The administration of fructose to normal rats led to hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hyper-FFA-emia. Troglitazone (CS-045)(CS) is one of a new class of anti-diabetic drugs which lower glucose, insulin, triglyceride (TG) and FFA levels in various diabetic animal models and in diabetics. Bezafibrate (Bf) is now clinically used as an anti-hyperlipidemic drug which lowers TG and FFA levels in diabetic animals and patients. Recently, we reported that Bf was also effective in lowering plasma glucose and serum insulin levels during OGTT in non-obese patients with hypertriglyceridemia and impaired glucose tolerance. To clarify the relationship between lipid and glucose metabolism in fructose-fed rats with insulin resistance, we independently examined the effects of CS and Bf on lipid metabolism and glucose tolerance in fructose-fed rats. The administration of CS (70mg/kg/day) or Bf (30mg/kg/day) for five weeks decreased hypertriglyceridemia and hyper-FFA-emia in fructose-fed rats. To clarify the mechanism by which these drugs ameliorate hyperlipidemia, we examined the triglyceride secretion rate (TSR) and postheparin plasma lipolytic activity (PHLA). The TSR and PHLA in the CS group demonstrated no significant change. In the Bf group, the TSR was decreased by 40%(162±40 vs 271±48mg/dl/hour, p<0.05), and the PHLA was increased by 50%(0.120±0.028 vs 0.080±0.019mEq/l/min, p<0.05). Moreover, we examined the effects of CS and Bf on glucose metabolism. CS ameliorated fasting hyperglycemia and hyperinsulinemia. The fasting plasma glucose and serum insulin levels in the Bf group showed no significant change as compared to levels in fructose-fed rats. In summary, these results suggest that 1) fructose-feeding causes insulin resistance, 2) administration of CS and Bf ameliorates hyperlipidemia, through different mechanisms, 3) CS diminishes basal hyperinsulinemia and hyperglycemia and 4) impaired glucose tolerance induced by fructose-feeding is different from that in non-obese patients with hypertriglyceridemia and impaired glucose tolerance.

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The present study was undertaken to clarify the effects of insulin and glucose on the utilization of non-esterified fatty acids (NEFA) in the skeletal muscles of normal and diabetic rats, using the hindlimb perfusion method. The hindlimb perfusion was performed for 1hr with a perfusion medium containing 1mmol/l palmitate, glucose, and/or insulin, to calculate the NEFA clearance (F value) of hindlimb skeletal muscle. In normal rats, glucose increased the F value to a maximum of 500mg/ dl. Furthermore, 62.5U/μml insulin had an enhancing effect on the F value in the presence of glucose, while a further increase in insulin concentrations suppressed it. Insulin had no effect on the F value in the absence of glucose. In diabetic rats, the F value was decreased under all conditions, as compared with the control. The results of the present study suggest that glucose plays a role in NEFA utilization in skeletal muscle, and that this NEFA utilization is decreased in the diabetic state. It is also suggested that this decrease may be related to the NEFA supply to the liver.

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To assess the effects of pancreas transplantation (PTX) on left ventricular (LV) function in insulin-dependent diabetes mellitus (IDDM), two-dimensional and Doppler echocardiography were performed in 3 patients with IDDM before and 6 months after PTX. Case 1 (female, 30 years) and Case 2 (female, 32 years) received simultaneous pancreas and kidney transplantation, while Case 3 (female, 37 years) underwent PTX after she had undergone kidney transplantation. All three showed normal hemoglobin A_1c without exogenous insulin administration during the 6 month period after PTX. Among echocardiographic features, LV end-diastolic dimensions did not differ in the 3 IDDM patients before, as compared with 6 months after, PTX. Before PTX, the slope of the early-diastolic flow velocily peak (EF slope) was decreased and the ratio of lale (atrial) to early peaks of diastolic flow velocity (A/E) was increased. This observation indicated reduced LV diastolic function. At 6 months after PTX, this parameter of LV diastolic function had significantly improved in Cases 1 and 2, but was minimally improved in Case 3.
Reducing ventricular loading and removing uremic toxins, by kidney transplantation, may improve cardiac function. Furthermore, normalization of blood glucose, by pancreas transplantation, might result in the improvement of LV diastolic dysfunction.

