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Although albumin excretion rate is commonly estimated by using albumin/creatinine ratio (A/C), gender and race differences in creatinine excretion may bias this estimate. The authors optimize the use of an untimed (spot) urine specimen among 3,371 Blacks and Whites aged 28-40 years in the Coronary Artery Risk Development in Young Adults Study in 1995-1996. Using three 24-hour collections during the year 5 examination, they determined k = 0.68 x 0.88 in Black men, 0.88 in Black women, 0.68 in White men, and 1.0 in White women to reflect gender and race differences in creatinine excretion. The authors then computed A/C adjusted for race and sex differences in creatinine excretion (A/kC) by using an untimed urine sample in the year 10 examination. A/kC >or= 25 mg/g (194 cases of microalbuminuria and 26 cases of clinical grade albuminuria) was more common among Blacks (9.1%) than among Whites (4.2%) and among men (8.2%) than among women (5.0%). Use of the unadjusted A/C underestimated the prevalence of microalbuminuria among men by 52% and among Blacks by 26%. Adjustment of A/C permitted more accurate estimation of albumin excretion rate. Men and Blacks have a higher albumin excretion rate than do women and Whites and may thereby have an increased risk of microvascular and macrovascular disease.

The aim of the study was to describe 5-year changes in meal-stimulated pancreatic insulin reserve in adults with normal and impaired glucose tolerance (NGT, IGT) and diabetes, with or without islet-related antibodies. This was a 5-year follow-up of 270 residents of Wadena, MN, of northern European origin, with good kidney function, defined as creatinine clearance greater than 60 mL/min/1.73 m(2). The subjects comprised a population-based sample originally studied in 1986 to 1987. Urine C-peptide (CP), in a 260-minute collection, was the integrated measure of insulin secretion; Ensure-Plus (Ross, Columbus, OH) was the liquid meal. Islet cytoplasmic antibodies (ICA), insulin autoantibodies (IAA), and glutamate decarboxylase antibodies (GAD65ab) were measured. In 182 subjects with NGT, there was no mean within-subject change in urine CP over 5 years (P =.34). In 41 subjects with impaired GT (IGT), there was a moderate, but nonsignificant, increase in mean CP, and 6 (15%) subjects increased. In 37 type 2 diabetic subjects not taking insulin (type 2-No Ins), who had a mean diabetes duration at the 5-year examination of 9.6 +/- 6.3 years, there was a 21% decrease in mean urine CP (P =.012), attributable mostly to a major drop in 8 of the 37 subjects (22%). Islet-related antibody tests were mostly negative; GAD65ab positivity was related to CP decline only among insulin-taking subjects. In summary, in Wadena adults, meal-stimulated urine CP was stable or increased over 5 years in subjects with NGT and IGT, but CP decreased significantly in about one fifth of type 2-No Ins subjects, with no relation to antibody test results., (Copyright 2002 by W.B. Saunders Company)

Objective: To determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution., Summary Background Data: Insulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants., Methods: From December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas-kidney (SPK) and 1 simultaneous pancreas-liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n = 14), historical; era 1, 1978 to 1986 (n = 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n = 461), all categories (SPK, PAK, and PTA), predominantly bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n = 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n = 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA., Results: Patient and primary cadaver pancreas graft functional (insulin-independence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n = 214) versus eras 3 and 4 combined (n = 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n = 36) versus 2 (n = 61) versus 3 (n = 84) versus 4 (n = 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n = 36) versus 2 (n = 72) versus 3 (n = 30) versus 4 (n = 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n = 136) than enteric drainage (n = 70), 82% versus 74% at 1 year (P =.03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic secondary complications were ameliorated in some recipients, and quality of life studies showed significant gains after the transplant in all recipient categories., Conclusions: Patient and graft survival rates have significantly improved over time as surgical techniques and immunosuppressive protocols have evolved. Eventually, islet transplants will replace pancreas transplants for suitable candidates, but currently pancreas transplants can be applied and should be an option at all stages of diabetes. Early transplants are preferable for labile diabetes, but even patients with advanced complications can benefit.

