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Objective: We investigated the clinical characteristics of intensive insulin therapy in Japanese type 2 diabetes patients who commenced intensive insulin therapy during the in-hospital diabetes education program at Tokai university hospital., Methods: 81 type 2 diabetes patients who received intensive insulin therapy and in-hospital diabetes education program were examined their clinical features., Results: Intensive insulin therapy maintained HbA(1C) below 7% at all time points during the 2-year follow-up, though it was not necessary to increase the insulin dose, thus highlighting the clinical utility of the therapy in preventing diabetic complications. Insulin therapy could be withdrawn from more than 25% of patients. The diabetic morbid period was shorter and urinary C-peptide level at admission was higher in patients of the withdrawal group than those of the non-withdrawal group, suggesting that patients with well maintained pancreatic β cell reserve could be withdrawn from insulin therapy., Conclusions: Based on our results of the efficacy of strict glycemic control for preventing the development and progression of diabetic complications, we recommend early introduction of intensive insulin therapy to achieve better glycemic control.

Objective: To determine the clinical usefulness of long-term intensive insulin therapy in Japanese patients with type 2 diabetes., Patients and Methods: Various clinical indicators and potential of withdrawal from insulin therapy were investigated in 20 type 2 diabetic patients receiving treatment in the outpatient clinic over a period of 8 years after starting intensive insulin therapy between April 1997 and March 1999., Results: The mean glycated hemoglobin (HbA1c) was approximately 6.5%, and there was no significant increase in insulin dose over a period of 8 years after commencement of intensive insulin therapy. Withdrawal from insulin therapy could be sustained in previously untreated patients., Conclusion: Our results indicated the clinical usefulness of intensive insulin therapy over the long term in Japanese patients with type 2 diabetes and that such therapy could be especially useful for previously untreated patients.

Type IV collagen is a major component released from the glomerular and tubular basement membranes. To investigate the alteration of renal type IV collagen turnover in early stage diabetic nephropathy, urinary type IV collagen was measured by a highly sensitive one-step sandwich enzyme immunoassay (EIA). Urinary samples were obtained from 94 diabetic patients without overt proteinuria. Among those patients, 61 were normoalbuminuric and 33 patients were in the microalbuminuric group. Levels of urinary type IV collagen were serially examined at the start of this study and again one year later. The levels of urinary type IV collagen in patients in the microalbuminuric group were significantly higher than those in the normoalbuminuric group (P < 0.01). There was a significant correlation between the concentration of urinary albumin and urinary type IV collagen in both groups (P < 0.05). Twenty-eight patients (45.3%) in the normoalbuminuric group who showed an abnormal elevation of urinary type IV collagen in comparison to the reference range of normal healthy adults (normal range; less than 3.5 microg/g x Cr). Seven (25%) out of these 28 normoalbuminuric patients with increased urinary type IV collagen progressed to the microalbuminuric group one year later. The levels of urinary type IV collagen in such patients were significantly increased. In the 21 patients who stayed within the normoalbuminuric group, the urinary type IV collagen levels were significantly decreased one year later. It appears that the levels of urinary type IV collagen might reflect ongoing alteration of the extracellular matrix (ECM) turnover and might define more specifically the early stage diabetic nephropathy than the detection of microalbuminuria. It is concluded that the serial measurement of urinary type IV collagen can be a useful marker for detecting renal injury in diabetes.

A diabetic patient with hemoglobin (Hb) J-Meerut and low HbA1C levels is reported. An automatic glycohemoglobin analyzer used for the determination of HbA1C revealed an abnormal peak of the peripheral blood obtained from a Japanese female with diabetes. She showed a lower HbA1C level (3.7%) than expected from her fasting plasma glucose (172 mg/dl). High performance liquid chromatography and isoelectric focusing indicated that her abnormal hemoglobin was Hb J-Meerut [alpha 120(H3)Ala-->Glu] and it accounted for 28.3% of the total hemoglobin. Abnormal hemoglobinemia should be considered when a major discrepancy between the levels of HbA1C and fasting plasma glucose is observed.

This is the first report on immunofluorescence staining of renal biopsy samples in human diabetic nephropathy (DN) using monoclonal antibodies to reduced glycated lysine. In order to detect the localization of glycated lysine in the mesangial matrix and/or the glomerular basement membrane (GBM), we examined immunofluorescence staining using antibodies against reduced glycated lysine in the glomeruli of 16 patients with DN and ten age-matched patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (DPGN) as controls. In the early stage of DN, immunofluorescence microscopy revealed the presence of intense staining for reduced glycated lysine in the GBM as well as in part of the tubular basement membrane, but not in the mesangial area. In contrast, immunofluorescence microscopy revealed less staining for glycated lysine in the GBM in the advanced stage of DN, and no reaction with any part of the renal tissue in patients with DPGN. It was concluded that detection of reduced glycated lysine in GBM in the early stage of DN might be associated with the initial pathogenesis of this disease.

