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Naoki Sakane1*, Kazuhiko Kotani1,2, Kokoro Tsuzaki1, Masami Nishi1,20, Kaoru Takahashi1,3, Takashi Murata4, Kazunori Yamada4, Kentaro Okazaki5, Katsuyuki Yanagisawa6, Kenichi Yamada7, Nobuichi Kuribayashi8, Yasuo Totsuka9, Toru Hiyoshi10, Motoji Naka11, Masatake Sugimoto12, Yuji Aoki13, Masako Waki14, Miyuki Furuya15, Haruko Kitaoka16, Mariko Oishi17, Ikki Shimizu18, Hiroaki Miyaoka19, Akira Okada20 and Toshikazu Yamamoto21

Glucagon is recommended to treat severe hypoglycemia in nonhospital environments, when a patient with type 1 diabetes mellitus (T1DM) is unconscious and unable to eat or drink. However, the actual possession rate of glucagon in Japan has not been investigated.We recruited 208 T1DM patients older than 15 years of age. The patients were treated at 16 hospitals and clinics in different regions of Japan. Answers were obtained using a self-administered questionnaire about the possession, the experience of usage, and the preference to possess glucagon after reading what is glucagon and when it is used. A stepwise logistic regression analysis was performed to assess the influence of various factors on the possession of glucagon.The possession rate of glucagon was 15.9%, and the rate of those who had experience of using glucagon to treat severe hypoglycemia was 6.0%. The rate of preference to possess glucagon at home after reading the description of glucagon was 39.0%. The possession of glucagon was significantly associated with results of the Glucagon Knowledge Test (odds ratio=24.1; 95% confidence interval, 3.2-183.3; P=0.002) and the history of severe hypoglycemia within 1 year (odds ratio=4.8; 95% confidence interval, 2.0-12.0; P=0.001).Glucagon as a measure to treat severe hypoglycemia was underutilized among T1DM patients in Japan.

The aim of the present study was to investigate the prevalence of fear of hypoglycemia, in association with severe hypoglycemia and social factors, in insulin-treated patients with type 2 diabetes mellitus. A questionnaire survey on hypoglycemia and patient-physician communication was carried out in 355 patients with insulin-treated type 2 diabetes mellitus patients at 16 hospitals and clinics. A fear of hypoglycemia was reported by 27.7% of patients. A stepwise logistic regression analysis found that severe hypoglycemia during the past 1 year was a significant determinant of fear of hypoglycemia (odds ratio 2.16, 95% confidence interval 1.06-4.41; P = 0.034), and age (odds ratio 1.02, 95% confidence interval 1.00-1.05, P = 0.038) and living alone (odds ratio 1.93, 95% confidence interval 1.00-3.73, P < 0.05) were significantly higher in patients with fear of hypoglycemia than in those without it.

Objective: Circulating levels of lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace reportedly increase in renal failure as well as in cardiovascular injuries. We investigated the alterations of L-PGDS in urine and plasma in the early stage of type-2 diabetic patients. Method: Thirty-six type-2 diabetic patients and 29 normal subjects were studied. Overnight spot urine and plasma samples were obtained in the morning. L-PGDS was measured by ELISA method using anti-L-PGDS antibody. Variables indicating renal function were determined. Results: Plasma L-PGDS concentration was slightly higher in the patients with diabetes mellitus than in the control subjects, whereas the urinary L-PGDS excretion almost doubled in the diabetic patients as compared with that in the control subjects. Plasma L-PGDS was determined by plasma creatinine (Cr) concentration while urinary L-PGDS excretion was correlated solely with urinary protein excretion. There was no relationship between plasma L-PGDS concentration and urinary L-PGDS excretion. The averaged plasma concentration of L-PGDS in the diabetics with a normal Cr level in plasma, corresponding to that in the controls, was determined by the plasma Cr concentration. On the other hand, the urinary L-PGDS excretion was determined by the amount of proteinuria and greater in the diabetics with a normal Cr level in plasma than in the controls even when the patients exhibited urinary protein excretion equal to that in the control subjects. Conclusions: Urinary L-PGDS excretion increased in the early stage of kidney injury in patients with type-2 diabetes mellitus. The urinary excretion was correlated independently with urinary protein excretion even when there was no difference in urinary protein or albumin excretions, thereby suggesting that urinary L-PGDS excretion is possibly a more sensitive indicator of renal injuries than proteinuria. Urinary L-PGDS may thus predict the progression of renal injuries in diabetic patients.