To investigate whether the influence of obesity on cardiovascular risk factors and glucose intolerance differs between Japan and the US, we conducted cross-sectional surveys in those with elevated plasma glucose in Tanushimaru, Japan, and a stratified random population sample, in Wadena, MN. Subjects numbered 204 in Tanushimaru and 334 in Wadena. Body mass index (BMI), blood pressure, blood lipids, fasting plasma levels of glucose, glycosylated hemoglobin A(1c,) insulin, and free fatty acids were assessed. Overweight was defined as BMI of 27.5-29.9 kg/m(2) and obesity as BMI> or =30 kg/m(2). Gradual increases in risk factors were seen as BMI increased in both studies. Most risk factors were associated with glucose intolerance, except for BMI in Tanushimaru. In Wadena, glucose intolerance increased sharply among the obese. Adjustment for BMI attenuated the associations of cardiovascular risk factors with glucose intolerance in Wadena, but not in Tanushimaru. Obesity has an exaggerated influence on risk factors, compared with being overweight. The associations of glucose intolerance with cardiovascular risk factors are more affected by adjustment for BMI in Wadena than in Tanushimaru, not because of a different influence of body weight on risk factors between the two cities, but because obesity is rare in Japan.

Background: In patients with type I diabetes mellitus who do not have uremia and have not received a kidney transplant, pancreas transplantation does not ameliorate established lesions of diabetic nephropathy within five years after transplantation, but the effects of longer periods of normoglycemia are unknown., Methods: We studied kidney function and performed renal biopsies before pancreas transplantation and 5 and 10 years thereafter in eight patients with type I diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. The biopsy samples were analyzed morphometrically., Results: All patients had persistently normal glycosylated hemoglobin values after transplantation. The median urinary albumin excretion rate was 103 mg per day before transplantation, 30 mg per day 5 years after transplantation, and 20 mg per day 10 years after transplantation (P=0.07 for the comparison of values at base line and at 5 years; P=0.11 for the comparison between base line and 10 years). The mean (+/-SD) creatinine clearance rate declined from 108+/-20 ml per minute per 1.73 m2 of body-surface area at base line to 74+/-16 ml per minute per 1.73 m2 at 5 years (P<0.001) and 74+/-14 ml per minute per 1.73 m2 at 10 years (P<0.001). The thickness of the glomerular and tubular basement membranes was similar at 5 years (570+/-64 and 928+/-173 nm, respectively) and at base line (594+/-81 and 911+/-133 nm, respectively) but had decreased by 10 years (to 404+/-38 and 690+/-111 nm, respectively; P<0.001 and P=0.004 for the comparisons with the base-line values). The mesangial fractional volume (the proportion of the glomerulus occupied by the mesangium) increased from base line (0.33+/-0.07) to 5 years (0.39+/-0.10, P=0.02) but had decreased at 10 years (0.27+/-0.02, P=0.05 for the comparison with the baseline value and P=0.006 for the comparison with the value at 5 years), mostly because of a reduction in mesangial matrix., Conclusions: Pancreas transplantation can reverse the lesions of diabetic nephropathy, but reversal requires more than five years of normoglycemia.

An increased albumin excretion rate (AER) is associated with impaired glucose tolerance and diabetes mellitus in some populations, but data on Americans of Northern European origin are lacking. In 1986-1987, AER and creatinine clearance were measured in 455 adults in a survey of the population of Wadena, Minnesota. Thirty-five subjects (8%) had an AER > or = 15 micrograms/minute, and eight of these had overt proteinuria (AER > or = 175 micrograms/minute). AER and creatinine clearance were uncorrelated except when AER was increased. Unadjusted mean AER in a stratified random sample of adults (n = 374) was 3.6 micrograms/minute. Adjusted values for 277 subjects with normal glucose tolerance and for 80 subjects with impaired glucose tolerance were very similar (3.8 and 3.7 micrograms/minute, respectively), whereas mean AER was 5.4 micrograms/minute for persons with non-insulin-dependent diabetes mellitus (NIDDM) who were not taking insulin and 9.4 micrograms/minute for persons with NIDDM who were taking insulin (p < 0.0001). After adjustment for age, mean creatinine clearance was unrelated to glucose tolerance. Systolic blood pressure was a major determinant of increased AER (p < 0.0001) and lowered creatinine clearance (p = 0.0011), independently of diabetes. AER was stable over 5 years among the 321 cases who were not taking insulin and were not severely hypertensive. The decrease in creatinine clearance was greater in ex-smokers and current smokers than in nonsmokers. The authors conclude that hypertension and NIDDM were independently associated with the risk of kidney damage in this population, as indicated by a higher AER. High-normal blood pressure, but not impaired glucose tolerance, was associated with microalbuminuria. These relatively mild changes may reflect an ethnically based resistance to the damaging effects of hyperglycemia on the kidney. Smoking may accelerate the aging-related decline in glomerular filtration rate.

