Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities. Stage 1 is characterized by early hyperfunction and hypertrophy. These changes are found at diagnosis, before insulin treatment. Increased urinary albumin excretion, aggravated during physical exercise, is also a characteristic finding. Changes are at least partly reversible by insulin treatment. Stage 2 develops silently over many years and is characterized by morphologic lesions without signs of clinical disease. However, kidney function tests and morphometry on biopsy specimens reveal changes. The function is characterized by increased GFR. During good diabetes control, albumin excretion is normal; however, physical exercise unmasks changes in albuminuria not demonstrable in the resting situation. During poor diabetes control albumin excretion goes up both at rest and during exercise. A number of patients continue in stage 2 throughout their lives. Stage 3, incipient diabetic nephropathy, is the forerunner of overt diabetic nephropathy. Its main manifestation is abnormally elevated urinary albumin excretion, as measured by radioimmunoassay. A level higher than the values found in normal subjects but lower than in clinical disease is the main characteristic of this stage, which appeared to be between 15 and 300 micrograms/min in the baseline situation. A slow, gradual increase over the years is a prominent feature in this very decisive phase of renal disease in diabetes when blood pressure is rising. The increased rate in albumin excretion is higher in patients with increased blood pressure. GFR is still supranormal and antihypertensive treatment in this phase is under investigation, using the physical exercise test. Stage 4 is overt diabetic nephropathy, the classic entity characterized by persistent proteinuria (greater than 0.5 g/24 h). When the associated high blood pressure is left untreated, renal function (GFR) declines, the mean fall rate being around 1 ml/min/mo. Long-term antihypertensive treatment reduces the fall rate by about 60% and thus postpones uremia considerably. Stage 5 is end-stage renal failure with uremia due to diabetic nephropathy. As many as 25% of the population presently entering the end-stage renal failure programs in the United States are diabetic. Diabetic nephropathy and diabetic vasculopathy constitute a major medical problem in society today.

Blood flow is a complex process combining fluid shearing in both plasma and the interior of red blood cells with elastic deformation of blood's solid elements. The red cell membrane is the major solid in blood, but platelets and white cells contribute solid behavior as well. Changes in blood's flow properties are often hidden by blood's ability to change its pattern of response. Capillary viscometry can be used to examine serum, plasma, and hemoglobin solutions directly, but rotational viscometry, where regularity of fluid shearing can be controlled to a narrow shear rate range, is required to study blood flow effectively. The most striking diabetic blood flow abnormality is best seen in time-based rotational viscometer studies that demonstrate the pattern of development of shear stress as flow becomes established. In such studies blood demonstrates both viscoelastic and thixotropic behavior; in diabetes blood's thixotropy is substantially increased. The diabetic pattern appears to be produced by a combination of reduced erythrocyte deformability and increased erythrocyte aggregation due to plasma protein changes. The plasma protein changes observed in diabetes are linked to the development of glucose intolerance but they are not specific to diabetes. The combined increase in aggregation and resistance to deformation of red blood cells produces blood flow abnormalities that can be detected primarily at low shear rate. Plasma protein changes and alteration in blood viscosity are absent from children with diabetes, while such changes tend to be associated with diabetic microangiopathy in adults. In some in vivo conditions, the effects on blood flow that can be linked to erythrocyte deformability are magnified out of proportion to measurements made in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

The earliest manifestations of clinical diabetic nephropathy, including proteinuria, hypertension, and declining GFR, represent very advanced diabetic glomerulopathy with especially prominent mesangial expansion. Mesangial expansion, by restricting glomerular capillary filtration surface and lumenal volume, stimulates compensatory mechanisms analogous to those resulting from a marked reduction in nephron number. These compensatory mechanisms involve alterations in glomerular hemodynamics designed to maintain glomerular filtration but which ultimately injure the kidney. These hemodynamic perturbations are not specific to diabetes but represent a final common pathway toward endstage renal failure that also characterizes the remnant kidney. This thesis concludes that the onset of clinical diabetic nephropathy augurs inevitable decline in kidney function, and that only studies and interventions exercised before clinical nephropathy develops can influence understanding and outcome of diabetic nephropathy.

