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Insulin Resistance in Type 2 Diabetes Mellitus May Be Related to Bone Mineral Density
Journal of Clinical Densitometry: Assessment of Skeletal Health, vol. 15, no. 2, 186e190, 2012 Ó Copyright 2012 by The International Society for Clinical Densitometry 1094-6950/15:186e190/$36.00 DOI: 10.1016/j.jocd.2011.11.005
Original Article
Insulin Resistance in Type 2 Diabetes Mellitus May Be Related to Bone Mineral Density Senay Arikan,*,1 Alpaslan Tuzcu,1 Mithat Bahceci,1 Sehmuz Ozmen,2 and Deniz Gokalp1 1
Department of Endocrinology, Dicle University Medical Faculty, Diyarbakır, Turkey; and 2Department of Nephrology, Dicle University Medical Faculty, Diyarbakır, Turkey
Abstract The mechanism of bone mineral density (BMD) changes in type 2 diabetes mellitus is not clear. We aimed to investigate the effect of insulin resistance in type 2 diabetics on BMD. Insulin resistance was determined using the homeostasis model assessment index (HOMA-IR). Nineteen type 2 diabetic patients with a HOMA-IR !2.7 (mean age, 51.5 9.6 yr; body mass index [BMI], 27.3 5.1 kg/m2; duration of diabetes, 10.5 7.3 yr) were included in Group A, and 30 BMI- and age-matched type 2 diabetic patients with a HOMA-IR 2.7 were included in Group B. The BMD was measured with dual-energy X-ray absorptiometry. Independent t-test was used for statistical analysis. The Group A values for mean fasting glucose and insulin levels were 160.1 77.0 mg/dL and 4.79 2.89 mU/L, respectively, whereas the Group B values were 195.1 58.9 mg/dL ( p O 0.05) and 19.30 16.89 mU/L ( p 5 0.0001). Significantly higher total lumbar vertebra T-score ( p 5 0.02) and total lumbar vertebra BMD in Group A were determined than Group B ( p 5 0.033). The lumbar vertebra total Z-score was significantly lower in Group B ( p 5 0.042). Marked insulin resistance may have a negative effect on BMD in type 2 diabetics, while the presence of hyperinsulinemia may be associated with the low BMD. Key Words: DXA; insulin resistance; osteoporosis; type 2 diabetes mellitus.
BMD in type 2 diabetic patients when compared with healthy controls (1,3e5). Both osteoporosis and obesity increase with aging (6). Obesity is known to have protective effects on the bone even if contributes to insulin resistance. It has recently been postulated that chronic low-grade inflammatory conditions lead to an association between insulin resistance and osteoporosis by causing oxidative stress (7). Type 2 diabetic patients are reported to have decreased osteocalcin levels with an increase in these levels once glycemic control is normalized (2). Bone turnover rate also increases in type 2 diabetics and bone formation usually decreases (8). On the contrary, bone resorption stays normal or decreases with poorly glycemic control, whereas both resorption and formation increases when glycemic control is normalized (8,9). Our aim in this study was to evaluate the effect of insulin resistance in type 2 diabetic patients on BMD and the
Introduction The relationship between axial bone mass and type 2 diabetes mellitus has been known for many years (1e3). However, it is still not clear which parameters such as bone mineral density (BMD), fracture incidence, and osteoporosis biochemical markers are influenced by diabetes (1). Diabetes is a heterogenous disease with a variable degree of obesity, intrinsic insulin secretion, and intrinsic insulin resistance between individuals (1,2). Type 2 diabetes can be accompanied by hyperinsulinemia or hypoinsulinemia. There are conflicting studies reporting an increase, decrease, or no change in Received 09/24/11; Revised 11/19/11; Accepted 11/20/11. *Address correspondence to: S¸enay Arıkan, PhD, Dicle € Universitesi Tıp Fak€ultesi, Endokrinoloji BD, Diyarbakir 21280, Turkey. E-mail: [email protected]
186
Effect of Insulin Resistance on Bone Mineral Density in Type 2 Diabetic Patients correlation between glycemic control and anthropometric parameters and the BMD value.
Subjects and Methods We included a total of 59 type 2 diabetes mellitus patients consisting of 34 females and 25 males that presented to the Dicle University Medical Faculty, Department of Endocrinology (mean age, 52 9 yr; duration of diabetes, 9.5 7.3 yr) in the study.
Determination of Insulin Resistance All patients were using regime of insulin or insulin plus oral antidiabetic drug because of poor glycemic control. Longacting and intermediate-acting insulins were stopped 24 h ago and regular insulin was given and insulin-sensitizing drugs, such as metformin or thiazolidinedione and acarbose, were discontinued at least 48 h before blood sampling. Blood samples were obtained by placing a catheter into the antecubital vein before administering insulin and/or oral antidiabetic drugs between 08:00 and 09:00 AM after a fast of at least 12 h. The blood samples were stored at 20 C for fasting glucose and insulin. Insulin resistance was calculated using the homeostasis model assessment index (HOMA-IR) formula: Fasting insulin ðmU=mLÞ HOMA-IR 5
Fasting glucose ðmmol=LÞ ð10Þ: 22; 5
The HOMA-IR is a useful, validated method for evaluating insulin resistance. Bonora et al (11) suggested that the top quintile of the HOMA-IR, that is, a value 2.77, had isolated insulin resistance in subjects with no metabolic disorders. Yeni-Komshian et al (12) suggested that the cutoff of HOMA-IR in 490 healthy nondiabetic volunteers based on determining the steady-state plasma glucose was 2.7. In this study, HOMA-IR cut-off value was determined to be 2.7 (2.7 resistant, !2.7 sensitive).