Insulin-dependent diabetes mellitus (IDDM) is associated with autoantibodies to several pancreatic islet antigens. We have described an assay in which autoantibodies displace a radiolabelled monoclonal anti-islet antibody. Sera from 87% of 429 children at time of diagnosis of IDDM were positive, while sera from control groups had much lower prevalences (1.3-19%). Sera from 41.9% of diabetic subjects remained positive after 20 years duration of IDDM. Sera from 23.6% of parents and 37.9% of non-diabetic siblings were positive. Twenty relatives who subsequently developed IDDM had the same prevalence of the antibodies (85%) as did the patients at time of diagnosis. These findings confirm that the autoantibodies detected by monoclonal antibody (mAb) 1A2 are common at the onset of IDDM and their presence prior to the onset of hyperglycaemia suggests that this method may be useful in screening non-diabetic populations. The high prevalence of antibodies in relatives reduces the efficacy for diabetes prediction, but suggests either that generation of these antibodies is an autosomal dominant trait, or that the antigen detected by these antibodies is cross-reactive with a common environmental antigen. Differentiation between these hypotheses will await the identification of the specific islet-cell antigen detected by mAb 1A2.

It has been suggested that serum insulin levels in subjects with recently diagnosed type II diabetes have been overestimated, and that after correction for proinsulin, true insulin levels are depressed rather than elevated. We tested this possibility in a cross-sectional study of a population-based sample of 328 adults living in Wadena, a Minnesota community in which residents are of northern European background. Specificity of insulin measurements was provided by an antibody blind to proinsulin and its major metabolite. Oral glucose tolerance and liquid mixed-meal (Ensure-Plus) tests were performed on separate days. Mean insulin levels before and 90 minutes after the mixed meal were as follows. Among 302 randomly ascertained adults not previously known to have diabetes, both fasting and postmeal levels in subjects with impaired glucose tolerance (IGT) and newly identified type II diabetes were equal to or greater than levels in subjects with normal glucose tolerance (fasting: normal 52 pmol/L, IGT 78, new type II 87; postmeal: 317, 565, and 406, respectively). The fasting insulin to glucose ratio was significantly increased in IGT and new type II diabetes subjects. Among 26 established (previously known) type II diabetic subjects not taking insulin, fasting levels were elevated and postmeal levels were normal in absolute terms (75 and 328), but were normal or low with respect to plasma glucose. Relationships among the groups were not materially changed by adjustment for body mass index (BMI), sex, age, or blood pressure. There was marked overlap of individual insulin levels from group to group. In summary, randomly selected adults in Wadena with IGT or asymptomatic diabetes showed, on average, elevated insulin levels, but physician-diagnosed diabetes was associated with relative diminution of serum insulin. In this population, the current view of insulin resistance in "early" diabetes was supported by insulin-specific measurements.

