Endocrine Journal 2014, 61 (4), 321-328

Or i g i n a l Glucose variability before and after treatment of a patient with Graves’ disease complicated by mellitus: Assessment by continuous glucose monitoring

Keiichi Torimoto, Yosuke Okada, Tadashi Arao, Hiroko Mori, Sunao Yamamoto, Manabu Narisawa, Akira Kurozumi and Yoshiya Tanaka

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushyu 807-8555, Japan

Abstract. A 48-year-old woman was diagnosed and treated for Graves’ disease (GD) in 1999 but she discontinued treatment at her own discretion. In 2011, she was admitted to a local hospital for management of thyrotoxic crisis. Treatment with propylthiouracil, iodide potassium (KI), and prednisolone (PSL) was started, which resulted in improvement of the general condition. PSL and KI were discontinued before she was transferred to our hospital. At the local hospital, fasting plasma glucose (FPG) was 212 mg/dL and hemoglobin A1c concentration was 11.2%; intensive therapy had been instituted. Upon admission to our hospital, FPG level was 122 mg/dL, but insulin secretion was compromised, suggesting aggravation of thyroid function and deterioration of glycemic control. The FPG level increased to 173 mg/dL; continuous glucose monitoring (CGM) identified dawn phenomenon at approximately 0400 h. Resumption of KI resulted in improvement of FPG and disappearance of the dawn phenomenon, as assessed by CGM. These results indicate that in patients with compromised insulin secretion, hyperthyroidism can induce elevation of not only postprandial blood glucose, but also FPG level due to the dawn phenomenon and that the dawn phenomenon can be alleviated with improvement in thyroid function. To our knowledge, no studies have assessed glucose variability by CGM before and after treatment of Graves’ disease. The observations made in this case shed light on the understanding of abnormal glucose metabolism associated with Graves’ disease.

Key words: Graves’ disease (GD), Continuous glucose monitoring (CGM), Dawn phenomenon