Creating Study Groups It was not possible to access fasting insulin or glucose results in 10 patients. Nineteen diabetic patients with HOMAIR !2.7 were placed in Group A (mean age, 51.5 9.6 yr; body mass index [BMI], 27.3 5.1 kg/m2; duration of diabetes, 10.5 7.3 yr), whereas 30 diabetic patients with HOMAIR 2.7 were put in Group B (mean age, 52.7 8.8 yr; BMI, 27.7 4.5 kg/m2; duration of diabetes, 9.7 8.2 yr).
Anthropometric Measurements The BMI was calculated without shoes using height and weight measurements (BMI [kg/m2] 5 body weight [kg]/ height2[m]). Electrical bioimpedance (TANITA Corporation 14-2, 1-chome, Maeno-cho, Itaba-shi-hu, Tokyo, Japan) was used to measure the fat mass (kg), fat percent (%F), and fat-free body weight (kg). Journal of Clinical Densitometry: Assessment of Skeletal Health
187
BMD Measurement In our study, the BMD of the hip and lumbar spine (L1eL4) were measured by dual-energy X-ray absorptiometry (DXA) (Hologic Discovery QDR 4500a, WA). In the total hip, BMD was measured. Posterior-anterior lumbar spine (L1eL4) scans were performed with the patient lying supine on the imaging table using the protocols recommended by the manufacturer. The measurement results were expressed in absolute values, as T-score (the difference in standard deviation [SD] with respect to the peak bone mass in a young adult of the same race and sex) and Z- score (the difference in SD with respect to that found for healthy age-matched controls of the same race and sex). Low bone density was defined as T-score between 1 and 2.5 SD. Osteoporosis was defined as T-score of !2.5 SD. BMDs was defined as bone mineral content (BMC) divided by the projected area of the scanned image: BMD 5
BMC Area ðg=cm2 Þ
Laboratory Investigation Plasma glucose was measured by using the glucose oxidase method with an automated glucose analyzer (Abott aeroset autoanalyzer, TOSHIBA, Japan). Serum insulin and C-peptide levels were determined by electrochemiluminescence immunoassay by using Modular Analytics E170 (Elecsys module) immunoassay analyzers (Roche Diagnostics 1010/2010, Mannheim, USA). HbA1c was measured on an Aeroset/C8000 autoanalyser (Abbott Diagnostics, Abbott Park, Illinois).
Statistical Analysis All results were presented as mean SD. The independent t-test was used to compare the groups. The chi-square test was used to determine the distribution of the groups by sex. Relationship between variables was evaluated with Pearson’s correlation test. Values p ! 0.05 were accepted as statistically significant.
Results The mean HbA1c value was 10.9 2.8% and the BMI was 27.7 4.8 kg/m2 on presentation for all patients (n 5 59). In addition, levels of mean HbA1c (%) were separately measured as 10.5 3.3 in Group A and 11.3 2.5 in Group B. They were not statistically different despite the HbA1c level in Group B was slightly higher from Group A. There was no difference between the groups (Group A and Group B) for age, BMI, or duration of diabetes. The demographic features of the groups were shown in Table 1. Mean fasting glucose and insulin levels were 160.1 77.0 mg/dL and 4.79 2.89 mU/mL, respectively, in Group A and 195.1 58.9 mg/dL ( p O 0.05) and 19.30 16.89 mU/mL in Group B ( p 5 0.0001). There were statistically significant differences between groups in the Volume 15, 2012
188
Arikan et al. Table 1 Demographic Features of the Type 2 Diabetic Patients Group A (HOMA-IR ! 2.7) (N 5 19)
Group B (HOMA-IR 2.7) (N 5 30)
p
51.5 9.6 12/7 70.6 11.1 27.3 5.1 25.0 11.1 33.8 12.7 44.7 11.7 10.5 7.3 160.1 77.0 284.1 150.1 4.79 2.89 2.1 1.6 10.5 3.3
52.7 8.8 17/13 73.1 10.9 27.7 4.5 22.2 12.8 28.4 13.0 51.1 8.6 9.7 8.2 195.1 58.9 291.0 66.9 19.30 16.89 3.9 1.3 11.3 2.5
NS NS NS NS NS NS NS NS NS NS 0.0001 0.01 NS
Age (yr) Sex (female/male) Body weight (kg) BMI (kg/m2) Fat mass (kg) Fat percentage (%) Fat-free body weight (kg) Duration of diabetes mellitus (yr) Fasting glucose (mg/dL) Postprandial glucose (mg/dL) Fasting insulin (mU/mL) Fasting C-peptide (ng/mL) HbA1c (%)
DXA measurements (mean total lumbar vertebra T-score 1.33 1.14 in Group B vs 0.29 1.93 in Group A, p 5 0.02) and (mean lumbar vertebra total BMD 0.91 0.13 gr/cm2 in Group B vs 1.03 0.21 gr/cm2 in Group A, p 5 0.033). The mean lumbar vertebra total Z-score was also significantly lower in Group B (Group A: 0.51 1.89; Group B: 0.51 1.04, p 5 0.042). The DXA results for the groups were presented in Table 2. We found no correlation between BMD, fasting and postprandial plasma glucose, insulin, and C-peptide levels. Total hip BMD measurements showed a positive correlation with BMI, fat mass, and fat percentage. But, we did not find any relation between lumbar vertebra BMD and anthropometric measurements. There was a negative correlation between
BMD and age. Duration of diabetes does not seem to be an important factor affecting BMD in type 2 diabetic patients, as we found no correlation between duration of diabetes and BMD. All results of correlation analysis were presented in Table 3.