In current clinical and research practice, the determination of diabetic status depends largely on plasma glucose levels 2 h after the ingestion of a standard 75-g glucose load, the oral glucose tolerance test (OGTT). The OGTT, however, remains inconvenient, not highly reproducible, and costly, especially for large-scale studies and population screening tests. Fasting plasma glucose (FPG) determinations are convenient, reliable, and valid measures of glucose intolerance, but the currently prescribed cut-off point of 140 mg/dl (7.8 mM) lacks sensitivity. We evaluated the reliability and validity of fasting plasma glucose (FPG) values compared with other measures of hyperglycemia for a diagnosis of diabetes in a population-based study of carbohydrate metabolism in Wadena, Minnesota, a community of predominantly northern European ancestry. As a part of this effort, a random sample of Wadena adults, stratified by age and gender, plus all known, previously diagnosed diabetics participated in 2 days of baseline testing and were followed prospectively and retested 5 years later. Cross-sectional analyses of baseline data are presented in this article. Diabetic status was ascertained by administering a standard OGTT according to National Diabetes Data Group (NDDG) specifications. Sensitivity and specificity levels obtained when using a FPG cut-off point of 6.4 mM were 95.2% and 97.4%, respectively. In study subjects with no known diagnosis of diabetes, the FPG cut-off point of 6.4 mM performed reasonably well with a sensitivity and specificity of 67.7% and 97.4%, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-dependent diabetes (IDDM) is frequently associated with autoimmune thyroid disease (ATD) within families. In these families, HLA polymorphism may modulate the susceptibility to each disease. Families with IDDM were further categorized as to the presence of ATD. IDDM-affected subjects from families without ATD were compared with subjects with ATD or with IDDM and ATD from IDDM/ATD families and with a control group. IDDM susceptibility in IDDM/ATD families was negatively associated with the presence of DQB1*0602 [relative risk (RR) = 0.038; P = 0.0001; corrected P (Pc) = 0.0005] and *0301 (RR = 0.3; P = 0.002; Pc = 0.01) and positively associated with the presence of DQB1*0201 (RR = 3.4; P = 0.0007; Pc = 0.0035) and *0302 (RR = 5; P = 0.0001; Pc = 0.0005), regardless of ATD. Compared with the IDDM-only group, the ATD-only group had an increased frequency of subjects with DQB1*0602 (RR = 0.14; P = 0.031), suggesting that the known IDDM-protective effect of this allele may be independent of susceptibility to ATD; however, this difference was not significant when the P value was correlated for the number of alleles tested. In these families, susceptibility to ATD was only associated with DQB1*0201 (RR = 5.71; P = 0.0043; Pc = 0.021). Among subjects with DQB1*0201, there was a weak negative association between the presence of DQB1*0302 on the second haplotype and Hashimoto's thyroiditis (RR = 0.237; P = 0.026; Pc > 0.05). We conclude that in IDDM/ATD families, IDDM-affected subjects are at risk for ATD, especially those carrying DQB1*0201. This risk may be influenced by the alleles carried on the second haplotype, with DQB1*0302 (or a closely linked gene) protecting from Hashimoto's thyroiditis and favoring Graves' disease.

Kidney tissue of acceptable quality was available from autopsies of 55 patients who had been followed prospectively for 3 to 15 years as participants in the University Group Diabetes Program, a study of vascular disease in Type 2 (non-insulin-dependent) diabetic patients. Slides were prepared for light microscopic reading by uniform histologic techniques, and then were randomly intermixed and coded with tissues identically prepared from matched non-diabetic subjects (morphologic controls). After independent review by three morphologists, the results were tabulated and assigned to one of four diagnostic groups: 1) typical diabetic nodular glomerulosclerosis; 2) mesangial changes suggestive of diabetes (diffuse lesion); 3) non-diabetic renal disease; 4) normal for age. Of the diabetic cases 31% (17 of 55) were found to show nodular glomerulosclerosis, and another 47% (26 of 55) showed suggestive changes; none of the morphologic control slides was read as showing nodular glomerulosclerosis, but some were judged to show suggestive mesangial (diffuse) changes. Although only 4 of the 17 diabetic patients with nodules had died of uraemia, many had hypertension, which may have contributed to their deaths from vascular disease. The patients with nodular glomerular changes also showed, on the average, the highest blood glucose levels during life. Type 2 diabetes in later life appears to be associated with a high risk for typical tissue changes of diabetic kidney damage, which may contribute significantly to morbidity and mortality and may be present before azotaemia and qualitative proteinuria have been recognized.