A review of the pathologic picture of diabetic retinopathy shows that available clinical methods of examination demonstrate the alteration of the blood-retinal barrier (leakage), microaneurysms, capillary closure, preferential channels, preretinal neovascularization and gross extravascular lesions. All of these changes may be shown by fluorescein angiography. The value of this method, however, is fundamentally related to the morphologic demonstration of these lesions and not their quantification. Quantitative evaluation of retinal involvement in diabetes is needed in order to delineate more clearly its natural history, criteria for prognosis, and effect of treatment. Vitreous fluorophotometry, a quantitative and sensitive method of evaluating the permeability of the blood-retinal barrier, has opened new perspectives for the evaluation of retinal involvement in diabetes. Vitreous fluorophotometry has shown that a disturbance of the blood-retinal barrier, possibly functional, appears in diabetic eyes before any lesion is clinically visible in the fundus, and that there is a close correlation between the severity of the vascular lesions and higher vitreous fluorophotometry readings. Recent studies also indicate an interesting correlation with metabolic control, particularly, glycosylated hemoglobin levels and insulin treatment. Finally, on the basis of these findings a working hypothesis for the pathogenesis of diabetic retinopathy is presented.

It has been postulated that abnormal platelet and endothelial function may contribute to microangiopathy in diabetes mellitus. If this proposal is correct, alterations in platelet and endothelial function should be found before the appearance of vascular disease in insulin-dependent patients and in animal models of diabetes mellitus. This appears to be the case for the following: platelet aggregation, increased platelet production of the proaggregatory prostaglandin metabolite thromboxane, decreased endothelial production of the antiaggregatory prostaglandin prostacyclin, and decreased platelet survival. Insulin therapy will return some of these findings to normal. Platelet-plasma interactions that promote platelet aggregation and increased plasma levels of the platelet-specific protein beta-thromboglobulin have been reported in insulin-dependent diabetic patients who have not manifested vascular complications as well as in those with vascular complications. It has now been demonstrated in animal models that platelet microthrombi are found in small retinal vessels after months of experimental diabetes. Collectively, these findings demonstrate that alterations in platelet and endothelial function that favor thrombosis occur early in the diabetic state and may contribute to microvascular disease. There are several ongoing studies of antiplatelet agents in diabetic vascular disease that will provide clinical evidence bearing on the major postulate. Until these and other studies are completed, the platelet-endothelial story remains an attractive hypothesis in the genesis of diabetic microvascular disease.

Published information derived from studies of prostaglandins on carbohydrate homeostasis and insulin secretion has been considered somewhat controversial by many investigators. An analysis of the literature published since 1876 suggests that this controversy has its roots in imprecise terminology and overgeneralization of data rather than irreconcilable scientific experiments. The two major sources of confusion have been failure to distinguish glucose-induced acute insulin responses from insulin secretion in general and failure to appreciate that the behavior of indomethacin is not consistent with the effects of other nonsteroidal antiinflammatory drugs (cyclooxygenase inhibitors) on glucose homeostasis and insulin secretion. When acute insulin responses to glucose specifically are examined and data from indomethacin studies are excluded, the available information consistently indicates that prostaglandin E has adverse effects on glucose homeostasis and insulin secretion.

In this paper the theoretical basis of alloreactivity and its relevance to transplantation biology is discussed prior to a review of work showing that culture of adult mouse pancreatic islets for 7 days in 95% O2 and 5% CO2 facilitates successful grafting to nonimmunosuppressed allogeneic recipients. These allografts function by reversing both chemically induced and spontaneous diabetes. The fetal mouse pancreas is more immunogenic than adult islets, and even after a culture period of 10 days in 95% O2 and 5% CO2, BALB/c allografts are consistently rejected by nonimmunosuppressed recipient mice. The immunogenicity of fetal pancreas is thought to be due to the presence of contaminating lymphoreticular cells in the mesentery surrounding the fetal pancreas. Digestion of the fetal pancreas with collagenase allows the isolation of proislets that develop into functional islet tissue on transplantation. Fetal proislets are less immunogeneic than the whole fetal pancreas and may provide a source of tissue for clinical transplantation. Established islet allografts are relatively stable and are not rejected following nonspecific stimulation of the recipient's immune system or following passive transfer of either antibody or antibody and complement. After prolonged residence in the recipient a state of allograft tolerance develops and such grafts resist rejection by specific stimulation of the recipient. The administration of donor antigen in the form of uv-irradiated cells enforces this state of allograft tolerance.