Hyperthyroidism can interfere with glucose ability patterns that were otherwise not possible with metabolism through various mechanisms, and 50% of the self-monitoring of blood glucose (SMBG). To our patients with thyrotoxicosis are reported to have abnor- knowledge, however, no studies have assessed glucose mal glucose tolerance [1]. Known factors responsi- variability by CGM before and after treatment of hyper- ble for abnormal glucose tolerance include enhanced thyroidism. Here, we report a patient with Graves’ dis- glucose absorption via the digestive tract [2, 3] and ease complicated by diabetes mellitus, who presented increased endogenous gluconeogenesis [4]. However, with disturbance of endogenous insulin secretion. In as a compensatory mechanism, excessive insulin secre- this patient, hyperthyroidism resulted in not only post- tion [5, 6] is typically effective; is often prandial hyperglycemia but also elevation of fasting absent even in patients with thyrotoxicosis. plasma glucose (FPG) level due to the dawn phenome- The prevalent use of continuous glucose monitor- non, and CGM was employed to confirm alleviation of ing (CGM) has provided details on blood glucose vari- the dawn phenomenon following improvement of thy- roid function. Submitted Oct. 2, 2013; Accepted Dec. 22, 2013 as EJ13-0410 Released online in J-STAGE as advance publication Jan. 11, 2014 Research Design and Methods Correspondence to: Yoshiya Tanaka, M.D., Ph.D., First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, The CGM device used to assess intraday glucose Yahatanishi-ku, Kitakyushu 807-8555, Japan. variability in the presence of hyperthyroidism (CGMS® E-mail: [email protected] System Gold™, Medtronic, Minneapolis, MN) can con- ©The Japan Endocrine Society 322 Torimoto et al. tinuously measure glucose level in the interstitial fluid system symptoms, and heart failure symptoms of the in the range of 40–400 mg/dL. The sensor is inserted Japan Thyroid Association diagnostic criteria of thy- into the subcutaneous tissue, and glucose levels in the roid storm [9]. Therefore, the diagnosis was confirmed interstitial fluid are converted to electrical signals, to be thyrotoxic crisis (a score of 60 according to the enabling measurement at 5-min intervals (288 mea- diagnostic criteria of Burch et al. [10] for thyrotoxic surement sessions per day at maximum). It has been crisis). Laboratory tests showed marked hyperglyce- reported that the interstitial glucose level measured by mia, with FPG level of 212 mg/dL and hemoglobin A1c CGM correlates well with the venous blood glucose concentration of 11.2%. She was thereafter started on level [7]. In this study, although the CGM measured intensive insulin therapy, as well as treatment for acute the interstitial glucose level, it was corrected by data heart failure, and also treated with propylthiouracil from SMBG; thus, the interstitial glucose level is here- (300 mg/day), potassium iodide (KI; 50 mg/day), and inafter referred to as “blood glucose level. For the val- prednisolone (PSL; 30 mg/day). The general condition ues measured by CGM devices, previous data indicate improved following the treatment, and she was referred ~15 to 20 mg/dL measurement error due to ~5-15 min- to our hospital after discontinuation of PSL and KI for ute time lag, compared with blood glucose level mea- further management. sured in venous blood, in addition to a lower accuracy On admission, she was 162.0 cm tall and weighed of measurement in [8]. 44.7 kg (body mass index, 16.7 kg/m2); blood pres- During hospitalization, the patient received a diabetic sure was 133/78 mmHg, heart rate was 80 bpm, and diet with a daily calorie intake of 1400 kcal (25 kcal/ consciousness was clear. Diffuse goiter was noted but kg ideal body weight; 60% carbohydrate, 20-25% lipid, no exophthalmos, ocular retraction, or lid lag were 15-20% protein), which was continued, without any evident on clinical examination. The respiratory and modification, following admission to another hospital. heart sounds were normal, and neurological examina- tion was normal. Case Report Laboratory tests on admission (Table 1) showed normal hepatic and renal functions, as well as normal Clinical summary serum electrolytes. Glucose metabolism-related tests The patient was a 48-year-old woman who was showed reduced endogenous insulin secretion [FPG, diagnosed in 1999 with Graves’ disease and treated 122 mg/dL; blood C-peptide reactivity (CPR), 0.8 ng/ with thiamazole. She discontinued the treatment at her mL; urinary CPR, 1.8 μg/day] associated with inten- own discretion 6 months later following alleviation of sive insulin therapy. Although the disease duration was symptoms. Around 2009, she began to lose weight and considered long based on the presence of preprolifera- eat greater amounts of food and snacks than before. tive diabetic retinopathy, the patient had no history of Around August 2010, she developed marked thirst, ketosis. However, the family history was positive for polydipsia, and polyuria. Early in January 2011, she diabetes and the patient was anti-GAD antibody-nega- began to experience palpitations at rest, accompanied tive. Thus, the patient was diagnosed with type 2 dia- by edema and dyspnea on effort. The dyspnea gradu- betes mellitus. ally worsened. Later, she developed dyspnea at rest On the day of admission to our hospital (hospital day and was transferred to a local hospital by ambulance, 1), thyroid function tests showed free T3 level of 4.0 where physical examination showed wheezing, pitting pg/mL and free T4 level of 2.6 ng/dL. Based on these edema of the upper and lower extremities, tachycar- findings, propylthiouracil treatment (300 mg/day) was dia, and hypoxemia, together with pulmonary conges- continued (Fig. 1). With regard to treatment of dia- tion on radiography. She was diagnosed with conges- betes mellitus, intensive insulin therapy with insulin tive heart failure (New York Heart Association class aspart (9 U in the morning, 7 U at noon, 6 U in the 4). Signs of hyperthyroidism were noted (TSH level evening) and insulin glargine (6 U in the evening) was <0.001 μIU/mL, 2.18 ng/dL free T4), accompanied continued without modification. However, glycemic by New York Heart Association class 4 heart failure control gradually worsened following the recurrence of and reduced consciousness (somnolence or Glasgow signs of thyrotoxicosis (e.g., tachycardia, palpitation, Coma Scale score 12 and Japan Coma Scale score and tremor). On hospital day 6, the FPG level was 173 II–10), meeting the essential items, central nervous mg/dL. From the fifth hospital day onward, CGM was CGM of glucose variability in GD 323