Discussion BMD is known to decrease in type 1 diabetics and increase in type 2 diabetics. This inconsistency of BMD in diabetics is attributed to hyperinsulinemia (13). But, our finding demonstrated that BMD was less in type 2 diabetic patients who have higher insulin resistance than diabetic patients with less insulin resistance. More importantly, this negative effect
Table 2 DXA Results of Type 2 Diabetic Patients Group A (HOMA-IR ! 2.7) (N 5 19) BMD (gr/cm2) (n 5 49) BMD (gr/cm2) T-score Z-score 0.26 1.95 0.31 1.89 0.10 2.44*** 0.27 2.01*
0.46 1.90 0.49 1.79 0.73 2.38 0.43 1.94**
Group B (HOMA-IR 2.7) (N 5 30) BMD (gr/cm2)
T-score
0.86 0.13 0.93 0.15 0.92 0.13*** 0.94 0.13**
0.86 1.14 1.13 1.30 1.48 1.18*** 1.68 1.21*
Z-score
L1 L2 L3 L4
0.92 0.19 1.00 0.20 1.07 0.26*** 1.07 0.21**
0.15 1.08 0.35 1.15 0.65 1.08** 0.76 1.12**
Total lumbar
1.03 0.21*** 0.29 1.93**
0.51 1.89**** 0.91 0.13*** 1.33 1.14**
0.51 1.04****
Neck Tro Inter
0.82 0.14** 0.69 0.15 1.24 0.20
0.27 1.39* 0.23 1.58 0.72 1.34
0.55 1.34* 0.28 1.51 1.13 1.30
0.73 0.11** 0.63 0.08 1.15 0.16
1.14 1.00* 0.86 0.83 0.14 1.04
0.20 1.00* 0.33 0.93 0.56 1.01
Total hip
1.04 0.18
0.64 1.58
1.23 1.50
0.97 0.13
0.02 1.09
0.61 1.11
Abbr: Neck, femoral neck; Inter, intertrochanteric area; Tro, trochanteric area. *p 5 0.01; **p 5 0.02; *** p 5 0.03; ****p 5 0.04. Journal of Clinical Densitometry: Assessment of Skeletal Health
Volume 15, 2012
Effect of Insulin Resistance on Bone Mineral Density in Type 2 Diabetic Patients
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Table 3 The Table Shows the Relation Between BMD and Glycemic Control and Anthropometric Measurements BMD (gr/cm2) (n 5 59)
Age
BMI
Fat Percent
Fat Mass
Duration of Diabetes Mellitus
p
r
p
r
p
r
p
r
p
r
L1 L2 L3 L4
0.003* 0.004* 0.01* 0.02*
0.38 0.37 0.33 0.28
0.175 0.209 0.245 0.164
0.17 0.16 0.15 0.18
0.423 0.428 0.073 0.130
0.13 0.13 0.30 0.25
0.160 0.140 0.06 0.108
0.23 0.25 0.31 0.27
0.548 0.481 0.333 0.996
0.08 0.09 0.12 0.00
Total lumbar
0.006*
0.35
0.261
0.14
0.162
0.23
0.083
0.29
0.561
0.07
Neck Tro Inter
0.05 0.06 0.02*
0.24 0.24 0.30
0.012* 0.001* 0.021*
0.32 0.44 0.30
0.002* 0.013* 0.004*
0.48 0.40 0.46
0.001* 0.002* 0.001*
0.53 0.50 0.51
0.884 0.914 0.673
0.02 0.01 0.05
Total hip
0.006*
0.35
0.01*
0.32
0.004*
0.47
0.001*
0.53
0.748
0.04
Abbr: BMD, bone mineral density. *p ! 0.05 was accepted as significant.