Urinary albumin fragments (uAF) from patients with NIDDM were analyzed as a possible factor in the early discovery of diabetic nephropathy before emergence of microalbuminuria. SDS-PAGE and immunoblot assay were employed for detection of uAF. Samples from 252 patients with NIDDM, 158 patients with non-diabetic diseases, and 48 healthy volunteers were examined; uAF were detected in 139 (55.2%), 94 (59.5%), only one (2.1%), respectively. In diabetic patients with normoalbuminuria, uAF were detected in 48 out of 159 cases (30.2%). Two years after the initial study, 3 of the 17 diabetic patients (17.6%) with normoalbuminuria and uAF showed micro- or macroalbuminuria. It was concluded that detection of uAF might be useful for the early detection of diabetic nephropathy in NIDDM.

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of human diabetic nephropathy. Renal tissues from 15 patients with type II (non-insulin-dependent) diabetes (NIDDM) were studied by immunofluorescence (IF) and immunogold electron microscopy (IEM) for the distribution of 2 type IV collagen peptides [alpha 3(IV) noncollagenous (NC) domain and alpha 4(IV) NC domain] and 2 classical type IV collagen chains [alpha 1(IV) NC domain and alpha 2(IV) domain]. There was intense staining for alpha 3(IV) NC and alpha 4(IV) NC domain in the GBM but not in the mesangial matrix of patients with overt diabetic nephropathy. In contrast, staining with antibodies to alpha 1(IV) NC and alpha 2(IV) NC domain reacted with mesangial matrix but was significantly decreased in the GBM in the patients with overt diabetic nephropathy. IEM confirmed the IF findings. These data suggest that expansion of the mesangial matrix and thickening of GBM in NIDDM involves separate and distinct type IV collagen components and that the site-specific matrix alterations in NIDDM and type I (insulin-dependent) diabetes are parallel.

Significance of serum IgA and IgA-class circulating immune complexes (IgA-CIC) elevation in patients with non-insulin-dependent diabetes mellitus (NIDDM) was described. Seventeen patients with NIDDM and 17 patients with diffuse mesangial proliferative glomerulonephritis without deposition of IgA (DPGN) as controls were examined. The levels of serum IgA in patients with NIDDM were significantly higher than those in patients with DPGN (p < or = 0.01). The levels of IgA-CIC in patients with NIDDM were also significantly higher than those in patients with DPGN (p < or = 0.01). Production of IgA derived from B cells and the proportion of IgA bearing B cells in patients with NIDDM were not significantly higher than those in patients with DPGN. Furthermore, the levels of IgA in pharyngeal washings from diabetic patients were not significantly higher than those for DPGN patients. Duration of diabetes, the level of HbA1c, and the presence of hypertension, microalbuminuria, or retinopathy showed no significant correlations with the levels of serum IgA or IgA-CIC in patients with NIDDM. It was postulated that the elevations of serum IgA and IgA-CIC were based on subclinical infection of the mucosa and/or deterioration of IgA clearance in patients with NIDDM.

We designed this study to elucidate a possible involvement of genetic factors which influence the progression of renal dysfunction in patients with non-insulin dependent diabetes mellitus (NIDDM). A total of 328 patients was randomly selected in the Tokai University Hospital. They had been cared for in our hospital as NIDDM for the past five years, until April, 1989. Fifty-six patients with persistent albuminuria, and an equal number of patients without persistent albuminuria were included in this study. No significant differences were observed between the two groups in terms of age, estimated period of illness, blood pressure, body-mass index, HbAlc, blood glucose, total cholesterol, triglyceride level and mean blood pressure. The family histories obtained by questionnaires revealed that there might be some genetic predisposing factors leading to the onset of nephropathy in patients with NIDDM, especially in cases with paternal high blood pressure. It is suggested that paternal hypertension might be related to the development of nephropathy in patients with NIDDM.

Long-term effects of urokinase on the preservation of renal function in patients with diabetic nephropathy were evaluated. Twenty-nine adult patients with non-insulin-dependent diabetes mellitus and overt proteinuria were randomly divided into two groups. One group was treated with daily oral administration of dipyridamole or dilazep dihydrochloride and weekly intravenous administration of urokinase; the other group was treated with dipyridamole alone. There was a significant decrease in the amount of proteinuria in the first group after 3 months of the treatment compared with the second group. There was also a significant preservation of renal function in the first group after three years of treatment compared with the second group. It was concluded that continuous administration of urokinase in addition to antiplatelet agents is useful in the treatment of patients with diabetic nephropathy.

