Structural-functional relationships in diabetic nephropathy.

Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.

Evaluating the benefits of human islet transplantation.

For important ethical and practical reasons, present human trials of islet transplantation in diabetes are restricted to subjects already committed to immunosuppression by the need for kidney transplantation. Following the morphology of the transplanted kidney for possible reversal of diabetes-related changes may be the most valuable technique for demonstrating benefit from the restoration of islet function. Amelioration of diabetic vascular disease is the compelling reason for efforts to achieve effective islet transplantation.

Metabolic effect of hemipancreatectomy in donors. Preoperative prediction of postoperative oral glucose tolerance.

Between November 1977 and January 1987, 55 transplantations of pancreas segments from living donors related to their recipients were performed at the University of Minnesota. A preliminary analysis of metabolic test results in donors tested 1 yr after hemipancreatectomy showed an increase in mean glucose and a decrease in mean insulin values during oral glucose tolerance tests (OGTTs) in 18 donors, a 14% increase in the mean of the mean glucose levels during 24-h metabolic profiles in 12 donors, and a decrease of 45% in the mean 24-h urinary C-peptide excretion in 21 donors. Including the studies performed postdonation, 11 of 31 (35%) donors developed an abnormal OGTT result. In a retrospective analysis, preoperative results of intravenous glucose tolerance tests (IVGTTs) and cortisone-stimulated OGTTs were found to be statistically significant predictors of an abnormal OGTT after hemipancreatectomy. The mean of the 5- to 50-min IVGTT insulin values was the best predictive test. With the cutoff value set at 62 microU/ml, this test result had a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 75% for identifying donors who developed an abnormal OGTT. The sum of the 5- and 10-min IVGTT insulin (cutoff 140 microU/ml) had a sensitivity of 100%, a specificity of 67%, and a predictive value of only 60%, whereas the delta-insulin had values of 86, 71, and 60%, respectively. Both the IVGTT mean insulin and the sum of the 5-min and 10-min insulin test results were 100% predictive of an abnormal test (0% risk), but the IVGTT mean insulin excluded the lowest proportion of otherwise suitable donors (a low "false-alarm" rate). The IVGTT mean insulin can be used to identify or exclude potential donors who would develop an abnormal OGTT result should hemipancreatectomy be performed.

Recurrence of disease in pancreas transplants.

In a series of 200 pancreas transplants with 6 mo to less than 9 yr of follow-up, recurrence of disease was identified as the cause of graft failure in 8 cases, all in non- or minimally immunosuppressed recipients of transplants from identical twin (n = 3) or HLA-identical sibling (n = 5) donors. Recurrence of disease was defined as selective loss of beta-cells; other endocrine cell types persisted and appeared normal within the islets of the graft. Isletitis was present in islets with residual beta-cells during the evolution of the process in all nonimmunosuppressed and in some immunosuppressed recipients, but isletitis resolved in all cases in which beta-cell destruction was complete and also resolved in some cases in which residual beta-cells were retained after the introduction of or an increase in immunosuppression. Recurrence of disease can be prevented by immunosuppression, and 2 recipients of identical twin grafts and 12 recipients of grafts from HLA-identical siblings had functioning grafts as of March 1988, the longest greater than 7 yr. The process has not been observed in patients in whom full-dose immunosuppression has been used, including HLA-identical siblings, and this may be the reason no cases of recurrence of disease have been identified in recipients of cadaveric grafts. Alternatively, the observations are consistent with, but not proof of, the hypothesis that recurrence of disease (autoimmune isletitis leading to diabetes) is a major histocompatibility complex-restricted phenomenon.

Clinical segmental pancreas transplantation without duct anastomosis in diabetic renal allograft recipients.

Segmental pancreatic allografts with unligated ducts were transplanted intraperitoneally to five diabetic patients who had received renal allografts more than 2 yr earlier. One patient is alive with a functioning graft 10.5 mo later. Two patients rejected their grafts at approximately 2 and 3 mo but are alive 8--9 mo later after resumption of exogenous insulin therapy. In both patients, carbohydrate metabolism was nearly normal during the period of graft function. Two patients died of infectious complications between 1 and 2 mo after transplantation. The main hazard of pancreas transplantation relates to the immunosuppression necessary to prevent rejection, setting the stage for infectious complications. Technically, pancreas transplantation is a feasible and efficient procedure, and, if better methods are developed for preventing rejection, it should be applicable to patients prone to develop secondary complications of diabetes.

