Basement membrane thickening is a chracteristic feature of diabetic microangiopathy. Type IV collagen is the major component of basement membrane. We investigated changes in serum levels of type IV collagen (7S) in 52 non-insulin-dependent diabetic patients (NIDDMs) without clinical proteinuria and 35 age-matched normal subjects. Serum levels of type IV collagen (7S) were significantly higher in diabetic patients than in normal subjects. Even in diabetic patients with normoalbuminumia without retinopathy, serum levels of type IV collagen (7S) were higher than in normal subjects (p<0.005). There was no relationship between serum levels of type IV collagen (7S) and HbA1c levels or duration of diabetes. We investigatedchanges in serum levels of type IV collagen (7S) in 10 NIDDM with normoalburinumia after treatment. Although fasting blood glucose levels and urinary glucose excretion were significantly lower after 4 weeks, serum levels of type IV collagen (7S) remained unchanged. These data suggest that serum levels of type IV collagen (7S) are elevated in NIDDMs, even when clinical symptoms of diabetic microangiopathy are not present. Elevated serum levels of type IV collagen (7S) may reflect a change in basement membrane metabolism. Moreover lower blood glucose levels do not seem to correct the altered basement membrane metabolism completely.

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In order to elucidate the influence of orthostatic hypotension (OH) on incipient diabetic nephropathy, responses of heart rate, blood pressure, urinary albumin excretion rate (UAE), and renal hemodynamics to the postural change from supine to standing were investigated in groups of diabetics without OH (n=9) and with OH (n=10), and in the group of healthy controls (n=5). In the standing position, heart rate was elevated in all the groups, however, there were no differences among these 3 groups. The group of diabetics with OH showed a significant (p<0.01) increase in UAE and a decrease in systolic blood pressure of more than 30 mmHg. Renal plasma flow (RPF) was reduced in all the groups, and marked reduction was observed in the group of diabetics with OH. Renal glomerular filtration rate (GFR) rose in the groups of diabetics without OH and healthy controls. In contrast, GFR significantly (p<0.05) fell in the group of diabetics with OH. These results indicate that OH affects kidney function of incipient diabetic nephropathy as a result of a decrease in both RPF and GFR. The precise mechanism of the increase in UAE is uncertain, however, OH may be considered to be a contributory factor to the development of diabetic nephropathy.

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The usefulness of laser Doppler flowmetry (LDF) for measuring sciatic nerve blood flow (NBF) wase examined in streptozocin-induced diabetic rats. Averaging 10 consecutive measurements using LDF was shown to minimize the variability of the measurements. Anesthesia did not significantly change NBF. There was a significant correlation between the results obtained using the hydrogen clearance method and LDF. Using LDF, treatment with prostaglandin E1 analogues for 4 weeks was found to improve decreased NBF, decreased MNCV, and increased nerve lactate content in streptozocin-induced diabetic rats. These results suggest that an improvement in decreased NBF and associated nerve hypoxia has a significant effect in the treatment of diabetic neuropathy and that LDF might be a useful tool in studying the pathogenesis and treatment of diabetic neuropathy.

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The present study evaluated the long-term effects of somatostatin analogue (SMS) on diabetic nephropathy (as indicated by urinary albumin excretio.) in streptozotocin-induced diabetic rats. Rats were divided into four groups as follows: non-diabetic rats injected with saline (control saline) or SMS (control SMS), and diabetic rats injected with saline (DM saline) or SMS (DM SMS). Saline or SMS was injected subcutaneously for two weeks. Rats in the control saline and control SMS groups showed significant increases in both urinary albumin excretion (UAE) and albumin clearance (AC). Rats in the DM saline group showed no significant differences in UAE and AC. Rats in the DM SMS group showed significant decreases in UAE (151±76 to 98±46 mg/day/kg, p<0.005) and AC (5.85±3.34 to 3.63±1.73 ml/day/kg, p<0.01). Increased creatinine clearance was observed in both non-diabetic and diabetic rats administrated saline, but this increase was suppressed in rats administrated SMS. There was no significant difference in kidney weight between the control saline and control SMS groups, but a significant difference was observed between the DM saline (3.35±0.39 g) and DM SMS groups (2.68±0.26g, p<0.001). The present study suggested that, in diabetics with hyperfiltration and increased kidney volume, the administration of SMS may be useful to prevent the progression of late diabetic nephropathy.

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To evaluate the effects of acute protein loadings on glomerular filtration rate (GFR), albumin excretion rate (AER), and concentration of plasma amino acids, ten healthy volunteers and six diabetics were studied before and after eating 0.7g/kg body weight of tuna fish, boiled egg white, cheese or tofu (bean curd) on separate days. In healthy subjects, GFR increased significantly (p<0.001), i.e., from 104.7±4.9 ml/min/1.73 m² during the baseline period to 136.8±5.7ml/min/1.73 m² after ingestion of tuna fish. No significant differences were found between before and after ingestion of egg white, cheese, or tofu. No significant differences were observed between baseline AER and after loading with any of the four kinds of protein. Plasma concentrations of alanine, glycine, and arginine (amino acids known to induce glomerular hyperfiltration) increased to a greater degree after ingestion of tuna fish than after administration of the other meals. Diabetic subjects had a response similar to that of healthy volunteers. These findings suggest that responses of GFR to acute protein loading may differ depending on the protein ingested.

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Differential determination of fasting serum ketone bodies acetoacetate [AcAc], and 3-hydroxybutyrate [3-OHBA] was conducted in 60 insulin dependent diabetes mellitus (IDDM) subjects given conventional insulin treatment and in 208 non-insulin dependent diabetes mellitus (NIDDM) subjects treated with diet or oral hypoglycemic agents in order to evaluate serum ketone body levels as a marker for insulin deficiency. Serum levels of 3-OHBA (557±59 (M±SE)μM) and AcAc (191±27) in IDDM were much higher than those (76±5, 58±2) in NIDDM in spite of a small difference in fasting plasma glucose levels (FPG)(199±11 vs 158±4 mg/dl) in the two groups. An equation which discriminates between IDDM and NIDDM by 3 metabolic factors (FPG, AcAc and 3-OHBA) was obtained as follows:
Z=-3.14-0.31×10^-3×(FPG)-0.73×10^-2×(AcAc) +1.69×10^-2×(3-OHBA)
In this equation, above 0 indicates IDDM, while below 0 indicates NIDDM, with 89% reliability, Serum 3-OHBA levels contribute greatly to the value of this equation and were inversely related to serum free insulin levels. These results indicate that the serum 3-0H BA level is a good metabolic marker for insulin deficiency and suggest that the determination of serum 3-OHBA may be useful in considering the requirement of insulin therapy and the dosage of insulin in diabetic subject.

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We measured aminotransferase activity and vitamin B₆ content in the livers of diabetic mice. Two different types of diabetic mice, spontaneously non-obese diabetic (NOD) and alloxan-induced diabetic (Allo) mice, were used. Control mice were either non-diabetic NOD or ICR. We have reported a marked increase in aspartate aminotransferase (AST) activity in the liver of diabetic mice compared with that in control mice. The diabetic livers also had more vitamin B₆ than normal livers ; pyridoxamine (PM) levels were particularly high but pyridoxal levels were not. The abundance of AST and B₆ in the diabetic liver is consistent with the great need for gluconeogenic substrate there. This is understandable in that most aminotransferases require vitamin B₆. A correlation between s-AST and PM was recognized in the diabetic liver, while AST and PM were negatively correlated in normal mice. A metabolic shift towards gluconeogenesis apparently produces more B₆ and PM while it induces holo-AST synthesis.

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