We determined the clinical characteristics of adult-onset NIDDM patients positive for antiglutamic acid decarboxylase antibody (GAD-Ab). The subjects were 40 patients who were diagnosed after the age of 20 years without ketosis at the onset, who required insulin therapy and were positive for GAD for 7 years of follow-up. The mean age at the time of the study was 53 years and the duration of diabetes was 7 years. The mean body mass index (BMI) was 20. 7. The controls were 18 adult-onset GAD-Ab-negative NIDDM patients who were matched for gender, age at the time of the study, disease duration and BMI. The mean duration from the onsetof diabetes to insulin therapy was 1. 6 years in the GAD-Ab-positive group and 3. 3 years in the negative group. The incidence a history of obesity was 22.5% inthe positive group and 16% in the negative group, and the incidence of a BMI over 22 was 30% in the positive group and 38% in the negative group. The GAD-positive group showed greater ICA and/or ICA 512 prevalence than the negative group. DR 4 and/or DR 9 were not significantly different in the two groups, while A 24 in the GAD-Ab positive group was 36%(0% in the GAD-Ab-negative group). Adult-onset GAD positive diabetes may cause autoimmune-pancreatic β-cell destruction.

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The influence of high glucose concentration on proliferation, cell cycle and fibronectin (FN) accumulation in cultured normal rat kidney (NRK) cells was studied. Quiescent cells were cultured in RPMI 1640 medium containing 0.5% fetal calf serum in the presence of 5mM glucose, 30mM glucose or 5mM glucose plus 25mM mannitol for 24h.(³H) thymidine incorporation was not changed in the 30-mM glucose condition. In addition, the cell cycle of these cells was not altered in the same condition. However, measurement of FN accumulation by ELISA showed increased concentration of FN in the supernatant of NRK cells grown in the 30-mM glucose condition. Five mM glucose plus 25mM mannitol did not stimulate FN accumulation as the control condition did. Western blot analysis revealed that 30mM glucose stimulated PKC α expression in the membrane fractions of these cells, whereas 5mM glucose plus 25mM mannitol did not stimulate PKCa expressions control conditions did. On the other hand, 5, μM or 10, μM H-7 and 50nM or 100nM staurosporine (protein kinase C inhibitors), suppressed FN accumulation induced by 30mM glucose. These results suggest that high blood glucose concentration may play an important role in the expansion of the interstitium in diabetic nephropathy.

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To learn the effects of alcohol and of the aldehyde dehydrogenase 2 (ALDH 2) genotype on diabetic neuropathy, 119 drinkers among 143 male NIDDM patients were studied. Subjects with different ALDH 2 genotypes were examined for a correlation of nerve conduction velocity (NCV) with clinical parameters. The results showed that 72 had an active ALDH 2 and 47 had an inactive ALDH 2 genotype. A positive correlation of NCV with current alcohol consumption was seen in the active ALDH 2 group (p <0.05). A negative correlation of NCV with past alcohol consumption was found in the inactive ALDH 2 group (p <0.01). These findings suggest a different association of the alcohol effect with neuropathy in the different ALDH 2 genotype groups. We speculate that, because alcohol intake in the absence of ALDH 2 activity facilitates acetaldehyde accumulation, acetaldehyde toxicity may precipitate peripheral neuropathy in the inactive ALDH 2 group. The positive correlation of current alcohol consumption with NCV in the active ALDH 2 group suggests that patients with less neuropathy in that group tend to drink more alcohol. We speculate that, in the artive ALDH 2 group, alcohol neither facilitates acetaldehyde accumulation nor injures nerves. Conversely, the vasodilative effect of alcohol may prevent progression of neuropathy. In conclusion, this is the first indication of a role of the ALDH 2 genotype in diabetic neuropathy. This gives new insight into the etiology of diabetic neuropathy.