on BMD developed despite hyperinsulinemia in type 2 diabetic patients. In addition, our data indicated that the negative effects of insulin resistance on BMD in type 2 diabetics were probably independent of body fat mass. Previously, many studies reported an increase in BMD in type 2 diabetics (13e17). Vestergaard (18) showed in a metaanalysis that BMD decreased in type 1 diabetic patients, but increased in type 2 diabetics and that there was an increased hip fracture risk in both type 1 and type 2 diabetics. The same metaanalysis showed BMI to be the major determining factor of BMD in diabetics (18). On the contrary, a recent study by Shan et al (19) showed that the high BMI levels decreased lumbar vertebra fracture risk in postmenopausal type 2 diabetic women and that low BMI was an indicator of osteoporosis. Probably, the heterogeneity of type 2 diabetes and/or the different study methodologies may be responsible for these conflicting results. In our study, we observed a positive correlation between total femur BMD and BMI, and fat mass and fat percentage in all study population. On the contrary, no correlation was found between lumbar vertebra BMD and anthropometric measurements, whereas there was a negative correlation between BMD and age in all diabetic patients. These results indicated that increased fat tissue in type 2 diabetics have a beneficial effect on BMD measurements, especially those from the hip. However, the exact mechanism increasing the BMD in type 2 diabetic patients is not fully understood. Our data indicated that clarified insulin resistance and hyperinsulinemia were a negative effect on BMD and it is appeared that this effect is independent from obesity because BMI were similar between the 2 groups. Moreover, advanced age is thought to have a negative effect on BMD, while increased duration of diabetes mellitus and poor glycemic control do not seem to be important factors in our study population. Recent cross-sectional studies revealed that the presence of type 2 diabetes mellitus is associated with higher fracture rates. Journal of Clinical Densitometry: Assessment of Skeletal Health
It is not clear why the fracture risk increases in type 2 diabetics despite the BMD increase. But it is thought that the bone quality and bone strength may decrease in type 2 diabetes mellitus (20). The combination of obesity and hyperglycemia in diabetic males has been shown to increase lumbar vertebra fracture risk although it increases BMD (21). A cross-sectional population-based study in Canada reported that type 2 diabetes was associated with higher BMD in women and men (1). These authors believe that hyperinsulinemia shows anabolic effects on bone structure especially when the hyperinsulinemia is prominent. However, BMD decreases in type 1 diabetic patients despite insulin usage (22). In contrast to other studies, our aim was to determine whether BMD really changed in patients with marked hyperinsulinemia. To our knowledge, our findings firstly indicated that endogen hyperinsulinemia did not show positive effects on BMD in type 2 diabetics. In addition, we also did not find any correlation between fasting and postprandial insulin and C-peptide levels and the BMD values. It is postulated that the hyperinsulinemia that develops in type 2 diabetic patients increases free hormone levels by decreasing the sex hormoneebinding globulin level and therefore protects the bone mass that decreases with age (23). A previous study on type 2 diabetic males has reported a statistical increase in femur neck BMD. In addition, another study suggested that body mass was a more important determinant of BMD than hyperinsulinaemia or insulin resistance in diabetic women. Among the diabetic men, there was a significant positive correlation between lean body mass and BMC and between serum insulin and femoral neck BMD. However, Ahmed et al (24) demonstrated that the diabetic men and women using insulin had increased hip fracture risk and duration of disease did not alter hip fracture risk. In addition, an increased risk of all nonvertebral fractures and, especially, hip fractures was associated with diabetes mellitus, especially type 1. Type 2 diabetes was associated Volume 15, 2012
190 with increased hip fracture risk in women only (22). Previous studies have reported that insulin stimulated osteoblast activity and increases the mineralization rate (25). On the contrary, Levin et al (26) reported a decrease in bone turnover in type 2 diabetics using insulin. Although it has been reported that metabolic control of diabetes mellitus influences serum osteocalcin levels and BMD, this has not been confirmed by others (13,14,20,27). In addition, the improvement in metabolic control increase in BMI and decrease in resorption markers could contribute to the stabilization of bone mass in type 1 diabetics (28). According to our finding, HbA1c, demonstrate glycemic control, was similar in our patient groups and we did not find any correlation between HbA1c and BMD in our study. More detailed studies are needed on the subject. In conclusion, the marked insulin resistance in type 2 diabetic patients may have an effect on BMD, leading to lower BMD values in type 2 diabetics even with hyperinsulinemia.
Acknowledgments This research did not receive any specific grant from any public-based, commercial or noneprofit sector-based funding agency.
References 1. Hanley DA, Brown JP, Tenenhouse A, et al. 2003 Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: cross-sectional results from the Canadian Multicentre Osteoporosis Study. J Bone Miner Res 18:784e790. 2. Yasuda S, Wada S. 2001 Bone metabolic markers and osteoporosis associated with diabetes mellitus. Clin Calcium 11:879e883. 3. Bauer DC, Browner WS, Cauley JA, et al. 1993 Factors associated with appendicular bone mass in older women. The Study of Osteoporotic Fractures Research Group. Ann Intern Med 118:657e665. 4. Tuominen JT, Impivaara O, Puukka P, R€onnemaa T. 1999 Bone mineral density in patients with type 1 and type 2 diabetes. Diabetes Care 22:1196e2000. 5. Gupta R, Mohammed AM, Mojiminiyi OA, et al. 2009 Bone mineral density in premenopausal Arab women with type 2 diabetes mellitus. J Clin Densitom 12(1):54e57. 6. Buday B, Horvath T, Kulcsar E, et al. 2007 Effect of progressive insulin resistance on the correlation of glucose metabolism and bone status. Orv Hetil 148:1127e1133. 7. Okazaki R. 2008 Links between osteoporosis and atherosclerosis; beyond insulin resistance. Clin Calcium 18:638e643. 8. Okazaki R, Totsuka Y, Hamano K, et al. 1997 Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab 82: 2915e2920. 9. Krakauer JC, McKenna MJ, Buderer NF, et al. 1995 Bone loss and bone turnover in diabetes. Diabetes 44:775e782. 10. Matthews DR, Hosker JP, Rudenski AS, et al. 1985 Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412e419.
