Improved Insulin Sensitivity during Pioglitazone Treatment Is Associated with Changes in IGF-I and Cortisol Secretion in Type 2 Diabetes and Impaired Glucose Tolerance
Background. Hypercortisolism and type 2 diabetes (T2D) share clinical characteristics. We examined pioglitazone's effects on the GH-IGF-I and HPA axes in men with varying glucose intolerance. Methods. 10 men with T2D and 10 with IGT received pioglitazone 30–45？mg for 12？weeks. OGTT with microdialysis in subcutaneous adipose tissue and 1？μg ACTH-stimulation test were performed before and after. Glucose, insulin, IGF-I, IGFBP1, and interstitial measurements were analyzed during the OGTT. Insulin sensitivity was estimated using HOMA-IR. Results. HOMA-IR improved in both groups. IGF-I was initially lower in T2D subjects ( ) and increased during treatment ( to SD; ); no change was seen in IGT ( SD before and during treatment). Fasting glycerol decreased in T2D ( ), indicating reduced lipolysis. Fasting cortisol decreased in T2D ( to ？nmol/L; ) but increased in IGT ( to ？nmol/L; ). Peak cortisol was lower in T2D during treatment ( to , versus to ？nmol/L in IGT; ). Conclusions. Pioglitazone improved adipose tissue and liver insulin sensitivity in both groups. This may explain increased IGF-I in T2D. Pioglitazone affected cortisol levels in both groups but differently, suggesting different mechanisms for improving insulin sensitivity between T2D and IGT. 1. Introduction Type 2 diabetes (T2D) is a significant public health issue due to its prevalence and complications. Obesity, particularly abdominal obesity, is a major risk factor for the disease. Central features of T2D include hyperglycemia, insulin resistance, and progressive β-cell failure. According to a theory developed by Bj？rntorp et al., there are also disturbances in the central hormone axes, with activity increased in the hypothalamus-pituitary-adrenal (HPA) axis and decreased in the growth hormone (GH) insulin-like growth factor I (IGF-I) and LH-testosterone axes [1]. As T2D develops via an insidious phase of impaired glucose tolerance (IGT) [2], it is of importance to understand the pathogenesis of both conditions in order to improve treatment options and prevent progression of IGT to T2D. Of the end products produced by the central hormone axes, IGF-I and cortisol have the greatest effects on insulin sensitivity. IGF-I is produced mainly in the liver [3] and has effects highly comparable to those of insulin [4]. Its production is dependent on GH, insulin, and nutritional status [5]. Cortisol has anti-insulin effects on glucose metabolism, increasing gluconeogenesis and decreasing glucose uptake [6]. However, chronic elevation of glucocorticoid levels as well as hyperinsulinemia result in the
References
[1]
P. Bj？rntorp, G. Holm, and R. Rosmond, “Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus,” Diabetic Medicine, vol. 16, no. 5, pp. 373–383, 1999.
[2]
P. L. Santaguida, C. Balion, D. Hunt et al., “Diagnosis, prognosis, and treatment of impaired glucose tolerance and impaired fasting glucose,” Evidence Report/Technology Assessment, no. 128, pp. 1–11, 2005.
[3]
D. R. Clemmons and J. J. Van Wyk, “Factors controlling blood concentration of somatomedin C,” Clinics in Endocrinology and Metabolism, vol. 13, no. 1, pp. 113–143, 1984.
[4]
E. R. Froesch, M. A. Hussain, C. Schmid, and J. Zapf, “Insulin-like growth factor I: physiology, metabolic effects and clinical uses,” Diabetes/Metabolism Reviews, vol. 12, no. 3, pp. 195–215, 1996.
[5]
N. Moller, M. H. Vendelbo, U. Kampmann et al., “Growth hormone and protein metabolism,” Clinical Nutrition, vol. 28, no. 6, pp. 597–603, 2009.
[6]
J. H. Exton, “Regulation of gluconeogenesis by glucocorticoids,” Monographs on Endocrinology, vol. 12, pp. 535–546, 1979.
[7]
P. Bj？rntorp, “The regulation of adipose tissue distribution in humans,” International Journal of Obesity, vol. 20, no. 4, pp. 291–302, 1996.
[8]
S. E. Meek, K. S. Nair, and M. D. Jensen, “Insulin regulation of regional free fatty acid metabolism,” Diabetes, vol. 48, no. 1, pp. 10–14, 1999.
[9]
L. C. Groop, R. C. Bonadonna, S. DelPrato et al., “Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance,” Journal of Clinical Investigation, vol. 84, no. 1, pp. 205–213, 1989.
[10]
D. Powell, P. D. K. Lee, L. A. DePaolis, S. L. Morris, and A. Suwanichkul, “Dexamethasone stimulates expression of insulin-like growth factor binding protein-1 in HEP G2 human hepatoma cells,” Growth Regulation, vol. 3, no. 1, pp. 11–13, 1993.
[11]
J. W. Eriksson, U. Smith, F. Waagstein, M. Wysocki, and P. A. Jansson, “Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?” Diabetes, vol. 48, no. 8, pp. 1572–1578, 1999.
[12]
P. Lonnroth and U. Smith, “The antilipolytic effect of insulin in human adipocytes requires activation of the phosphodiesterase,” Biochemical and Biophysical Research Communications, vol. 141, no. 3, pp. 1157–1161, 1986.
[13]
N. Rajamand, U. Ungerstedt, and K. Brismar, “Subcutaneous microdialysis before and after an oral glucose tolerance test: a method to determine insulin resistance in the subcutaneous adipose tissue in diabetes mellitus,” Diabetes, Obesity and Metabolism, vol. 7, no. 5, pp. 525–535, 2005.