Deposition of immunoglobulins or acute phase reactant (APR) proteins in the dermal and glomerular capillary walls from patients with diabetes mellitus was examined to determine whether development of microangiopathy in such patients was related to exudation and/or entrapment of these proteins. Skin and renal biopsy specimens were obtained from patients with diabetic nephropathy and diabetes mellitus without nephropathy. These biopsy samples were stained with FITC-labeled anti-human IgG, IgA, IgM, C3, APR proteins, and beta-lipoprotein antisera. Linear depositions of IgA, IgG, and/or APR proteins were observed in the dermal and/or glomerular capillary walls from some patients with diabetic nephropathy or diabetes mellitus without nephropathy. It is indicated that deposition of such immunoglobulins in the dermal and glomerular capillary walls might be due to exudation and/or entrapment of these substances in patients with diabetes mellitus.

The percentages of glycosylated proteins or albumin, or glycohemoglobin A1 (HbA1) in sera from patients with noninsulin dependent diabetes mellitus (NIDDM) were measured to elucidate whether such measurements are useful for evaluation of the mean levels of blood glucose during short intervals in these patients. Forty patients with NIDDM and twenty healthy adults were examined. The percentages of glycosylated proteins or albumin were quantitated by a Glyc-Affin system and those of HbA1 were measured by electrophoresis. It was indicated that the percentages of glycosylated proteins or albumin, and HbA1 in sera from patients with NIDDM were significantly higher than those in sera from healthy adults. There was a significant correlation between the percentages of HbA1 in sera and the mean levels of fasting blood sugar (FBS) during short intervals in patients with NIDDM. It was concluded that the measurement of HbA1 is a useful method for evaluation of the mean levels of blood glucose during short intervals in patients with NIDDM compared with those of glycosylated proteins or albumin.

A diabetic patient with renal insufficiency and a giant ventricular aneurysm was treated by continuous ambulatory peritoneal dialysis (CAPD). No apparent exacerbation of the patient's cardiovascular function was observed after starting CAPD therapy, although his ejection fraction remained low and his angina attacks persisted. It is suggested that CAPD therapy has no deleterious effects on the cardiovascular system of patients with ventricular aneurysms, and that the benefits outweigh the risks.

Correlations of renal histopathologic changes, duration of diabetes, and the degree of control of blood glucose in patients with diabetic nephropathy were determined. Biopsies from 17 patients with diabetic nephropathy due to Type II diabetes were examined. Mild histopathologic changes in renal tissues were observed in patients with good blood glucose control, even if their disease was of more than 5 years' duration. Moderate to severe renal histopathology was found in patients with poor blood glucose control regardless of the duration of diabetes. It is concluded that strict control of blood glucose during the course of diabetes is important in inhibiting the progression of renal involvement in patients with Type II diabetes.

A study of double immunofluorescence staining of sialic acids and IgG in the glomeruli from patients with diabetic nephropathy is described. Renal biopsy specimens from seven patients with diabetic nephropathy were stained with rhodamine-labeled tricum vulgaris (WGA), limulus polyphemus (LPA), and FITC-labeled anti-human IgG antiserum. Both binding of WGA and deposition of IgG in glomerular capillary walls were observed in all patients with diabetic nephropathy. However, the binding of LPA in tissue from the same patients was minimal, although deposition of IgG was marked. It is suggested that an accumulation of substances with an affinity for WGA (most probably N-acetyl glucosamine or N-acetyl neuraminic acid) occurs in the glomerular capillary walls of patients with diabetic nephropathy.

Measurement of sialic acid and acute phase reactant (APR) proteins in sera of patients with diabetic nephropathy was performed. Twenty-six patients with non-insulin-dependent diabetes mellitus (NIDDM) were examined. The levels of sialic acid in sera, with or without treatment of neuraminidase, were measured by the thiobarbiturate method. The levels of alpha 1-antitrypsin (alpha 1-AT), alpha 1-acid glycoprotein (alpha 1-AG) or alpha 2-macroglobulin (alpha 2-MG) were measured by laser nephelometry. The levels of sialic acid or APR proteins in sera of patients with diabetic nephropathy were increased markedly. There was a significant correlation between the levels of sialic acid and those of alpha 1-AT in sera of patients with NIDDM. The mobility of alpha 1-AT in sera of patients with NIDDM treated with neuraminidase was decreased markedly in the immunofixation test. It is suggested that the increase of APR proteins in diabetic sera is mainly composed of sialic acid in patients with NIDDM with or without nephropathy.