Journal of Clinical Densitometry: Assessment of Skeletal Health
Arikan et al. 11. Bonora E, Kiechl S, Willeit J, et al. 1998 Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 47:1643e1649. 12. Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. 2000 Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Diabetes Care 23:171e175. 13. Thrailkill KM, Lumpkin CK Jr, Bunn RC, et al. 2005 Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 289:E735eE745. 14. Strotmeyer ES, Cauley JA, Schwartz AV, et al., Health ABC Study. 2004 Diabetes is associated independently of body composition with BMD and bone volume in older white and black men and women: the Health, Aging, and Body Composition Study. J Bone Miner Res 19:1084e1091. 15. Sert M, Tetiker T, Kirim S, et al. 2003 Type 2 diabetes mellitus and osteopenia: is there an association? Acta Diabetol 40:105e108. 16. Dennison EM, Syddall HE, Sayer AA, et al. 2004 Type 2 diabetes mellitus is associated with increased axial bone density in men and women from the Hertfordshire Cohort Study: evidence for an indirect effect of insulin resistance? Diabetologia 47: 1963e1968. 17. Van Daele PL, Stolk RP, Burger H, et al. 1995 Bone density in non-insulin-dependent diabetes mellitus. The Rotterdam Study. Ann Intern Med 122:409e414. 18. Vestergaard P. 2007 Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetesda meta-analysis. Osteoporos Int 18:427e444. 19. Shan PF, Wu XP, Zhang H, et al. 2009 Bone mineral density and its relationship with body mass index in postmenopausal women with type 2 diabetes mellitus in mainland China. J Bone Miner Metab 27(2):190e197. 20. Rakic V, Davis WA, Chubb SA, et al. 2006 Bone mineral density and its determinants in diabetes: the Fremantle Diabetes Study. Diabetologia 49:863e871. 21. Kanazawa I, Yamaguchi T, Yamamoto M, et al. 2008 Combination of obesity with hyperglycemia is a risk factor for the presence of vertebral fractures in type 2 diabetic men. Calcif Tissue Int 83:324e331. 22. Hamilton EJ, Rakic V, Davis WA, et al. 2009 Prevalence and predictors of osteopenia and osteoporosis in adults with type 1 diabetes. Diabet Med 26:45e52. 23. Rishaug U, Birkeland KI, Falch JA, Vaaler S. 1995 Bone mass in non-insulin-dependent diabetes mellitus. Scand J Clin Lab Invest 55:257e262. 24. Ahmed LA, Joakimsen RM, Berntsen GK, et al. 2006 Diabetes mellitus and the risk of non-vertebral fractures: the Tromsø Study. Osteoporos Int 17(4):495e500. 25. Barrett-Connor E, Kritz-Silverstein D. 1996 Does hyperinsulinemia preserve bone? Diabetes Care 19:1388e1392. 26. Levin ME, Boisseau VC, Avioli LV. 1976 Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. N Engl J Med 294:241e245. 27. Miazgowski T, Czekalski S. 1998 A 2-year follow-up study on bone mineral density and markers of bone turnover in patients with long-standing insulin-dependent diabetes mellitus. Osteoporos Int 8:399e403. 28. Campos Pastor MM, L opez-Ibarra PJ, Escobar-Jimenez F, et al. 2000 Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int 11: 455e459.
Volume 15, 2012
Original Article
Insulin Resistance in Type 2 Diabetes Mellitus May Be Related to Bone Mineral Density Senay Arikan,*,1 Alpaslan Tuzcu,1 Mithat Bahceci,1 Sehmuz Ozmen,2 and Deniz Gokalp1 1
Department of Endocrinology, Dicle University Medical Faculty, Diyarbakır, Turkey; and 2Department of Nephrology, Dicle University Medical Faculty, Diyarbakır, Turkey
Abstract The mechanism of bone mineral density (BMD) changes in type 2 diabetes mellitus is not clear. We aimed to investigate the effect of insulin resistance in type 2 diabetics on BMD. Insulin resistance was determined using the homeostasis model assessment index (HOMA-IR). Nineteen type 2 diabetic patients with a HOMA-IR !2.7 (mean age, 51.5 9.6 yr; body mass index [BMI], 27.3 5.1 kg/m2; duration of diabetes, 10.5 7.3 yr) were included in Group A, and 30 BMI- and age-matched type 2 diabetic patients with a HOMA-IR 2.7 were included in Group B. The BMD was measured with dual-energy X-ray absorptiometry. Independent t-test was used for statistical analysis. The Group A values for mean fasting glucose and insulin levels were 160.1 77.0 mg/dL and 4.79 2.89 mU/L, respectively, whereas the Group B values were 195.1 58.9 mg/dL ( p O 0.05) and 19.30 16.89 mU/L ( p 5 0.0001). Significantly higher total lumbar vertebra T-score ( p 5 0.02) and total lumbar vertebra BMD in Group A were determined than Group B ( p 5 0.033). The lumbar vertebra total Z-score was significantly lower in Group B ( p 5 0.042). Marked insulin resistance may have a negative effect on BMD in type 2 diabetics, while the presence of hyperinsulinemia may be associated with the low BMD. Key Words: DXA; insulin resistance; osteoporosis; type 2 diabetes mellitus.
