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The present studies show that a number of functional abnormalities are present in the kidney in early diabetes, especially during poor regulation. Normalization of these functions and changes in renal and glomerular size are found during complete diabetes control. The results further support the idea that great efforts should be made to maintain the best possible control situation in diabetic patients. Our studies also indicate that antihypertensive therapy may be beneficial for young, proteinuric diabetics and may postpone the stage of renal insufficiency.

The effect of IV injection of 7 to 8 I. U. of insulin on renal haemodynamics and on urinary excretion of beta-2-microglobulin and of albumin was examined in 5 juvenile diabetics. Plasma glucose decreased from a mean value of 250 mg/100 ml to 117 mg/100 ml during the first 85 min after insulin. None of the patients had symptoms of hypoglycaemia and plasma adrenaline did not increase. There was no change in arterial blood pressure after insulin whereas pulse rate increased from 66/min to a maximum of 75/min. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were decreased by 9 per cent and 13 per cent, respectively, during the first 90 min after insulin (2 p less than 0.01). There was also a statistically significant decrease in urine flow and urine secretion of several electrolytes, while filtration fraction remained almost constant. IV insulin decreased urinary excretion of beta-2-microglobulin and increased albumin excretion (2 p less than 0.05). The albumin excretion induced by insulin is most likely due to increased amounts of filtered albumin, the mechanism of which remains unexplained.

We have studied the long-term effects (9 months) in plasma lipoprotein concentrations during continuous subcutaneous insulin infusion (CSII) (n = 11, six females, five males) and compared these changes to conventional insulin therapy (CIT) (n = 12, six females, six males). The two groups were allocated to CSII or CIT randomly, and were comparable as regards lipoprotein values at the start of the study. There were initially normal total plasma cholesterol values in both groups (CSII group: mean plasma cholesterol 3.77 +/- 0.57 mmol/l, CIT group: mean plasma cholesterol 4.37 +/- 0.55 mmol/l, means +/- SD). Further, there were normal total plasma triglyceride values at the start of the study (CSII group: mean plasma triglyceride 0.86 +/- 0.23 mmol/l, CIT group: mean plasma triglyceride 0.84 +/- 0.26 mmol/l, means +/- SD). There were no alterations seen in total plasma cholesterol and total plasma triglyceride in either groups during a 9 months observation period. In the same period no changes in LDL and HDL levels were registered. The very low density lipoprotein (VLDL) was separated into VLDL-1 and VLDL-2 by its binding to heparin-sepharose columns. It was found that CSII treatment for 9 months resulted in a decline in VLDL-2-triglyceride values (0.18 +/- 0.07 mmol/l before versus 0.10 +/- 0.07 mmol/l after, p less than 0.05, means +/- SD) which was not seen in the CIT group. Decline in VLDL-2-triglyceride might delay the development of late diabetic manifestations.

The microvascular permeability to small and large molecules was studied during good and poor metabolic regulation in ten short duration juvenile diabetics. The following variables were measured; daily urinary albumin and beta2-microglobulin-excretion rates, whole body transcapillary escape rate of albumin (TER), glomerular filtration rate (GFR), capillary filtration coefficient (CFC), and capillary diffusion capacity (CDC). The urinary albumin and beta2-microglobulin concentration were measured by sensitive radioimmunoassays; TER was detemined from the initial disappearance of intravenously injected 125I-labelled human serum albumin; GFR was measured on the forearm by straingauge plethysmography and CDS for 51Cr-EDTA clearance; CFC was measured on the forearm by straingauge plethysmography and CDC, for 51Cr-EDTA was determined in the jyperaemic anterio tibial muscle by the local clearance technique. All the above mentioned variables, except CDC, were significantly increased during poor metabolic regulation, indicating a functional microangiopathy. The mechanisms of these alterations appear to be increased filtration pressure in the microcirculation and/or increased porosity of the microvasculature. The findings of increased microvascular albumin passage are compatible with the hypothesis that the organic - histologicallly demonstrated - diabetic microangiopathy is a long-term effect of periods of increased extravasation of plasma proteins, with subsequent protein deposition in the microvascular wall, i.e. the concept to plasmatic vasculosis.

The effect on glomerular filtration rate (GFR), renal plasma flow (RPF) and excretion of albumin and beta-2-microglobulin in the urine after a high oral protein or amino acid load was investigated in young healthy males. After both test meals an increase in GFR of 10%, and in RPF of about 9-18%, was seen. The filtration fraction and albumin excretion rates were unchanged. The increase in GFR was significant from 20 to 60 min after intake of meat and remained elevated for more than 2 h. After the meat meal, a decrease in renal vascular resistance and an increase in S-creatinine, S-phosphate, S-carbamide and beta-2-microglobulin excretion rates was seen, but not after the amino acid load. During the experiments a gradual decrease in S-protein was noted. We conclude that the increase in RPF and GFR caused by intake of protein or amino acids in short-term experiments is not associated with impaired permselective properties of the glomerular membrane expressed in the albumin excretion rate.

