride + metformin glimepride insulin and/or glimepride, metformin, a-glucosidase inhibitor
M.J. Kim et al. / Diabetes Research and Clinical Practice 77S (2007) S247–S251 Table 2 Clinical and biochemical changes before and after pinitol treatment Pre-treatment Post-treatment P-value Weight (kg) 65.3 9.4 65.7 9.4 26.3 2.7 26.2 3.2 BMI (kg/m2) Fat content (kg) 20.1 5.0 20.9 4.6 Muscle content (kg) 42.6 8.2 42.3 8.3 FPG (mmol/L) 11.1 2.1 9.4 2.8 PP2hrG (mmol/L) 16.5 4.7 12.9 4.1 HbA1c (%) 9.8 1.6 8.3 1.1 C-peptide (nmol/L) 0.8 0.5 0.6 0.3 Total cholesterol (mmol/L) 5.2 0.9 5.3 1.5 Triglyceride (mmol/L) 4.8 3.5 4.0 2.5 HDL-cholesterol (mmol/L) 1.3 0.3 1.4 0.3 LDL-cholesterol (mmol/L) 3.0 0.8 3.5 1.3 GOT (IU/L) 26.6 18.6 25.5 12.3 GPT (IU/L) 33.2 28.2 34.7 27.8 24 h urinary protein 292.5 369.9 114.2 51.2 (mg/day) 24 h urinary albumin 63.9 167.4 32.9 71.1 (mg/min)
NS NS NS NS 0.03 0.02 0.008 NS NS NS NS NS NS NS NS NS
Data is expressed as the mean S.D.; FPG: fasting plasma glucose concentration; PP2hrG: post-prandial 2 h glucose concentration.
3.4. Plasma adipocytokine changes after pinitol administration The plasma adiponectin, leptin, FFA and CRP levels were not significantly different between before and after pinitol administration (Table 4). 4. Discussion Defective metabolism of D-chiro-inositol may be one of the causes of impaired insulin action and insulin resistance in type 2 diabetes. Inositol phosphoglycans are generated from membrane glycosylphosphatidyli-
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Table 3 Clinical and biochemical differences between the responsive and unresponsive group Responsive
Unresponsive P-value
Number (n) 15 5 Age (year) 57.6 11.9 54.2 6.5 DM duration (year) 9.9 8.3 9.4 2.6 Height (cm) 156.8 8.2 159.2 10.3 Weight (kg) 65.3 9.8 65.2 8.6 26.6 3.0 25.6 1.0 BMI (kg/m2) Fat content (kg) 20.8 5.5 17.9 2.4 Muscle content (kg) 41.9 7.8 44.8 9.9 FPG (mmol/L) 10.6 2.1 12.5 1.6 PP2hrG (mmol/L) 16.4 5.3 16.7 2.3 HbA1c (%) 10.0 1.6 9.0 1.3 C-peptide (nmol/L) 0.6 0.3 1.4 0.9 Total cholesterol (mmol/L) 5.2 1.0 5.2 0.7 Triglyceride (mmol/L) 4.9 3.5 4.4 3.8 HDL-cholesterol (mmol/L) 1.3 0.3 1.3 0.3 LDL-cholesterol (mmol/L) 2.9 0.9 3.1 0.3 GOT (IU/L) 28.2 21.1 21.8 6.6 GPT (IU/L) 36.1 32.1 24.4 6.9
NS NS NS NS NS NS NS NS NS NS 0.04 NS NS NS NS NS NS
Data is expressed as the mean S.D.; FPG: fasting plasma glucose concentration; PP2hrG: post-prandial 2 h glucose concentration.
nositol (GPI) phospholipids and/or GPI proteins as a result of insulin receptor binding [7,8]. Although inositol phosphoglycans have been shown to have insulin-like effects, their precise role in the insulinsignaling pathway is still unknown [9]. Reduced chiroinositol levels were associated with insulin resistance in animal studies [4,9] and with type 2 diabetes [10,11]. Nestler et al. demonstrated increased insulin action and recovery of insulin resistance in women with polycystic ovary syndrome treated with D-chiro-inositol [12]. This study showed that 12 weeks of pinitol administration significantly reduced plasma fasting glucose, post-prandial glucose and HbA1c levels. Fasting cpeptide levels were reduced after pinitol treatment, but not significantly. The observed reduction in fasting cpeptide levels may indicate a recovery of insulin resistance, but this cannot be confirmed because the decrease was not statistically. DeFronzo et al. reported that the hyperinsulinemic euglycemic clamp technique is
Table 4 Adipocytokine levels before and after pinitol treatment Pre-treatment
Fig. 1. Fasting glucose, post-prandial glucose and HbA1c changes between pre-and post-pinitol treatments. Data is expressed as the mean S.D; FPG: fasting plasma glucose concentration; PP2hrG: post-prandial 2 h glucose concentration.
Post-treatment P-value
Adiponectin (mg/mL) 6.1 3.3 6.0 2.9 Leptin (ng/mL) 7.5 6.2 8.6 5.8 Free Fatty Acid (mEq/L) 486.9 374.4 421.7 288.4 CRP (mg/dL) 0.2 0.4 0.3 0.4 Data is expressed as the mean S.D.