Table 1 Results of laboratory tests on admission Peripheral blood Brain natriuretic peptide 133 pg/mL White blood cells 4000/μL Fasting plasma glucose 131 mg/dL Red blood cells 415×104/μL HbA1c (NGSP) 11.0% Hemoglobin 11.2 g/dL C-peptide immunoreactivity 0.8 ng/mL Platelets 26.7×104/L Anti-GAD antibody < 1.3 U/mL Blood biochemistry TSH 0.01 µIU/mL Total protein 6.0 g/dL fT3 4.00 pg/mL Albumin 3.1 g/dL fT4 2.66 ng/dL Aspartate aminotransferase 12 U/L TRAb 10.9 U/mL Alanine aminotransferase 10 U/L Tg-Ab 578 U/mL γ-glutamyltranspeptidase 23 U/L TPO-Ab 141.7 U/mL Blood urea nitrogen 15 mg/dL TSAb 188% Creatinine 0.30 mg/dL Uric acid 4.7 mg/dL Urinalysis Sodium 138 mEq/L C-peptide immunoreactivity 1.8 µg/day

Chloride 97 mEq/L ACR 364.5 mg/g ● Cre Potassium 3.9 mEq/L HbA1c was estimated as the National Glycohemoglobin Standardization Program (NGSP) equivalent value, which was calculated as HbA1c (NGSP) (%) = HbA1c (Japan Diabetes Society [JDS]) (%) + 0.4%. fT3, free T3; fT4, free T4; TRAb, TSH receptor antibody; Tg-Ab, anti-thyroglobulin antibody; TPO-Ab, anti thyroperoxidase antibody; TSAb, thyroid stimulating antibody; ACR, albumin-creatinine ratio

Fig. 1 Clinical course Serum thyroid hormones increased after discontinuation of potassium iodide, and hyperthyroidism was successfully treated after re-instatement of potassium iodide therapy. Daily profile of blood glucose was examined before and after resumption of potassium iodide therapy. fT3, free T3; fT4, free T4; CGM, continuous glucose monitoring; SMBG, self monitoring blood glucose. 324 Torimoto et al. carried out to assess glucose variability. Such mon- U at noon, 6 U in the evening) and insulin glargine (6 itoring showed marked dawn phenomenon occurring U in the evening). The dawn phenomenon, observed at approximately 0400 h with postprandial hypergly- at approximately 0400 h during the previous CGM ses- cemia (Fig. 2). From the seventh hospital day onward, sion, disappeared, together with marked improvement the insulin dose was increased (insulin aspart: 11 U in in the early morning pre-breakfast blood glucose level. the morning, 7 U at noon, 6 U in the evening; insulin However, thyroid function remained abnormal, together glargine: 8 U in the evening). with persistent hyperglycemia after each meal, similar Repeat thyroid function tests on hospital day 9 dem- to the findings after the first CGM session (Fig. 4). The onstrated deterioration of thyroid function (free T3: 11.5 average, SD, and mean amplitude of glycemic excur- pg/mL, free T4: 6.5 ng/dL, Fig. 1). KI (100 mg/day) sions (MAGE), as assessed by the CGM, improved with was resumed the same evening. The insulin glargine improvement in thyroid function, while the mean post- dosing method and dosage were modified the follow- prandial glucose excursion (MPPGE), reflecting post- ing day (hospital day 10). Early morning blood glu- prandial hyperglycemia, did not (Table 2). cose level began to improve before the insulin glargine After discharge from the hospital, thyroid hormone dosing method and dosage was modified (Fig. 3). The levels returned to normal and the results of the second blood glucose level continued to improve rapidly after assessment of insulin secretion capacity were FPG 110 such modification. Thus, the total insulin glargine dos- mg/dL and CPR 0.9 ng/mL. age was later reduced from 9 U to 6 U. The improve- ment also included alleviation of symptoms of thyro- Discussion toxicosis, together with falls in free T3 to 5.3 pg/mL and free T4 to 2.9 ng/dL on hospital day 16 (Fig. 1). To date, there have been no reports on the use of After the tendency for improvement of thyroid func- CGM to evaluate intraday glucose variability in patients tion was confirmed, CGM was resumed to assess glu- with hyperthyroidism. To our knowledge, this is the cose variability on hospital day 18 under continued first report of CGM-based evaluation of intraday glu- treatment with insulin aspart (11 U in the morning, 7 cose variability before and after management of hyper-