Cardiac function was studied by echocardiography in 80 insulin-dependent diabetic patients with no signs of ischemic heart disease and in 40 healthy control subjects. Echocardiographic findings were related to the urinary albumin excretion rate (UAE). In the diabetes group, fractional shortening of the left ventricle (FS) was 37.3% versus 34.3% (P less than .01) in the control group, whereas indices of preload and afterload were at the same levels as in control subjects. In diabetic patients with preclinical nephropathy (UAE 20-200 micrograms/min), FS was 41.1% compared to 37.0% (P less than .002) in patients with no signs of nephropathy (UAE less than 20 micrograms/min) and 34.8% (P less than .001) in patients with clinical nephropathy (UAE less than 200 micrograms/min). Furthermore, in patients with preclinical nephropathy, afterload was significantly decreased, whereas preload was at the same level as in the other two groups of UAE. In conclusion, a condition of cardiac hyperfunction has been found in diabetic patients with no signs of ischemic heart disease and seems pronounced in diabetic patients developing microvascular disease (patients with preclinical nephropathy), probably secondarily to a condition of hyperperfusion in these patients.

The daily urinary albumin and beta 2-microglobulin excretion rates were measured with sensitive radioimmunoassays in 14 patients with systemic lupus erythematosus (SLE). The duration of SLE ranged from 0.5 to 18 years, mean 10 years. The mean age was 37 years. All patients except 5 received prednisone, 5-20 mg/day. None of the patients had proteinuria as judged by the "Albustix" test, and all had normal serum creatinine. The daily urinary albumin and beta 2-microglobulin excretion rates were nearly the same as those previously found by us in 27 adult control subjects with a mean age of 44 years. Our study shows that SLE patients without clinical proteinuria have a completely normal renal glomerular and tubular protein handling, irrespective of the duration of the disease.

The effect of a single oral dose (1 g) of acetylsalicylic acid (ASA) on renal function and hepatic enzymes as well as prothrombin time was studied in two series of experiments on normal human volunteers. Radioimmunoassay of albumin and beta 2-microglobulin excretion rates in urine revealed a statistically significant increase in both beta 2-microglobulin and albumin excretion rates within 2 h after dosage. Hepatic enzymes were not influenced by a single dose of ASA, while a statistically significant reduction in prothrombin time was registered. High-pressure liquid chromatography was used for measuring serum levels of ASA and salicylic acid (SA). Peak levels of 500 mumol/l and 150 mumol/l for SA and ASA, respectively, were found.

Glomerular hyperfiltration may be a risk factor for late nephropathy. It has been shown that considerable protein restriction can lower glomerular filtration rate (GFR). To elucidate the effect of moderate protein limitation in type 1 (insulin-dependent) diabetics with normoalbuminuria, eight such patients were selected for the study (age 38 +/- 7 years SD, diabetes duration 21 +/- 9 years). The patients were randomized to follow, alternately, four weeks of their usual protein intake (19% of energy) and four weeks of a limited protein intake (12% of energy). Kidney function was investigated after the two dietary periods. GFR and renal plasma flow (RPF) were measured using a constant infusion technique (125I-iothalamate/131I-hippuran), and urinary albumin excretion (UAE) by radioimmunoassay. It was found that the limited protein diet reduced GFR from 146 +/- 23 to 132 +/- 24 ml/min/1.73 m2 (2P less than 0.005). A tendency towards a fall in RPF was seen (549 +/- 128 vs. 503 +/- 125 ml/min; 2P = 0.06), while total renal resistance rose from 0.17 +/- 0.03 to 0.20 +/- 0.05 mm Hg/ml/min (2P = 0.05). No significant changes in filtration fraction, UAE and blood pressure were seen. HbA1c, fructosamine, insulin dose and body weight were unchanged during the two diets; also serum protein, albumin, phosphate and calcium remained unaltered. Serum urea was significantly reduced on the limited protein intake. Patients were generally pleased with the limited protein diet. Thus, limitation of the often high protein intake in diabetics might be valuable and realistic. The long-term renal protective effect remains to be investigated.

Amino acids and derivatives were injected intravenously in normal man and the effect on the urinary excretion of albumin, free light chains and beta-2-microglobulin determined. From the results we hypothesise that the initial event in normal protein reabsorption is binding between a free positive amino- or guanidino-group of the protein molecule and a negative site on the tubular cell surface. This initial event in the reabsorption process is impeded by molecules containing similar charged groups (arginine, ornithine, lysine, EACA and Cyclocaprone). Using high doses of lysine, complete or near-complete inhibition of tubular protein reabsorption is obtained. The glomerular filtration rate in preliminary experiments is found to be of the order of 300 microgram/min for albumin.

Glomerular filtration rate and renal plasma flow were examined in 16 young male non-proteinuric diabetics (mean age 28.4 years) with a duration of diabetes of over 15 years (mean duration 21.5 years.) In this selected group of long-term diabetics the glomerular filtration rate was clearly increased, the mean being 136 ml/min (+/-S.D. 11.8) (normal value 114 ml/min (+/-14.1), being comparable to that found earlier in short-term diabetics. There was no change in renal plasma flow. It is concluded that kidney function is generally well preserved in long-term diabetics who have not developed proteinuria.