BMD in type 2 diabetic patients when compared with healthy controls (1,3e5). Both osteoporosis and obesity increase with aging (6). Obesity is known to have protective effects on the bone even if contributes to insulin resistance. It has recently been postulated that chronic low-grade inflammatory conditions lead to an association between insulin resistance and osteoporosis by causing oxidative stress (7). Type 2 diabetic patients are reported to have decreased osteocalcin levels with an increase in these levels once glycemic control is normalized (2). Bone turnover rate also increases in type 2 diabetics and bone formation usually decreases (8). On the contrary, bone resorption stays normal or decreases with poorly glycemic control, whereas both resorption and formation increases when glycemic control is normalized (8,9). Our aim in this study was to evaluate the effect of insulin resistance in type 2 diabetic patients on BMD and the
Introduction The relationship between axial bone mass and type 2 diabetes mellitus has been known for many years (1e3). However, it is still not clear which parameters such as bone mineral density (BMD), fracture incidence, and osteoporosis biochemical markers are influenced by diabetes (1). Diabetes is a heterogenous disease with a variable degree of obesity, intrinsic insulin secretion, and intrinsic insulin resistance between individuals (1,2). Type 2 diabetes can be accompanied by hyperinsulinemia or hypoinsulinemia. There are conflicting studies reporting an increase, decrease, or no change in Received 09/24/11; Revised 11/19/11; Accepted 11/20/11. *Address correspondence to: S¸enay Arıkan, PhD, Dicle € Universitesi Tıp Fak€ultesi, Endokrinoloji BD, Diyarbakir 21280, Turkey. E-mail: [email protected]
186
Effect of Insulin Resistance on Bone Mineral Density in Type 2 Diabetic Patients correlation between glycemic control and anthropometric parameters and the BMD value.
Subjects and Methods We included a total of 59 type 2 diabetes mellitus patients consisting of 34 females and 25 males that presented to the Dicle University Medical Faculty, Department of Endocrinology (mean age, 52 9 yr; duration of diabetes, 9.5 7.3 yr) in the study.
Determination of Insulin Resistance All patients were using regime of insulin or insulin plus oral antidiabetic drug because of poor glycemic control. Longacting and intermediate-acting insulins were stopped 24 h ago and regular insulin was given and insulin-sensitizing drugs, such as metformin or thiazolidinedione and acarbose, were discontinued at least 48 h before blood sampling. Blood samples were obtained by placing a catheter into the antecubital vein before administering insulin and/or oral antidiabetic drugs between 08:00 and 09:00 AM after a fast of at least 12 h. The blood samples were stored at 20 C for fasting glucose and insulin. Insulin resistance was calculated using the homeostasis model assessment index (HOMA-IR) formula: Fasting insulin ðmU=mLÞ HOMA-IR 5
Fasting glucose ðmmol=LÞ ð10Þ: 22; 5
The HOMA-IR is a useful, validated method for evaluating insulin resistance. Bonora et al (11) suggested that the top quintile of the HOMA-IR, that is, a value 2.77, had isolated insulin resistance in subjects with no metabolic disorders. Yeni-Komshian et al (12) suggested that the cutoff of HOMA-IR in 490 healthy nondiabetic volunteers based on determining the steady-state plasma glucose was 2.7. In this study, HOMA-IR cut-off value was determined to be 2.7 (2.7 resistant, !2.7 sensitive).
Creating Study Groups It was not possible to access fasting insulin or glucose results in 10 patients. Nineteen diabetic patients with HOMAIR !2.7 were placed in Group A (mean age, 51.5 9.6 yr; body mass index [BMI], 27.3 5.1 kg/m2; duration of diabetes, 10.5 7.3 yr), whereas 30 diabetic patients with HOMAIR 2.7 were put in Group B (mean age, 52.7 8.8 yr; BMI, 27.7 4.5 kg/m2; duration of diabetes, 9.7 8.2 yr).
Anthropometric Measurements The BMI was calculated without shoes using height and weight measurements (BMI [kg/m2] 5 body weight [kg]/ height2[m]). Electrical bioimpedance (TANITA Corporation 14-2, 1-chome, Maeno-cho, Itaba-shi-hu, Tokyo, Japan) was used to measure the fat mass (kg), fat percent (%F), and fat-free body weight (kg). Journal of Clinical Densitometry: Assessment of Skeletal Health
187
BMD Measurement In our study, the BMD of the hip and lumbar spine (L1eL4) were measured by dual-energy X-ray absorptiometry (DXA) (Hologic Discovery QDR 4500a, WA). In the total hip, BMD was measured. Posterior-anterior lumbar spine (L1eL4) scans were performed with the patient lying supine on the imaging table using the protocols recommended by the manufacturer. The measurement results were expressed in absolute values, as T-score (the difference in standard deviation [SD] with respect to the peak bone mass in a young adult of the same race and sex) and Z- score (the difference in SD with respect to that found for healthy age-matched controls of the same race and sex). Low bone density was defined as T-score between 1 and 2.5 SD. Osteoporosis was defined as T-score of !2.5 SD. BMDs was defined as bone mineral content (BMC) divided by the projected area of the scanned image: BMD 5
BMC Area ðg=cm2 Þ
Laboratory Investigation Plasma glucose was measured by using the glucose oxidase method with an automated glucose analyzer (Abott aeroset autoanalyzer, TOSHIBA, Japan). Serum insulin and C-peptide levels were determined by electrochemiluminescence immunoassay by using Modular Analytics E170 (Elecsys module) immunoassay analyzers (Roche Diagnostics 1010/2010, Mannheim, USA). HbA1c was measured on an Aeroset/C8000 autoanalyser (Abbott Diagnostics, Abbott Park, Illinois).
Statistical Analysis All results were presented as mean SD. The independent t-test was used to compare the groups. The chi-square test was used to determine the distribution of the groups by sex. Relationship between variables was evaluated with Pearson’s correlation test. Values p ! 0.05 were accepted as statistically significant.