Fig. 2 Continuous glucose monitoring preformed after withdrawal of potassium iodide 1/30-31: Aspart initiated with 9 U at breakfast, 7 U at lunch and 6 U at dinner. Glargine initiated with 6 U at dinner. 2/1: Aspart initiated with 11 U at breakfast, 7 U at lunch and 6 U at dinner. Glargine initiated with 8 U at dinner. CGM of glucose variability in GD 325

Fig. 3 Self monitoring blood glucose preformed after the start of potassium iodide therapy 2/2: Aspart initiated with 11 U at breakfast, 7 U at lunch and 6 U at dinner. Glargine initiated with 8 U at dinner. 2/3-4: Aspart initiated with 11 U at breakfast, 7 U at lunch and 6 U at dinner. Glargine initiated with 3 U at morning and 6 U at dinner.

Fig. 4 Continuous glucose monitoring preformed after treatment with potassium iodide 2/12-14: Aspart initiated with 11 U at breakfast, 7 U at lunch and 6 U at dinner. Glargine initiated with 6 U at breakfast. 326 Torimoto et al.

Table 2 The parameters of glycemic variability measured by the continuous glucose monitoring system day5 day6 day7 day18 day19 day20 Average (mg/dL) 243 282 231 141 163 168 Min (mg/dL) 111 189 115 87 74 100 Max (mg/dL) 385 378 297 223 286 259 SD (mg/dL) 67 49 49 33 54 33 MAGE (mg/dL) 191 137 145 91 153 95 MPPGE (mg/dL) 85 81 70 71 112 75 MODD (mg/dL) 45 52 34 36 %CV 28% 17% 21% 23% 33% 20% Duration Above High Limit (>180 mg/dL) 77% 100% 82% 19% 31% 38% Duration within Limits (70 180 mg/dL) 23% 0% 18% 81% 69% 62% Duration Below Low Limit (<70 mg/dL) 0% 0% 0% 0% 0% 0% SD, standard deviation; MAGE, mean amplitude of glycemic excursion; MPPGE, mean postprandial glu- cose excursion; MODD, mean of the daily difference; %CV, percentage coefficient of variation

thyroidism. The CGM data obtained from our patient When our patient underwent the first session of indicate that in patients with compromised basal insu- CGM in the presence of thyroid hormone excess, she lin secretion, hyperthyroidism can cause not only post- was found to have not only marked postprandial hyper- prandial hyperglycemia but also elevation of FPG level glycemia but also early morning fasting hyperglyce- due to the dawn phenomenon, and in such patients, the mia due to the marked dawn phenomenon beginning FPG elevation associated with the dawn phenomenon, at approximately 0400 h. The dawn phenomenon is a can be alleviated rapidly following improvement of concept proposed in 1981 by Schmidt et al. [17]. It is thyroid function. defined as “elevation of blood glucose level or increase It has been reported that abnormal glucose tolerance in insulin demand seen towards early morning” attrib- is seen in 44–65% of patients with hyperthyroidism [1]. uted to a rise in insulin-antagonizing hormone level, It has long been known that enhancement of gastroin- increased in peripheral tissue, and testinal motility causes elevation of blood glucose lev- increased gluconeogenesis [18-20]. Among insulin els due to increased glucose absorption via the digestive counter-regulatory hormones, GH secretion was espe- tract, the so-called oxyhyperglycemia-type postpran- cially reported to be closely related to the dawn phe- dial hyperglycemia [2, 3]. Other mechanisms of the nomenon [21, 22]. It has been reported that excessive abnormal glucose tolerance include increased endoge- insulin secretion can also occur in patients with thy- nous gluconeogenesis (due to thyroid hormone excess) rotoxicosis in response to increased gluconeogenesis and insulin resistance. Stimulation of the glycolysis or insulin-antagonizing hormones through the above- system in the presence of thyroid hormone excess can mentioned mechanism if glucose tolerance is normal lead to excess lactic acid, a precursor to gluconeogen- [5, 6]. Therefore, elevation of FPG is absent in many esis, which enters the Cori cycle to stimulate gluconeo- cases. However, the dawn phenomenon was marked genesis [4]. Furthermore, thyroid hormones increase in the present case, probably because the compensa- the cell membrane level of GLUT2, a major glucose tory mechanism mediated by insulin secretion for the transporter isoform expressed in hepatocytes [11, 12], management of increased gluconeogenesis and insulin- resulting in increased release of glucose into the blood antagonizing hormones had collapsed due to concom- from the liver, which serves as a cause of abnormal itant diabetes mellitus associated with compromised glucose metabolism. In the presence of thyrotoxico- insulin secretion. In blood tests performed during the sis, catecholamine stimulation leads to enhanced lipid hyperthyroid state (day 9), no suppression of GH secre- degradation, thereby increasing free fatty acids, which tion was detected despite hyperglycemia; fasting blood in turn stimulates gluconeogenesis in the liver [13, 14]. glucose was 148 mg/dL and GH was 6.42 ng/mL. In Insulin resistance also increases following the increase the hyperthyroid state, 24-hour GH secretion levels are in free fatty acids [15] and interleukin-18 [16]. reportedly increased [23] and the suppressive effect of CGM of glucose variability in GD 327