Transplantation of dispersed pancreatic islet tissue in humans: autografts and allografts.

Islet transplantation is successful in animals and holds considerable promise as endocrine replacement therapy for patients with diabetes mellitus, but clinical application to diabetic patients has been difficult. We have shown the technical feasibility of human islet transplantation by autotransplantation of dispersed pancreatic islet tissue into the portal vein in three patients with chronic pancreatitis and incapacitating, intractable pain who underwent near-total (greater than 97%) pancreatectomy. In all three patients, the excised pancreas was dispersed by collagenase digestion, but no effort was made to purify the islets. Islet yield, as judged by tissue insulin content, ranged from 24 to 55%. The first patient, who never received insulin after the pancreatectomy and islet autotransplantation, had a normal oral glucose tolerance test by 3 wk and has remained normoglycemic for over 2 yr. In the second patient, viable islets were histologically identified in the liver parenchyma. The third patient was treated with hyperalimentation for 3 wk after the pancreatectomy and islet autotransplantation and, during this period, required insulin. After cessation of hyperalimentation and initiation of oral geedings, the patient was withdrawn from insulin. Although abnormalities of carbohydrate metabolism were present, the patient did not require insulin for more than 1 yr. Seven diabetic renal allograft recipients have received allografts of dispersed pancreatic islet tissue prepared in the same way. No patients were cured of diabetes, although transient evidence of islet function--increase in serum or urinary C-peptide levels or decrease in exogenous insulin requirements--occurred in some. Although rejection was probably responsible for most of the failures, transplantation of allogeneic human islet tissue as a free graft is metabolically inefficient. With the current state of immunosuppressive therapy, the primary role of islet transplantation may be in a situation where rejection cannot occur: as an autograft to obviate the occurrence of diabetes after extensive pancreatectomy for benign disease.

Relationship of muscle capillary basement membrane to renal structure and function in diabetes mellitus.

Muscle capillary basement membrane (MCBM) thickening has been considered to reflect microvascular changes in other tissues in diabetes mellitus. To explore the relationships between MCBM width and nephropathy, 27 patients aged 22-55 yr with type I diabetes for 14-33 yr were studied with creatinine clearances, urinary albumin excretion rates, multiple blood pressure measurements, glycosylated hemoglobin measurements, and renal and quadriceps muscle biopsies that were evaluated using standard stereologic techniques. MCBM width did not correlate with age, duration of diabetes, creatinine clearance, urinary albumin excretion, or fractional volume of the glomerular mesangium. MCBM width did correlate, although weakly, with glomerular basement membrane width (r = 0.47) and glycosylated hemoglobin (r = 0.44). There was no difference in MCBM width between patients with and without clinical nephropathy. Patients with normal fractional volume of mesangium exhibited a full range of MCBM width. Thus, while MCBM width may reflect glycemic control and glomerular basement membrane thickening, it does not relate to the functional or structural renal changes associated with progressive diabetic nephropathy.

Pancreas-transplant outcome in relation to presence or absence of end-stage renal disease, timing of transplant, surgical technique, and donor source.

The differences in pancreas-transplant outcome according to recipient status, surgical approach, and donor source are illustrated by an analysis of results at one institution with experience in several categories. From July 1978 to January 1988, 210 pancreas transplants were performed, and 67 grafts are still functioning, the longest for 9.7 yr. Since October 1984, a uniform immunosuppressive protocol has been used, antilymphocyte globulin, cyclosporin, azathioprine, and prednisone for induction and the last three drugs for maintaining antirejection therapy. During this period, 110 pancreas transplants were performed, 62 in nonuremic non-kidney transplants, 28 in recipients of a previous kidney, and 20 simultaneous with a kidney; 64 with bladder and 43 with enteric drainage; and 25 from related and 85 from cadaver donors. The overall patient survival rate at 1 yr was 91%, and there were no significant differences between the various categories. Graft survival rates, however, differed between the various categories created by combinations of the above variables. With bladder drainage, 1-yr function rates were 58% (n = 30), 47% (n = 15), and 77% (n = 19) in recipients of a pancreas transplant alone, a pancreas after a kidney, or a simultaneous pancreas-kidney transplant; with enteric drainage, 1-yr function rates were 33% (n = 32) and 36% (n = 11) in the pancreas transplant alone and pancreas after kidney categories (enteric drainage was not done in double-transplant patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic nephropathy. A perspective.