[14]
P. Arner, J. Bolinder, A. Eliasson, A. Lundin, and U. Ungerstedt, “Microdialysis of adipose tissue and blood for in vivo lipolysis studies,” American Journal of Physiology-Endocrinology and Metabolism, vol. 255, no. 5, p. 18/5, 1988.
[15]
H. Yki-J？rvinen, “Thiazolidinediones,” New England Journal of Medicine, vol. 351, no. 11, pp. 1106–1158, 2004.
[16]
B. Ambrosi, C. Dall'Asta, S. Cannavò et al., “Effects of chronic administration of PPAR-γ ligand rosiglitazone in Cushing's disease,” European Journal of Endocrinology, vol. 151, no. 2, pp. 173–178, 2004.
[17]
G. Puavilai, S. Chanprasertyotin, and A. Sriphrapradaeng, “Diagnostic criteria for diabetes mellitus and other categories of glucose intolerance: 1997 Criteria by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (ADA), 1998 WHO Consultation criteria, and 1985 WHO criteria,” Diabetes Research and Clinical Practice, vol. 44, no. 1, pp. 21–26, 1999.
[18]
U. Tossman, J. Segovia, and U. Ungerstedt, “Extracellular levels of amino acids in striatum and globus pallidus of 6-hydroxydopamine-lesioned rats measured with microdialysis,” Acta Physiologica Scandinavica, vol. 127, no. 4, pp. 547–551, 1986.
[19]
N. R. Ekberg, N. Wisniewski, K. Brismar, and U. Ungerstedt, “Measurement of glucose and metabolites in subcutaneous adipose tissue during hyperglycemia with microdialysis at various perfusion flow rates,” Clinica Chimica Acta, vol. 359, no. 1-2, pp. 53–64, 2005.
[20]
V. Grill, J. Pigon, S. G. Hartling, C. Binder, and S. Efendic, “Effects of dexamethasone on glucose-induced insulin and proinsulin release in low and high insulin responders,” Metabolism, vol. 39, no. 3, pp. 251–258, 1990.
[21]
P. Bang, U. Eriksson, V. Sara, I. L. Wivall, and K. Hall, “Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand,” Acta Endocrinologica, vol. 124, no. 6, pp. 620–629, 1991.
[22]
A. Hilding, K. Brismar, M. Degerblad, M. Thoren, and K. Hall, “Altered relation between circulating levels of insulin-like growth factor- binding protein-1 and insulin in growth hormone-deficient patients and insulin-dependent diabetic patients compared to that in healthy subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 80, no. 9, pp. 2646–2652, 1995.
[23]
G. Povoa, A. Roovete, and K. Hall, “Cross-reaction of serum somatomedin-binding protein in a radioimmunoassay developed for somatomedin-binding protein isolated from human amniotic fluid,” Acta Endocrinologica, vol. 107, no. 4, pp. 563–570, 1984.
[24]
A. R. Saltiel and J. M. Olefsky, “Thiazolidinediones in the treatment of insulin resistance and type II diabetes,” Diabetes, vol. 45, no. 12, pp. 1661–1669, 1996.
[25]
C. Meyer, W. Pimenta, H. J. Woerle et al., “Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans,” Diabetes Care, vol. 29, no. 8, pp. 1909–1914, 2006.
[26]
G. Sesti, A. Sciacqua, M. Cardellini et al., “Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance,” Diabetes Care, vol. 28, no. 1, pp. 120–125, 2005.
[27]
I. Bogacka, H. Xie, G. A. Bray, and S. R. Smith, “The effect of pioglitazone on peroxisome proliferator-activated receptor-γ target genes related to lipid storage in vivo,” Diabetes Care, vol. 27, no. 7, pp. 1660–1667, 2004.
[28]
J. Lovejoy, F. D. Newby, S. S. P. Gebhart, and M. DiGirolamo, “Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin,” Metabolism, vol. 41, no. 1, pp. 22–27, 1992.
[29]
K. A. Virtanen, K. H？llsten, R. Parkkola et al., “Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects,” Diabetes, vol. 52, no. 2, pp. 283–290, 2003.
[30]
J. S. Moore, J. P. Monson, G. Kaltsas et al., “Modulation of 11 β-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 11, pp. 4172–4177, 1999.
[31]
T. A. M. Abdu, T. A. Elhadd, R. Neary, and R. N. Clayton, “Comparison of the low dose short synacthen test (1？μg), the conventional dose short synacthen test (250？μg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 3, pp. 838–843, 1999.
[32]
P. Darmon, F. Dadoun, C. Frachebois et al., “On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis,” European Journal of Endocrinology, vol. 140, no. 1, pp. 51–55, 1999.
[33]
S. A. R. Doi, I. Lasheen, K. Al-Humood, and K. A. S. Al-Shoumer, “Relationship between cortisol increment and basal cortisol: implications for the low-dose short adrenocorticotropic hormone stimulation test,” Clinical Chemistry, vol. 52, no. 4, pp. 746–749, 2006.
[34]
E. J. Nye, J. E. Grice, G. I. Hockings et al., “Comparison of Adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1-24) infusion tests,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 10, pp. 3648–3655, 1999.
[35]
A. Agha and J. P. Monson, “Modulation of glucocorticoid metabolism by the growth hormone-IGF-1 axis,” Clinical Endocrinology, vol. 66, no. 4, pp. 459–465, 2007.