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We experienced a case of Basedow's disease complicated with glutamic decarboxylase (GAD) antibody-positive non-insulin-dependent diabetes mellitus, pseudohypoparathyroidism type II and frequent hypoglycemic attacks. This case seems to be the first one of pseudohypoparathyroidism type II with Basedow's disease and diabetes mellitus. A 29-year-old woman who was diagnosed as having Basedow's disease in September of 1994 was found to be suffering from non-insulindependent diabetes mellitus with GAD antibody in March of 1996. Three months later, she was foundto have hypocalcemia which was due to pseudohypoparathyroidism type II. From thepresence of GAD antibody and HLA typing, it was thought that she would have insulin-dependent diabetes mellitus in the future. The cause of her pseudohypoparathyroidism type II is assumed to have been a defect in the response to PTH at a loucus beyond that of cyclic AMP production. In view of the fact that she has two other autoimmune diseases, pseudohypoparathyroidism type II in our patient may be due to the presence of an autoantibody to some substances in target cells to PTH. Polyglandular autoimmune syndrome (PGA) is known to be a multiple endocrine gland disorder which is induced by autoimmune pathogenesis. Our patient is characteristic in that the plasma intact-PTH level was increased, whereas it is decreased in PGA, since the existence ofparathyroid gland-specific autoantibodies in patients with PGA causea a decrease in plasma PTH levels. The finding suggests that an autoantibody against some substances in target cells to PTH may be associated with high levels of plasma PTH. If so, our patient may be thought to have anew type of PGA. As for the cause of her frequent hypoglycemia attacks, we examined her serum for the presence of islet-cell-stimulating-antibody. However, we could not detect such an antibody.

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We experienced two patients who received allogenic bone marrow transplantation which induced diabetes mellitus (D.M.) following treatment with FK 506. In case 1, after three-week oral adminis trarionof FK 506 for chronic graft-versus-host disease (GVHD), the fasting blood sugar (FBS) level increased from 90 mg/dl to 156 mg/dl, and the C-peptide immunoreactivity (CPR) in the urine was concomitantly decreased to 9.7μg/day. At that time, the FK 506 concentration in the blood was 10 to 15ng/ml. Along with the reduction of the dose of FK 506, the CPR in the urine increased to 47.3yg/day. In case 2, after three-week intravenous administration of FK 506 for chronic GVHD, the FBS level increased from 80 mg/dl to 254 mg/dl and the urine CPR decreased from 256μg/day to 21.6μg/day. At that time, the FK 506 concentration was 15 to 20 ng/ml. Two weeks after readministration of CsA, the FBS level became 84 mg/dl. These findings indicate that D.M. is inducible in a dose-dependent manner in patients receiving a therapeutic dose of FK 506, while the FK 506-induced D. M. can be reversed by the reduction and/or discontinuation of the administra tionof FK 506.

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A 56-year-old woman was placed on insulin therapy after developing diabetes accompanied by severe acute pancreatitis in January 1992.From January 1996, glycemic control was poor and colic attacks resembling those caused by urinary calculus often appeared.The patient was hospitalized and had such attacks during hospitalization.A diagnosis of renal papillary necrosis complicated by emphaematous pyelonephritis was made based on urinary excretion of necrotized tissue, abdominal ultrasonograms, and CT scans. The necrosis resolved after palliative treatment in the form of antibiotics and intensified insulin therapy.Since the duration of diabetes was only 4 years and microangiopathic complications were absent, the colic attacks were presumably attributable to hyperglycemia and urinary infection.Patients with renal papillary necrosis have a poor prognosis and may develop renal insufficiency if the condition is not detected early.Early diagnosis and treatment of patients presenting with colic attacks similar to those caused by urinary calculus is therefore important, as there is a possibility of renal papillary necrosis.

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To assess the relationship between cytokines and diabetic complications, IL-1βand TNF-αconcentrations of peripheral blood were measured in NIDDM patients. The presence of microangiopathy was determined by positive simple/proliferative diabetic retinopathy, or persistent proteinuria. The presence of macroangiopathy was also estimated by positive findings of electrocardiography, cardiac catheter methods, brain CT/MRI, or deterioration of pulsation in the lower extremities. Concentrations of IL-1βand TNF-αwere measured with an ELISA system. As a result, TNF-αwas higher (2116±1074 vs.1406±918pg/m/, p<0.05) in the patients with macroangiopathy than in those without macroangiopathy, whereas IL-1βwas not different IL-1β and TNF-αlevels were not affected by the presence of diabetic microangiopathy. These results suggest that TNF-a might contribute to the development of diabetic macroangiopathy.

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