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.

Pregnancy in a juvenile diabetic after renal transplantation (class T diabetes mellitus).

The successful outcome of a pregnancy in a juvenile diabetic after renal transplantation is reported. It is proposed that class T be added to the classification of pregnancies complicated by diabetes mellitus. Pregnancy prevention should be considered until significant longevity can be demonstrated in diabetics receiving renal transplants.

Long-term follow-up of polyneuropathy in diabetic kidney transplant recipients.

Nerve conduction and electromyography (EMG) of insulin-dependent (type 1) diabetic patients with end-stage nephropathy was studied before and up to 10 yr after kidney transplantation (KTx). A series of nondiabetic KTx patients served as a comparison group. Motor nerve conduction velocity (NCV) was measured in the ulnar, median, peroneal, and tibial nerves; sensory NCV was measured in the median nerve. EMG was performed in the first dorsal interosseus, flexor carpi radialis, anterior tibialis, and gastrocnemius muscles. In 68 pre-KTx diabetic patients, the mean NCV was below normal in all nerves, and the mean amplitudes of the evoked muscle action potential (MAP) were low normal in the upper extremity and below normal in the lower extremity. The values of the comparison group were within the normal range. At 1 (n = 57), 5 (n = 23), and 10 (n = 10) yr after KTx, the mean NCV of the diabetic patients remained essentially unchanged, but MAP amplitudes of all muscles had declined. EMG revealed progression of the denervation process, especially in muscles of the lower extremities. We conclude that diabetic neuropathy continues to progress by a progressive axonal loss after correction of uremia by KTx.

Immunopathology of renal extracellular membranes in kidneys transplanted into patients with diabetes mellitus.

Kidneys of patients with severe diabetic nephropathy demonstrate marked linear immunofluorescent staining of extracellular membranes, including the tubular and glomerular basement membranes (TBM and GBM) and Bowman's capsule. Immunofluorescent studies were carried out on kidney tissue obtained from 12 diabetic and 17 nondiabetic patients from two to 12 years following renal transplantation. The frequency and intensity of SgG and albumin staining of these membranes were significantly greater in the diabetic than in the nondiabetic patients (P less than 0.0005). TBM, GBM, and Bowman's capsule staining did not occur in any of the seven kidneys studies at the time of their transplantation into diabetic recipients. Thus, the abnormalities leading to the deposition or trapping of proteins in renal extracellular membranes occur early after the placement of normal kidneys into the abnormal metabolic environment of the diabetic transplant recipient. The present study supports the concept that basement membrane alterations in diabetes are a consequence of the biochemical perturbations of diabetes rather than a separately inherited genetically linked disorder.

Cyclosporin A for immunosuppression: observations in rat heart, pancreas, and islet allograft models and in human renal and pancreas transplantation.

Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.

Population-based study of impaired glucose tolerance and type II diabetes in Wadena, Minnesota.

The Wadena City Health Study was undertaken to assess the nature of type II (non-insulin-dependent) diabetes and its relationship to aging. This article reports the study methodology and prevalence estimates for type II diabetes and impaired glucose tolerance (IGT) for the adult population of Wadena, Minnesota. The sampling frame for the study included all known diabetic individuals and all other residents based on a complete citywide census of residents greater than or equal to 20yr of age. A stratified random sample that included three stratifying factors (age [20-39, 40-59, greater than or equal to 60 yr], sex, and self-reported weekly use of any prescribed medication was drawn from the other residents). The study protocol required diet preparation and two full mornings of testing. Data collected included height, weight, and blood pressure measurements and both a personal interview and a medications questionnaire. A 75-g oral glucose tolerance test (OGTT) and a test with a standard liquid meal (Ensure-Plus challenge test [EPCT], Ross) were done on two mornings, with the order of testing randomly assigned. Clinical tests included one-time samples for hemoglobin, glycosylated hemoglobin, plasma cholesterol, triglycerides, and lipoproteins. Blood samples for glucose and creatinine assays were taken during the OGTT; blood samples for glucose, free fatty acid, creatinine, and C-peptide were taken during the EPCT. Urine collections were performed for both challenge tests and assayed for C-peptide and creatinine. Seventy-one percent of the known diabetic subjects, and 65% of the stratified random sample participated in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of glucagon response to hypoglycemia in diabetic autonomic neuropathy.