Results The mean HbA1c value was 10.9 2.8% and the BMI was 27.7 4.8 kg/m2 on presentation for all patients (n 5 59). In addition, levels of mean HbA1c (%) were separately measured as 10.5 3.3 in Group A and 11.3 2.5 in Group B. They were not statistically different despite the HbA1c level in Group B was slightly higher from Group A. There was no difference between the groups (Group A and Group B) for age, BMI, or duration of diabetes. The demographic features of the groups were shown in Table 1. Mean fasting glucose and insulin levels were 160.1 77.0 mg/dL and 4.79 2.89 mU/mL, respectively, in Group A and 195.1 58.9 mg/dL ( p O 0.05) and 19.30 16.89 mU/mL in Group B ( p 5 0.0001). There were statistically significant differences between groups in the Volume 15, 2012
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Arikan et al. Table 1 Demographic Features of the Type 2 Diabetic Patients Group A (HOMA-IR ! 2.7) (N 5 19)
Group B (HOMA-IR 2.7) (N 5 30)
p
51.5 9.6 12/7 70.6 11.1 27.3 5.1 25.0 11.1 33.8 12.7 44.7 11.7 10.5 7.3 160.1 77.0 284.1 150.1 4.79 2.89 2.1 1.6 10.5 3.3
52.7 8.8 17/13 73.1 10.9 27.7 4.5 22.2 12.8 28.4 13.0 51.1 8.6 9.7 8.2 195.1 58.9 291.0 66.9 19.30 16.89 3.9 1.3 11.3 2.5
NS NS NS NS NS NS NS NS NS NS 0.0001 0.01 NS
Age (yr) Sex (female/male) Body weight (kg) BMI (kg/m2) Fat mass (kg) Fat percentage (%) Fat-free body weight (kg) Duration of diabetes mellitus (yr) Fasting glucose (mg/dL) Postprandial glucose (mg/dL) Fasting insulin (mU/mL) Fasting C-peptide (ng/mL) HbA1c (%)
DXA measurements (mean total lumbar vertebra T-score 1.33 1.14 in Group B vs 0.29 1.93 in Group A, p 5 0.02) and (mean lumbar vertebra total BMD 0.91 0.13 gr/cm2 in Group B vs 1.03 0.21 gr/cm2 in Group A, p 5 0.033). The mean lumbar vertebra total Z-score was also significantly lower in Group B (Group A: 0.51 1.89; Group B: 0.51 1.04, p 5 0.042). The DXA results for the groups were presented in Table 2. We found no correlation between BMD, fasting and postprandial plasma glucose, insulin, and C-peptide levels. Total hip BMD measurements showed a positive correlation with BMI, fat mass, and fat percentage. But, we did not find any relation between lumbar vertebra BMD and anthropometric measurements. There was a negative correlation between
BMD and age. Duration of diabetes does not seem to be an important factor affecting BMD in type 2 diabetic patients, as we found no correlation between duration of diabetes and BMD. All results of correlation analysis were presented in Table 3.
Discussion BMD is known to decrease in type 1 diabetics and increase in type 2 diabetics. This inconsistency of BMD in diabetics is attributed to hyperinsulinemia (13). But, our finding demonstrated that BMD was less in type 2 diabetic patients who have higher insulin resistance than diabetic patients with less insulin resistance. More importantly, this negative effect
Table 2 DXA Results of Type 2 Diabetic Patients Group A (HOMA-IR ! 2.7) (N 5 19) BMD (gr/cm2) (n 5 49) BMD (gr/cm2) T-score Z-score 0.26 1.95 0.31 1.89 0.10 2.44*** 0.27 2.01*
0.46 1.90 0.49 1.79 0.73 2.38 0.43 1.94**
Group B (HOMA-IR 2.7) (N 5 30) BMD (gr/cm2)
T-score
0.86 0.13 0.93 0.15 0.92 0.13*** 0.94 0.13**
0.86 1.14 1.13 1.30 1.48 1.18*** 1.68 1.21*
Z-score
L1 L2 L3 L4
0.92 0.19 1.00 0.20 1.07 0.26*** 1.07 0.21**
0.15 1.08 0.35 1.15 0.65 1.08** 0.76 1.12**
Total lumbar
1.03 0.21*** 0.29 1.93**
0.51 1.89**** 0.91 0.13*** 1.33 1.14**
0.51 1.04****
Neck Tro Inter
0.82 0.14** 0.69 0.15 1.24 0.20
0.27 1.39* 0.23 1.58 0.72 1.34
0.55 1.34* 0.28 1.51 1.13 1.30
0.73 0.11** 0.63 0.08 1.15 0.16
1.14 1.00* 0.86 0.83 0.14 1.04
0.20 1.00* 0.33 0.93 0.56 1.01
Total hip
1.04 0.18
0.64 1.58
1.23 1.50
0.97 0.13
0.02 1.09
0.61 1.11
Abbr: Neck, femoral neck; Inter, intertrochanteric area; Tro, trochanteric area. *p 5 0.01; **p 5 0.02; *** p 5 0.03; ****p 5 0.04. Journal of Clinical Densitometry: Assessment of Skeletal Health
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Table 3 The Table Shows the Relation Between BMD and Glycemic Control and Anthropometric Measurements BMD (gr/cm2) (n 5 59)
Age
BMI
Fat Percent
Fat Mass
Duration of Diabetes Mellitus
p
r
p
r
p
r
p
r
p
r
L1 L2 L3 L4
0.003* 0.004* 0.01* 0.02*
0.38 0.37 0.33 0.28
0.175 0.209 0.245 0.164
0.17 0.16 0.15 0.18
0.423 0.428 0.073 0.130
0.13 0.13 0.30 0.25
0.160 0.140 0.06 0.108
0.23 0.25 0.31 0.27
0.548 0.481 0.333 0.996
0.08 0.09 0.12 0.00
Total lumbar
0.006*
0.35
0.261
0.14
0.162
0.23
0.083
0.29
0.561
0.07
Neck Tro Inter
0.05 0.06 0.02*
0.24 0.24 0.30
0.012* 0.001* 0.021*
0.32 0.44 0.30
0.002* 0.013* 0.004*
0.48 0.40 0.46
0.001* 0.002* 0.001*
0.53 0.50 0.51
0.884 0.914 0.673
0.02 0.01 0.05
Total hip
0.006*
0.35
0.01*
0.32
0.004*
0.47
0.001*
0.53
0.748
0.04
Abbr: BMD, bone mineral density. *p ! 0.05 was accepted as significant.