GH on hyperglycemia becomes inadequate [24]. Thus, the effects of thyroid hormones on different organs in our patient, we consider the increased GH secretion and their threshold values are considered to be differ- level to be related to the increased thyroid function and ent. In this patient, thyroid function improved imme- probably contributed to the occurrence of the dawn diately (e.g., free T3 decreased from 11.54 to 5.32 pg/ phenomenon. mL and free T4 from 6.55 to 2.97 ng/dL) after re-ad- In practice, this case exhibited rapid improvement ministration of potassium iodide, although the func- of glycemic control, as assessed by SMBG data, in tion did not return to normal levels and the patient was response to treatment with KI. When the intraday still in a state of mild hyperthyroid state at that point. glucose variability following improvement of thy- Oxyhyperglycemia associated with enhanced glucose roid function were assessed in the second CGM ses- absorption in the gut due to increased gastrointestinal sion, fasting hyperglycemia due to the dawn phenom- motility is attributable to the actions of the small intes- enon had clearly been alleviated, compared to that tine alone. In contrast, the dawn phenomenon involves observed in the presence of thyroid hormone excess. various organs involved in the regulation of insulin Abnormal glucose tolerance in previously untreated counter-regulatory hormones, peripheral insulin resis- patients with hyperthyroidism reportedly improves tance and increased glyconeogenesis. Thus, we con- in response to anti-thyroid drug treatment [25]. To sider the threshold values for thyroid hormones causing our knowledge, however, there have been no reports oxyhyperglycemia or dawn phenomenon to be differ- describing improvement of the dawn phenomenon. ent; hence, the mild hyperthyroid state was associated Catecholamines are known to stimulate fat degradation with amelioration of the dawn phenomenon, though during hyperthyroidism, causing increased free fatty oxyhyperglycemia state remained unresolved. acids during fasting in particular, thus contributing CGM, performed in our patient with Graves’ disease to insulin resistance [15] and gluconeogenesis in the and diabetes mellitus, with compromised endogenous liver [13, 14]. This may be one of the factors respon- insulin secretion, uncovered the dawn phenomenon-as- sible for the dawn phenomenon observed in the present sociated fasting hyperglycemia associated with hyper- case. Other studies also reported that improvement of thyroidism, and confirmed improvement of the dawn thyroid function can suppress catecholamine-induced phenomenon following improvement of thyroid func- fat degradation [13, 26], suggesting that in the present tion. When patients with hyperthyroidism complicated case, thyroid function improvement also suppressed fat by diabetes mellitus are treated, the dawn phenome- degradation and alleviated gluconeogenesis suppres- non can induce a rise in FPG level, leading to marked sion and insulin resistance, leading to improvement of hyperglycemia, as seen in the present case, but gly- the dawn phenomenon. cemic control can also be restored rapidly following In this patient, amelioration of the dawn phenomenon establishment of euthyroidism. These findings should was noted as thyroid function improved, and the mean ± be kept in mind when determining the strategy for treat- SD value of blood glucose and MAGE also improved, ment of diabetes mellitus in such cases. while MPPGE did not. The effects of hyperthyroid- ism on glycometabolism are influenced by a variety of Disclosure mechanisms (e.g., those that govern the functions of the alimentary tract, circulatory dynamics, insulin secre- All authors declare no conflict of interest associated tion and insulin counter-regulatory hormones), while with this research.

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