Glucagon response to insulin hypoglycemia was tested in diabetics with autonomic neuropathy (N=9), diabetics without neuropathy (N=8), and normals (N=9). With similar levels of hypoglycemia, growth hormone and plasma cortisol increased in all groups. The glucagon response in normals (121+/-19 vs. 308+/-30 pg./ml., mean+/-S.E.M. of baseline vs. hypoglycemia peak) was significantly less in nonneuropathic diabetics than in normals (128+/-13 vs. 209+/-30) and absent in neuropathic diabetes (128+/-23 vs. 115+/-20). Arginine stimulation produced a glucagon response in the neuropathic diabetics (106+/-16 vs. 523+/-103). The data indicate that the capacity to release glucagon during hypoglycemia is lost in diabetic neuropathy while glucagon responsiveness to arginine is retained. Neuropathy in diabetes may contribute to metabolic instability.

Long-term study of normal kidneys transplanted into patients with type I diabetes.

We examined the rate of development of the lesions of diabetic nephropathy in transplanted kidneys residing for 6-14 yr in type I (insulin-dependent) diabetic kidney-allograft recipients. Although each recipient had end-stage diabetic nephropathy with his/her own kidneys, there was marked variability in the rate of development of mesangial expansion observed in the transplanted kidneys. The progression of glomerular pathology, including widening of the glomerular basement membrane and expansion of the mesangium, did not correlate significantly with several potential risk factors (e.g., donor source--cadaver or living related, histocompatibility match, age of the recipient or donor, age at onset of diabetes, duration of diabetes before renal failure, immunosuppressive drug dose, blood pressure, and severity of lesions of chronic rejection). However, there was a direct albeit imprecise relationship between the index of mesangial expansion at the final biopsy and the index of glycemic control (r = .61, P less than .01). These observations suggest that currently unknown factor(s) may modulate the progression of diabetic renal disease, even in a population that had uniformly demonstrated nephropathy risk. Our data support the hypothesis that in addition to glycemic control per se, there are risk factors intrinsic to the kidney itself.

HLA in maturity-onset type of hyperglycemia in the young.

HLA haplotypes in a kindred with a maturity-onset type of hyperglycemia in the young (MOHY) were studied. All diabetics had mild hyperglycemia of early onset, and the inheritance pattern suggested an autosomal dominant trait. Eight of 11 subjects with hyperglycemia shared haplotype A3, Bw15. When only this haplotype was considered, there appeared to be a significant association with hyperglycemia chi2 = 6.36). However, since both haplotypes in the proband could be associated with hyperglycemia (both proband's parents had hyperglycemia), the data for both haplotypes were combined, and analysis for an association between both haplotypes and hyperglycemia was not significant (chi2 = 2.53). Linkage between a diabetes gene causing MOHY and the HLA, evaluated by lod score analysis, was suggested, but the values were not significant.

Urinary C-peptide as a measure of beta-cell function after a mixed meal in healthy subjects: comparison of four-hour urine C-peptide with serum insulin and plasma C-peptide.

Urinary C-peptide (UCP) is a noninvasive measure of integrated insulin production, and the usefulness of 24-h collections has been previously reported. Only small numbers of subjects have been studied using shorter urine collections. To see how well 4-h urine collections for C-peptide (UCP) correlate with serum immunoreactive insulin (SI) and plasma C-peptide (PCP), we studied 41 healthy subjects (19 men, 22 women) using as a stimulus a 600-kcal mixed meal and the same mixed meal after oral prednisone. UCP values correlated best with the area under the curves for SI (r = 0.457, P less than 0.001) and PCP (r = 0.557, P less than 0.001). UCP was also significantly correlated with peak SI (r = 0.382, P less than 0.001), peak PCP (r = 0.496, P less than 0.001), fasting SI (r = 0.297, P = 0.007), and fasting PCP (r = 0.341, P = 0.007) values. Urinary C-peptide was significantly correlated with SI and PCP concentrations in a broad range of physiologic values for SI and PCP supporting the usefulness of UCP as a simple, noninvasive measure of beta-cell function. Four-hour collections for UCP may be useful in further studies of beta-cell function.