on BMD developed despite hyperinsulinemia in type 2 diabetic patients. In addition, our data indicated that the negative effects of insulin resistance on BMD in type 2 diabetics were probably independent of body fat mass. Previously, many studies reported an increase in BMD in type 2 diabetics (13e17). Vestergaard (18) showed in a metaanalysis that BMD decreased in type 1 diabetic patients, but increased in type 2 diabetics and that there was an increased hip fracture risk in both type 1 and type 2 diabetics. The same metaanalysis showed BMI to be the major determining factor of BMD in diabetics (18). On the contrary, a recent study by Shan et al (19) showed that the high BMI levels decreased lumbar vertebra fracture risk in postmenopausal type 2 diabetic women and that low BMI was an indicator of osteoporosis. Probably, the heterogeneity of type 2 diabetes and/or the different study methodologies may be responsible for these conflicting results. In our study, we observed a positive correlation between total femur BMD and BMI, and fat mass and fat percentage in all study population. On the contrary, no correlation was found between lumbar vertebra BMD and anthropometric measurements, whereas there was a negative correlation between BMD and age in all diabetic patients. These results indicated that increased fat tissue in type 2 diabetics have a beneficial effect on BMD measurements, especially those from the hip. However, the exact mechanism increasing the BMD in type 2 diabetic patients is not fully understood. Our data indicated that clarified insulin resistance and hyperinsulinemia were a negative effect on BMD and it is appeared that this effect is independent from obesity because BMI were similar between the 2 groups. Moreover, advanced age is thought to have a negative effect on BMD, while increased duration of diabetes mellitus and poor glycemic control do not seem to be important factors in our study population. Recent cross-sectional studies revealed that the presence of type 2 diabetes mellitus is associated with higher fracture rates. Journal of Clinical Densitometry: Assessment of Skeletal Health
It is not clear why the fracture risk increases in type 2 diabetics despite the BMD increase. But it is thought that the bone quality and bone strength may decrease in type 2 diabetes mellitus (20). The combination of obesity and hyperglycemia in diabetic males has been shown to increase lumbar vertebra fracture risk although it increases BMD (21). A cross-sectional population-based study in Canada reported that type 2 diabetes was associated with higher BMD in women and men (1). These authors believe that hyperinsulinemia shows anabolic effects on bone structure especially when the hyperinsulinemia is prominent. However, BMD decreases in type 1 diabetic patients despite insulin usage (22). In contrast to other studies, our aim was to determine whether BMD really changed in patients with marked hyperinsulinemia. To our knowledge, our findings firstly indicated that endogen hyperinsulinemia did not show positive effects on BMD in type 2 diabetics. In addition, we also did not find any correlation between fasting and postprandial insulin and C-peptide levels and the BMD values. It is postulated that the hyperinsulinemia that develops in type 2 diabetic patients increases free hormone levels by decreasing the sex hormoneebinding globulin level and therefore protects the bone mass that decreases with age (23). A previous study on type 2 diabetic males has reported a statistical increase in femur neck BMD. In addition, another study suggested that body mass was a more important determinant of BMD than hyperinsulinaemia or insulin resistance in diabetic women. Among the diabetic men, there was a significant positive correlation between lean body mass and BMC and between serum insulin and femoral neck BMD. However, Ahmed et al (24) demonstrated that the diabetic men and women using insulin had increased hip fracture risk and duration of disease did not alter hip fracture risk. In addition, an increased risk of all nonvertebral fractures and, especially, hip fractures was associated with diabetes mellitus, especially type 1. Type 2 diabetes was associated Volume 15, 2012
190 with increased hip fracture risk in women only (22). Previous studies have reported that insulin stimulated osteoblast activity and increases the mineralization rate (25). On the contrary, Levin et al (26) reported a decrease in bone turnover in type 2 diabetics using insulin. Although it has been reported that metabolic control of diabetes mellitus influences serum osteocalcin levels and BMD, this has not been confirmed by others (13,14,20,27). In addition, the improvement in metabolic control increase in BMI and decrease in resorption markers could contribute to the stabilization of bone mass in type 1 diabetics (28). According to our finding, HbA1c, demonstrate glycemic control, was similar in our patient groups and we did not find any correlation between HbA1c and BMD in our study. More detailed studies are needed on the subject. In conclusion, the marked insulin resistance in type 2 diabetic patients may have an effect on BMD, leading to lower BMD values in type 2 diabetics even with hyperinsulinemia.
Acknowledgments This research did not receive any specific grant from any public-based, commercial or noneprofit sector-based funding agency.
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