NS NS NS NS
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currently regarded as the gold standard for measuring insulin sensitivity [13]. However, this method requires highly trained personnel. QUICK (quantitative insulin sensitivity check index) and HOMAIR are also known as reliable indices of insulin sensitivity [14]. In our study, we did not perform a hyperinsulinemic euglycemic clamp study. Because of the insulin therapy status of patients, we were not able to perform QUICK or HOMAIR. To get an accurate measure of the effect of pinitol treatment on insulin resistance, we will need to perform a hyperinsulinemic euglycemic clamp study or an insulin tolerance test (ITT). After 12 weeks of pinitol treatment, HbA1c levels were significantly reduced (9.8 1.6% ! 8.3 1.1%). The mechanism by which pinitol lowers glucose may involve metabolism of inisitol phosphoglycan and enhanced insulin action on peripheral target tissues. Its action is similar to that of thiazolidinedion (TZD), the ‘‘insulin sensitizer’’. Treatment with TZD improves insulin-stimulated (i.e., muscle) glucose uptake [15,16]. TZD reduces triglyceride levels and FFA, and increases the total cholesterol and HDL-cholesterol levels [16]. After pinitol treatment, the lipid profile showed a change similar to that seen with TZD treatment, but the difference was not significant. Adverse reactions to TZD that occurred with a greater frequency than in the placebo group included edema and fluid retention [16]. Weight gain is more augmented with a sulfonylurea drug combination. During pinitol treatment, no patients complained of edema or weight gain. After pinitol treatment, 15 (75%) patients had decreased fasting glucose or HbA1c levels. Only fasting c-peptide levels showed a significant difference between the responsive and unresponsive group. Fasting glucose, post-prandial glucose levels, weight, age, diabetes duration and lipid levels did not differ between the responsive and unresponsive group. We presume that high fasting c-peptide levels represent increased insulin resistance status. The glucose-lowering effect of pinitol is more effective in the low c-peptide level group, indicating higher effectiveness in patients with low insulin resistance. Fat composition did not affect the difference between responsive and unresponsive group. Adiponectin is a 244-amino acid protein, with high structural homologies to collagen VIII, X and the complement C1q [17–20], as well as TNF-a [21]. Plasma adiponectin levels are lower in obese Caucasians [22] and Japanese with type 2 diabetes [23]. Berg et al. showed that TZD treatment increased plasma adiponectin concentrations and improved insulin resistance in db/db mice [24]. Leptin inhibits insulin secretion in b-cells and induces insulin resistance [25,26]. FFA is also an adipocytokine derived
from adipose tissue, and high levels of FFA are associated with insulin resistance [27]. After pinitol administration, plasma adiponectin, leptin, FFA and CRP levels were not changed. Plasma adiponectin, leptin, FFA and CRP levels were affected by body fat amounts, age, gender, and glucose status. This suggests that it is important to specifically address pinitol effects on adipocytokines. Our stuffy had some limitation. In the future, we must design a double-blinded placebo study to determine the exact effects of pinitol on glucose lowering. The glucose lowering effects of pinitol cannot be explained by pinitol treatment alone. Second, we will need to use objective methods, such as a hyperglycemic clamp study or insulin tolerance test, to prove insulin sensitization. Pinitol combination treatment may improve glucose metabolism in hyperglycemic patients independently of insulin or sulfonylurea drug treatment. Even so, additional research is needed to clarify the physiological and potential therapeutic effects of pinitol administration. References [1] K.L. Kelly, J.M. Mato, I. Merida, L. Jarrett, Glucose transport and antilipolysis are differentially regulated by the polar head group of an insulin-sensitive glycophospholipid, Proc. Natl. Acad. Sci. U.S.A. 84 (1987) 6404–6407. [2] J. Larner, G. Allan, C. Kessler, P. Reamer, R. Gunn, L. Cuang, Phosphoinositol glycan derived mediators and insulin resistance: prospects for diagnosis and therapy, J. Basic Clin. Physiol. Pharmacol. 9 (1988) 127–137. [3] M.C. Fonteles, L.C. Huang, J. Larner, Infusion of pH 2.0 D-chiroinositol glycan insulin putative mediator normalizes plasma glucose in streptozotocin diabetic rats at a dose equivalent to insulin without inducing hypoglycemia, Diabetologia 39 (1996) 731–734. [4] H.K. Ortmeyer, L.C. Huang, L. Zhang, B.C. Hansen, L. Larner, Chiroinositol deficiency and insulin resistance. II. Acute effects of D-chiroinositol administration in streptozotocin-diabetic rats, normal rats given a glucose load, and spontaneously insulinresistance rhesus monkeys, Endocrinology 132 (1993) 646–651. [5] H.K. Ortmeyer, J. Larner, B.C. Hansen, Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys, Obes. Res. 3 (1995) S605–S608. [6] A. Davis, M. Christiansen, J.F. Horowitz, S. Klein, M.K. Hellerstein, R.E. Ostlund Jr., Effect of pinitol treatment on insulin action in subjects with insulin resistance, Diabetes Care 23 (2000) 1000–1005. [7] G. Romero, J. Larner, Insulin mediators and the mechanism of insulin action, Adv. Pharmacol. 24 (1993) 21–50. [8] M.G. Low, A.R. Saltiel, Structural and functional roles of glycosylphosphatidylinositol in membrane, Science 239 (1988) 268–275. [9] J. Larner, L.C. Huang, C.F. Schwartz, A.S. Oswald, T.Y. Shen, M. Kinter, et al., Rat liver insulin mediator which stimulates
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