Exciting new findings have been reported in the past few years that indicate that islets can be transplanted successfully across major histocompatibility barriers without the continuous use of immunosuppressive agents by techniques designed to eliminate passenger leukocytes. In vitro culture of donor islets either at a low temperature (24 degrees C) with a single injection of antilymphocyte serum or culture of megaislets in the presence of 95% O2 before transplantation permitted the successful transplantation of islet allografts and xenografts (rat to mouse). Definitive evidence in support of the passenger leukocyte concept has been obtained recently. Mouse islet cells have been shown to express the class I antigens of the H-2 complex, but do not express Ia antigens. Treatment of fresh mouse islets with specific anti-Ia sera and complement completely prevented rejection of islets transplanted across a major histocompatibility barrier. These findings indicate that Ia-positive cells (possibly dendritic cells) are primarily responsible for the initiation of immune rejection of the transplants. This is of particular importance with respect to the eventual transplantation of islets into human diabetics since it may be feasible to utilize antisera to HLA-DR antigens for pretreatment of islets before transplantation. In addition, these new developments may also be applicable to the transplantation of other organs such as the parathyroid, heart, kidney, liver, and skin.

Metabolic acidosis with a normal anion gap results from either bicarbonate loss or a urine acidification defect. The bicarbonate loss may be via the gastrointestinal tract or the urine, or may be indirect due to excretion of the sodium and potassium as opposed to the ammonium salts of ketone body anions. Defects in urine acidification in the diabetic have several etiologies: first, hydrogen ion secretion may be decreased because of an intrinsic defect in the hydrogen ion pump (i.e., diseases of the renal medulla); second, there may be a failure to augment hydrogen ion secretion by a favorable electrical gradient (e.g., reduced mineralocorticoids); and third, there may be a failure to generate a favorable chemical gradient to augment hydrogen ion secretion (e.g., reduced urine ammonia). Reduced levels of aldosterone associated with hyporeninemia has been termed type IV RTA, and these patients have specific therapeutic needs.

Atherosclerosis is the most common complication of diabetes. Epidemiologic and pathophysiologic evidence suggest a number of possible reasons for this. They include alterations in lipoproteins, platelets, soluble clotting factors, the balance of prostacyclin-thromboxane, blood pressure regulation, and arterial smooth muscle cell metabolism and proliferation. Many of these alterations may accompany hyperinsulinemia and may account for the recent evidence that hyperinsulinemia is a risk factor for atherosclerosis. Advances in this area will require the recognition that neither diabetes nor atherosclerosis are single disorders. Furthermore, new approaches are needed to study these disorders in which there may be many years of very subtle changes before any end point is apparent.

A profile characteristic of fuel economy in the mother during normal pregnancy has been delineated. The evidence indicates that pregnancy changes the metabolism of every class of foodstuff. The mechanisms by which the conceptus may be implicated are reviewed. The gestational interactions create a pattern of "accelerated starvation" whenever food is withheld, especially in late pregnancy, and they tend to "facilitate anabolism" when food is ingested. The consequent heightened metabolic oscillations during the shuttlings from fed to fasted state provide a basis for more aggressive therapy with exogenous insulin when endogenous insulin is lacking in pregnancy. It is emphasized that developing fetal structures may be exquisitely attuned to fine alterations in maternal fuel economy and that pregnancy complicated by diabetes may merely exaggerate these normal dependencies since maternal insulin affects all maternal fuels. The manifest changes in the offspring of mothers with even the mildest limitations in insulin reserve, i.e., gestational diabetes, attest to the sensitivity of the relationships. It is suggested that concepts of teratogenesis should be expanded to include alterations occurring subsequent to organogenesis during the differentiation and proliferation of fetal cells. Such changes could cause long-range effects upon behavioral, anthropometric, and metabolic functions. It is hypothesized that all of these could constitute expressions of fuel-mediated teratogenesis and that the potentialities should be incorporated into any evaluation of the outcome of pregnancy in gestations attended by disturbances in maternal fuel metabolism.