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In the present study we tried to determine whether dry blood samples spotted on a sheet of filter paper could be used to measure HbA_1c. Blood samples obtained by fingerprick were spotted on filter paper and arrived in our laboratory three days after being mailed. HbA_1c was measured by turbidimetric inhibition immunoassay (TINIA) using hemolysates eluted from the spotted filter paper by immersing it in the hemolyzing solution. For comparison, HbA_1c values were measured in fresh venous blood samples from the same subjects by HPLC, which was shown not to be feasible for measurement of HbA_1c using hemolysates of dry blood samples.
Within-day and between-day precision of HbA1c measurements by TINIA yielded coefficients of variation of 1.22-1.99% and 2.32-3.81%, respectively. The HbA_1c values of fresh venous bood samples measured by HPLC were well correlated with the values obtained using spotted fingerprick blood (r=0.975, p<0.001) and spotted venous blood samples (r=0.975, p<0.001) analyzed by TINIA.
In conclusion, mailed dry blood samples spotted on filter paper can be used to measure HbA_1c by TINIA.

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We describe two cases of IDDM with acute onset at the age of 67 and 68 years. The first case was in a 67-year-old man, who consulted our department because of thirst and general fatigue. His blood studies showed marked elevations of blood glucose and of urinary ketones, and secretion of C-peptide (CPR) was markedly reduced. The DR4, A24 and BW54 haplotypes of human leukocyte antigen (HLA) were positive. The second case was in a 68-year-old woman who complained of general fatigue after flu-like symptoms. She later developed cyclic vomiting and her consciousness became unclear. Blood studies showed marked elevations of blood glucose and urinary ketones. The patient was treated with insulin, but her diabetic state could not be adequately controlled, and she consulted our hospital. Daily urinary CPR excretion was low, and the DR9 and BW61 HLA haplotypes were positive. These are only the fifth and sixth case of acute onset IDDM in the elderly discribed in the Japanese literature.

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Internal and total condylar depression of the proximal end of the tibia was found in an insulin dependent diabetic (IDDM) patient and a non-insulin dependent diabetic (NIDDM) patient, respectively. The patients had advanced somatic and autonomic neuropathy with long-standing poorly controlled diabetes. The IDDM patient suffered severe gastroenteropathy with nausea and vomiting, whereas the NIDDM patient had diabetic amyotrophy. The patients' daily activity was markedly diminished long before the fractures. Diabetic sensory disturbance, muscle weakness, and decreased physical strength were pointed out as causal factors of the fractures. Amenorrhea was also found in the IDDM patient, whose hypogonadism may have exacerbated osteoporosis.
The fractures were triggered by minor events such as ordinary walking. Therefore, when slight pain in the joints or feet diabetic patients experience, early diagnosis by X-ray and MRI of the bone followed by appropriate treatment, such as non-weight-bearing by the lesions is mandatory to prevent progression to Charcot's joint or severe diabetic osteoarthropathy.

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A 48-year-old woman with diabetes associated with Werner's syndrome was admitted to Nagasaki University Hospital because of poorly controlled diabetes. After admission, she was treated with a 1200 kcal diet and exercise therapy. Her mean plasma glucose (PG) decreased from 276mg/dl to 232mg/dl within 3 weeks, but was unchanged at 6 weeks (229mg/dl). The new oral hypoglycemic agent CS-045 (Troglitazone) was then administered'. After CS-045 (400mg/day), mean PG decreased markedly (152mg/dl 3 weeks after starting CS-045 versus 137mg/dl 6 weeks).
The area under the insulin curve (AUC insulin) during 75g OGTT was measured to assess insulin secretion. AUC insulin increased from 4573μU/ml·min to 7497μU/ml after diet therapy. AUC insulin after taking CS-045 also increased (8646μU/ml·min), but the degree of the increment was smaller than after diet therapy. Insulin sensitivity was measured using Bergman's minimal model. The insulin sensitivity index (Si) on admission was less than 0.01×10^-4min^-1·pM^-1. Si after diet therapy increased (0.37×10^-4min^-1·pM^-1). Si after taking CS-045 increased markedly, from 0.37×10^-4min^-1·pM^-1 to 2.67×10^-4min^-1·pM. This patient's diabetes was successfully treated by CS-045, and the mechanism of the decrease in plasma glucose was thought to be improvement of insulin sensitivity and glucose toxicity.