C-peptide response to meal challenge in nondiabetic and diabetic adults living in Wadena, Minnesota.

OBJECTIVE: The goal of the study was to provide cross-sectional descriptive data on the response of C-peptide to a vigorous meal stimulus in a population-based sample of nondiabetic adults compared with a population-based sample of adults with NIDDM. Available information is scanty, especially in subjects greater than 50 yr old. RESEARCH DESIGN AND METHODS: The group under study included 377 adults without previously known diabetes randomly chosen from the population of the city of Wadena, Minnesota, almost all of northern European background, and 88 adults with known diabetes. PCP was measured 90 min after ingestion of 480 ml liquid meal Ensure-Plus, which includes 95 g dextrose, 26 g protein, and 25 g fat. C-peptide also was measured in a 260-min urine collection after the meal challenge. Novo antibody M1221 was used for C-peptide assay throughout the study. Participants whose medical record indicated insulin-dependent diabetes with a history of acetone production were excluded from analyses. RESULTS: The distribution of UCP and PCP in this group of subjects appears very broad. Both the highest and lowest values for C-peptide were observed in individuals with diabetic glucose tolerance. The mean and median values in the nondiabetic group are higher than in previously published reports. After statistical adjustment for age, sex, BMI, and concomitant plasma glucose, participants with IGT produced significantly more C-peptide than the group with NGT (3.48 vs. 2.96 nM PCP, P less than 0.05). Participants with diabetic glucose tolerance and who were not taking insulin produced as much or more C-peptide than either the NGT or IGT groups, depending on the statistical model used for adjusting for plasma glucose. Diabetic participants who were taking insulin produced significantly lower amounts of C-peptide than any of the non-insulin-taking groups (approximately 30% of the C-peptide produced by the non-insulin-taking diabetic participants). A decline in PCP production with increasing years since diagnosis (5.7%/yr) was observed exclusively in the insulin-taking NIDDM participants. Effect modification by glucose tolerance classification was observed on the relationship between plasma glucose and PCP: PCP increased with increasing plasma glucose in NGT and IGT groups, but a nonsignificant negative relationship was exhibited in diabetic participants. CONCLUSIONS: The data suggest that two forms of NIDDM may exist, crudely distinguished by the clinical decision to use insulin to control blood glucose levels. The insulin-taking diabetic individuals may experience a greater likelihood of pancreatic failure, whereas non-insulin-taking diabetic individuals probably experience stable pancreatic function over the course of their disease. Longitudinal observation of the Wadena cohort will provide more insight into this possibility.

Xylitol, a partial homologue ot alpha-D-glucopyranose: potent stimulator of insulin release in dogs.

A direct comparison was made in healthy female dogs of the potency of xylitol and mutarotated glucose as stimulators of insulin release (both first and second phases), and also of their urinary excretion and arterio-venous difference across a hind-limb. Xylitol or glucose was given by constant infusion into a systemic vein for 50 minutes in paired experiments. Three dose levels were used in 12 dogs. Plasma insulin levels during xylitol infusion were as high as or higher than those during glucose infusion, with increases in arterial xylitol levels equal to or less than those in glucose. More xylitol was lost in the urine, but the overall uptake of xylitol was at least 70% also the arteriovenous difference for xylitol across the hind-limb was greater than for glucose, when each was divided by the arterial sugar concentration. It is suggested that both the striking potency of xylitol in stimulating both phases of insulin release, and its rapid uptake by tissues, may result from its homology with alpha-D-glucopyranose, the alpha-anomer of glucose. The concept of a glucoreceptor on the surface of the pancreatic beta-cell, with stereospecificity for alpha-D-glucopyranose or closely similar molecules, is supported by our results.