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Yuka Kinoshita, Hiroko Fujii, Akira Takeshita, Manabu Taguchi, Megumi Miyakawa, Kenich Oyama, Shozo Yamada and Yasuhiro Takeuchi

Objective

Impaired glucose metabolism is common in acromegaly, but it is not clear how glucose metabolism is impaired or what predicts its restoration after cure of the disease. To identify factors involved in the impairment of glucose metabolism in acromegaly, we evaluated clinical parameters before and immediately after surgical cure of the disease.

Design and methods

We retrospectively analyzed clinical data of 92 consecutive Japanese patients with acromegaly who underwent successful pituitary surgery. Patients who had received medical therapy for acromegaly or insulin treatment for diabetes were excluded. We evaluated insulin resistance (IR) and pancreatic β-cell function in addition to GH and IGF1 levels before and after surgery.

Results

In this study of Japanese patients with acromegaly, average body mass index (BMI) was 23.4, and no patient had a BMI>30. IR was involved in the impairment of glucose metabolism, which was restored upon surgical cure of acromegaly if β-cell function was preserved. Insufficient β-cell function did not improve after normalization of GH/IGF1 and was associated with impaired glucose metabolism before and after surgery. Results of receiver operating characteristic analysis of preoperative clinical parameters suggest that insulinogenic index (IGI) >0.50 best predicts restoration of normal glucose metabolism upon cure of acromegaly in Japanese patients.

Conclusions

IR impairs glucose metabolism in acromegaly. Once β-cell function is impaired, abnormal glucose metabolism persists even after cure of acromegaly. IGI>0.50 indicates that β-cell function is preserved in non-obese Japanese patients with acromegaly.

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Shozo Yamada, Noriaki Fukuhara, Hiroshi Nishioka, Akira Takeshita, Hisanori Suzuki, Megumi Miyakawa and Yasuhiro Takeuchi

Objective

The aim of this study was to determine the frequency and characteristics of severe GH deficiency (sGHD) in patients after treatment of acromegaly by surgery alone.

Design and methods

One hundred and eighty-six patients fulfilling the criteria for cure of acromegaly were examined by GH-releasing peptide-2 stimulation test or arginine stimulation test as well as oral glucose tolerance test (GTT). In addition, the Japanese adult hypopituitarism questionnaire was completed to determine the quality of life (QoL).

Results

sGHD was found in 17 patients (9.1%; the GH-deficient group), and not found in 169 patients (90.9%; the GH-sufficient group). There were no significant differences in preoperative serum GH levels, IGF1 levels, incidence of hyperprolactinemia, tumor volumes, or incidence of microadenoma between the two groups. Upon follow-up examination, IGF1 levels and Z-scores of IGF1 levels were significantly lower in the GH-deficient group than in the GH-sufficient group, whereas neither basal GH levels nor nadir GH levels during 75 g GTT were significantly different between the two groups. Moreover, sGHD patients had a substantially higher incidence of multiple pituitary failures (17.6 vs 2.4%) and dyslipidemia (60 vs 16.2%). sGHD patients had a substantially poorer condition-related QoL.

Conclusions

This is the first large-scale, single-center, clinical study to evaluate sGHD in patients after cure of acromegaly by surgery alone. This study found that sGHD occurred in ∼9% of patients and assessment of GHD by stimulation tests is critical after successful treatment of acromegaly by surgery.

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Motoyasu Saji, Osamu Isozaki, Toshio Tsushima, Mariko Arai, Megumi Miyakawa, Yoshito Ohba, Yumi Tsuchiya, Tomohide Sano and Kazuo Shizume

Abstract. The effect of iodide on growth of rat thyroid cells (FRTL-5) was studied. TSH-stimulated cell growth was inhibited by iodide in a concentration-dependent manner, and an effect of iodide was detected at 10−6 mol/l. KClO4 or 1-methylimidazole-2-thiol blocked the effect of iodide, suggesting that iodide uptake and its organification are required to produce the inhibitory effect of iodide on cell growth. Iodide not only decreased TSH-stimulated cAMP production in FRTL-5 cells but also cell growth induced by cAMP. These observations suggest that iodide inhibits TSH-stimulated growth of the cells by attenuating cAMP production and also by acting on the step(s) distal to cAMP generation. The inhibitory effect of iodide was also seen in growth stimulated by insulin, insulin-like growth factor-I or 12-O-tetradecanoyl phorbol 13-acetate, suggesting multiple sites of action of iodide in the process of growth of FRTL-5 cells.