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We report a 50-year-old man who developed painful neuropathy after treatment with an oral hypoglycemic drug. Although the duration of the NIDDM was unknown, he had a two-year history sensory disturbance of the lower extremities.
Diet therapy and oral hypoglycemic agent were prescribed after admission. Although his blood glucose level normalized in 2 weeks, he suffered dysesthetic pain in the foot and a gait disturbance. At that time, the blood study results were normal. No sensory nerve action potentials were detected electromyographically in the sural nerves, and left sural nerve biopsy was performed. The light microscopic findings were compatible with diabetic neuropathys, But electron microscopy showed very few regenerating fibers. Although the pain of diabetic neuropathy has been attributed to the sprouting of unmyelinated and small myelinated fibers, our case suggests that the cause of painful diabetic neuropathy might be related not only to the regeneration of small fibers in the peripheral nerves, but to other causes as well.

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We report the cases of two infertile diabetic women who delivered healthy infants after undergoing in vitro fertilization and embryo transfer (IVF-ET).
Patient 1 was 33 years old with a previous history of IDDM and hypothalamic amenorrhea since 28 years of age. During her first pregnancy, the fetus died after a keto-acidotic episode. She was then referred to our Diabetes Center.
Patient 2 was 34 years old with NIDDM diagnosed at age 19 years. After getting married at the age of 27, she became amenorrheic and infertile due to tubal adhesion. Because of their great desire to have children they agreed to undergo IVF-ET. They became pregnamt by IVF-ET after several unsuccessful gamete intrafallopian transfers. Throughout the gestational period, thier HbA1c levels ranged from 4% to 6% and no complications occurred.
Patient 1 delivered a healthy female infant weighing 3080g by cesarean section. This was indicated because of uterus bicornis at 38 weeks and 4 days gestation. Patient 2 delivered a healthy female infant weighing 3190g at 40 weeks and 4 days.
To the best of our knowledge, in Japan, there are no previous reports of diabetic women who achieved successful pregnancy and delivery after undergoing IVF-ET. We recommend that diabetic women, as well as non-diabetic women with sterility undergo IVF-ET.

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Although the debate continues over whether young diabetic women are at increased risk for developing eating disorders, no one questions the devastating effect of abnormal eating behaviors on the clinical course of diabetes. However, the treatment of eating disorders in diabetics remains largely unstudied. The literature is limited to a handful of case studies. Herein, we report an IDDM case with eating disorders who improved remarkably with behavioral therapy on an inpatient basis. The case was a 23-year-old woman who had been diagnosed as having IDDM at 17 years of age. Her metabolic control was poor, HbA_1c 11-14%, because she was unable to follow her prescribed dietary therapy regimen. She developed Bulimia Nervosa at the age of 22, and Anorexia Nervosa at 23. On admission, we primarily treated the eating disorder, utilizing mainly behavioral therapy together with individual counseling, group therapy and family counseling. The treatment was successful and 18 months after inpatient treatment ended, she continued to maintain stable eating behaviors and metabolic control.

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To clarify the mechanism by which intra-abdominal fat accumulated, we examined the influence of sex hormones on fat distribution and glucose intolerance in genetically obese-hyperglycemic OLETF rats, which are characterized by mesenteric fat accumulation. Male and female OLETF rats aged 5 weeks were orchiectomized and ovariectomized, respectively, and followed together with sham-operated control male and female OLETF rats until 35 weeks of age. At the age of 35 weeks, an oral glucose tolerance test (OGTT) showed a significant decrease in plasma glucose levels in the orchiectomized group compared with those in control group. There were no significant differences in insulin response during the OGTT between the orchiectomized and control groups. Although the mesenteric (M) and subcutaneous (S) fat weight in orchiectomized group significantly incressed compared to the control group, the increase in S fat weight was more marked than in M fat weight, and the M/S fat weight ratio in orchiectomized group decreased significantly compared to the control group.
In contrast, there were no significant differences in glucose tolerance, insulin response during OGTT or fat distribution between the ovariectomized and controlgroups.

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