Patients with poorly controlled noninsulin dependent diabetes mellitus (NIDDM) are shown to have higher bone mass. However, the influence of changes in glycemic control on bone turnover is not known. To clarify whether metabolic improvement of poorly controlled NIDDM affects bone turnover, markers for glucose, mineral, and bone metabolism were assessed before and after glycemic control for 3 weeks in 78 poorly controlled NIDDM patients with initial hemoglobin A1c over 8%. Metabolic improvement caused a reduction in urinary calcium (Ca) and phosphate (Pi) and serum 1,25(OH)2D levels, and an increase in serum Pi without changes in serum Ca or parathyroid hormone levels. Bone resorption markers, urinary deoxypyridinoline (Dpd) and type I collagen carboxy-terminal telopeptide (CTx), as well as a bone formation marker, serum bone type alkaline phosphatase (BALP), were reduced. However, another bone formation marker, serum osteocalcin (OC), was low before treatment and was elevated after treatment. The decrease in Dpd, CTx and BALP, but not the increase in OC, correlated with each other and with the improvement in glycemic indices. In conclusion, metabolic improvement of poorly controlled NIDDM decreases bone turnover within a short period. Thus, glycemic control may protect NIDDM patients from bone loss. It is possible that serum OC is affected by hyperglycemia per se, and may not correctly reflect bone turnover.

We encountered two patients with non-insulin-dependent diabetes mellitus (DM) who developed normocytic normochromic anemia. Routine hematological examinations revealed no specific causes except for the reduced serum levels of erythropoietin. Since their renal functions were preserved, the anemias may not have been due to chronic renal failure. Treatment with human recombinant erythropoietin (rHuEPO) improved anemia, ascribing the cause of anemia to low levels of erythropoietin in these patients. Underlying common clinical features of the two patients were longstanding poorly controlled diabetes mellitus accompanied with advanced neuropathy. Since erythropoietin production is regulated in part by autonomic nervous system, the results suggest that erythropoietin production could be prematurely impaired in patients with severe diabetic autonomic neuropathy.

Background/Aims: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/β-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. Methods: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 ± 0.20%; creatinine (Cr), 85.1 ± 2.4 µmol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. Results: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 ± 27.4 vs. 73.8 ± 7.8 µg/mmol Cr, p < 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 ± 21.1, p < 0.0001 and 338.6 ± 62.5 µg/mmol Cr, p < 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 ± 6.6 vs. 118.1 ± 2.6 (SE) µg/mmol Cr, p < 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. Conclusion: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes.

In a 37-year-old man who had Cushing's syndrome, investigations, including overnight dexamethasone suppression test, corticotropin-releasing hormone (CRH) test, pituitary MRI and inferior petrosal sinus sampling suggested the presence of ectopic adrenocorticotropin (ACTH) production. Interestingly, gonadotropin-releasing hormone (GnRH) increased plasma ACTH from 73 pg/ml to 708 pg/ml at 15 min. Furthermore, desmopressin also increased plasma ACTH whereas CRH and thyrotropin-releasing hormone (TRH) had no effect. Such paradoxical responses of plasma ACTH were observed repeatedly. A thoracic CT scan revealed a right anterior mediastinal mass, which was surgically resected. Histological and immunohistochemical examination confirmed that the tumor was an ACTH-producing carcinoid. ACTH and cortisol decreased immediately following surgery. Neither desmopressin nor GnRH administration resulted in elevation of plasma ACTH while ACTH-responsiveness to dexamethasone and CRH was restored. To our knowledge, this is the first report documenting GnRH responsiveness in ectopic ACTH syndrome.

We report a 64-year-old male with granulocytopenia and dermatitis due to cyanamide treatment. We administered cyanamide for alcoholism. After about one month he suffered from scaly erythema over his whole body and granulocytopenia (granulocyte; 140/μl) with maturation arrest in bone marrow. After cessation of cyanamide and the start of granulocyte colony-stimulating factor administration, the skin eruption ameliorated gradually, and the peripheral blood granulocyte counts increased. Cyanamide showed positive results in the drug lymphocyte stimulation test (198%) and the patch test led to the diagnosis of granulocytopenia and dermatitis induced by cyanamide. After restarting glibenclamide and diazepam administration, his granulocytopenia did not reoccur. To our knowledge, this is the first report of a case with granulocytopenia induced by cyanamide.(Internal Medicine 36: 640-642, 1997)

• Cough productive of sputum, exertional dyspnea, and hypoxemia developed in two patients with Graves' disease after six months (patient 1) or three weeks (patient 2) of treatment with propylthiouracil, 300 mg/day. Chest roentgenograms and transbronchial lung biopsy specimens revealed diffuse interstitial pneumonitis. Lymphocyte transformation by phytohemagglutinin was highly stimulated by propylthiouracil. Symptoms and signs improved after cessation of the drug therapy and administration of prednisolone acetate. These cases represent the first report of a complication of diffuse interstitial pneumonitis induced by propylthiouracil. (Arch Intern Med1984;144:1764-1765)