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Mariko Arai, Toshio Tsushima, Osamu Isozaki, Hiroshi Demura, Kazuo Shizume, Naoya Emoto, Megumi Miyakawa, Yasuko Nozoe, Hitomi Murakami and Eiji Ohmura

Arai M, Tsushima T, Isozaki 0, Demura H, Shizume K, Emoto N, Miyakawa M, Nozoe Y, Murakami H, Ohmura E. Effects of transforming growth factor α (TGF-α) on DNA synthesis and thyrotropin-induced iodine metabolism in cultured porcine thyroid cells. Eur J Endocrinol 1995;132:242–8. ISSN 0804–4643

Transforming growth factor α (TGF-α) is a potent mitogen that is similar structurally to epidermal growth factor (EGF). As EGF is a potent growth stimulator and an inhibitor of iodine metabolism in cultured thyroid cells of several species, we studied whether TGF-α has similar effects using porcine thyroid cells in culture. Recombinant human TGF-α dose-dependently stimulated DNA synthesis of thyroid cells, with maximal stimulation (eight- to ninefold above basal) occurring at 2 nmol/l. The potency was approximately 50% that of mouse EGF and correlated with the ability to compete with EGF for receptor binding, suggesting that the action of TGF-α is mediated by interaction with EGF receptors. When thyroid cells were cultured for 3 days with thyrotropin (TSH) in the presence of TGF-α, TSH-induced iodide uptake was inhibited in a dose-dependent manner. The potency of TGF-α again was approximately 50% that of EGF. Transforming growth factor α did not inhibit TSH-stimulated cAMP production. Moreover, iodide uptake stimulated by either forskolin or 8-bromo-cAMP also was inhibited by TGF-α. Thus, we conclude that TGF-α inhibits TSH-induced iodine metabolism largely by acting at the steps distal to cAMP production. Northern blot analysis revealed expression of TGF-α mRNA in porcine thyroid cells. These observations suggest that TGF-α acts as an autocrine modulator of growth and differentiated functions in porcine thyroid cells.

T Tsushima, Department of Medicine 2, Tokyo Women's Medical College, Kawadacho 8–1, Shinjukuku, Tokyo 162, Japan

Free access

Naohiro Yoshida, Hiromasa Goto, Hisanori Suzuki, Kaoru Nagasawa, Akira Takeshita, Minoru Okubo, Megumi Miyakawa, Yasumichi Mori, Noriaki Fukuhara, Hiroshi Nishioka, Shozo Yamada and Yasuhiro Takeuchi

Objective

Excess GH causes insulin resistance and impaired glucose metabolism. The objective of this study was to clarify the prevalence of ketoacidosis as the initial presenting symptom of acromegaly.

Design and methods

Data were collected from 860 patients with acromegaly who underwent pituitary surgery at Toranomon Hospital over the last 32 years, between 1980 and 2011.

Results

Nine cases had ketoacidosis before being diagnosed with acromegaly, including seven males and two females with a mean±s.d. age of 38.8±14.2 years. Serum GH and IGF1 levels were 155±203 ng/ml and 9.86±0.68 SDS before pituitary surgery and 3.6±1.7 ng/ml and 3.72±3.40 SDS after surgery respectively. The maximum tumor diameter was 28.2±11.6 mm (ranging from 15 to 47 mm, n=8). None of the patients were diagnosed with diabetes mellitus (DM) nor were they positive for antibodies related to type 1 DM. A possible precipitating factor for ketoacidosis in six cases was excessive ingestion of sugar-containing soft drinks. All the cases had invasive pituitary adenomas. After pituitary surgery, plasma glucose levels were under control without requiring insulin in all cases. Furthermore, six patients did not need oral hypoglycemic agents.

Conclusions

Approximately 1% of patients with acromegaly presented with diabetic ketoacidosis as their first clinical condition.