Epidemiologic data suggest that a parental history of Type 2 (non-insulin-dependent) diabetes mellitus increases the risk of Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 and Type 2 diabetes. We have previously reported evidence that HLA-DR4-linked factors may represent a homogeneous subset of diabetes susceptibility. First, HLA-DR4 frequency was higher in Type 1 diabetic study subjects with a Type 2 diabetic parent than in Type 1 diabetic subjects whose parents were not diabetic. Second, a DR4-haplotype was transmitted from the Type 2 diabetic parent to the Type 1 offspring more often than expected. These data are consistent with the hypothesis that families with a Type 2 diabetic parent and Type 1 diabetic child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility. In this report, we further explore the relationship between the high-risk HLA antigen (HLA-DR4) in study subjects with differing glycaemic status (National Diabetes Data Group criteria). In this community-based study, we find evidence that HLA-DR4 is increased in study subjects with Type 2 diabetes and may be a marker for Type 2 diabetes susceptibility.

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.

Cardiovascular risk factors were examined in 453 subjects participating in the Wadena City Health Study, a population-based study to assess the relationship between diabetes and glucose intolerance with age. Each subject was classified as either having non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance (IGT), or normoglycemia, using WHO criteria. Age- and body-mass-adjusted levels of systolic and diastolic blood pressure were lowest for those with normoglycemia, intermediate for those with IGT, and highest for those with NIDDM. Age- and body-mass-adjusted levels of high-density lipoprotein cholesterol were lowest for those with NIDDM, intermediate for those with IGT, and highest for those with normoglycemia, while triglyceride levels were highest for those with NIDDM, intermediate for those with IGT, and lowest for those with normoglycemia in women but not in men. Low-density lipoprotein cholesterol levels were lowest for those with NIDDM, intermediate for those with IGT, and highest for those with normoglycemia. With the exception of men with IGT, no differences by glycemic strata were observed for plasma total cholesterol. The prevalence of smoking showed no consistent pattern by glycemic status. These findings suggest that individuals with IGT have an atherogenic risk factor pattern that may put them at greater risk for coronary heart disease than those with normoglycemia. Intervention strategies such as diet, exercise, and/or drug therapy should be tested to evaluate whether these are effective in preventing conversion to overt diabetes and normalizing cardiovascular disease risk factors.

Objective: To assess age-related changes in stimulated plasma C-peptide in a population-based sample of adults., Design: Cross-sectional study., Setting: Wadena, Minnesota, a city of 4,699 residents (1980 census) in west central Minnesota, approximately 150 miles from Minneapolis/St. Paul., Study Subjects: 344 non-diabetic subjects (NDDG standards) from a stratified random sample of the total adult population of Wadena, MN. The six-study strata were men and women from three age groups: young, 20-39 years of age; middle-aged, 40-59; and older, greater than 60 years of age., Measurements: During a liquid meal of Ensure-Plus (Ensure-Plus challenge test; EPCT; Ross Laboratories), blood samples were taken for glucose, free fatty acids, creatinine, and C-peptide. Plasma C-peptide taken 90 minutes after the EPCT was used as a surrogate measure for insulin. Clinical tests included one-time samples for hemoglobin, glycosylated hemoglobin, plasma cholesterol, triglycerides, and lipoproteins. Physical measurements included height, weight, and blood pressure. Urine was assayed for C-peptide and creatinine. Assays of urine and plasma C-peptide used antibody M1221 (from Novo; Copenhagen, Denmark)., Main Results: No differences were observed for the relationship between age and C-peptide within each of the three age groups for men and the three age groups for women. However, the levels of plasma C-peptide for older men or women were statistically significantly higher than levels for the young age groups of the same sex; fasting plasma glucose also was higher for older groups of both sexes, and postmeal glucose was significantly higher for older women. There were decreases with age in urine C-peptide clearance for women and men; the decline for women was statistically significant. In multiple regression models for men alone and women alone, that controlled for age, post-meal plasma glucose best explained plasma C-peptide levels. For young men, plasma glucose alone provided the best prediction of plasma C-peptide levels; body mass index (BMI) and plasma glucose provided the best prediction for young women. For older men and both middle-aged and older women, a combination of urine C-peptide clearance and plasma glucose best predicted plasma C-peptide levels; for middle-aged men, BMI also contributed to the prediction., Conclusions: Secretion of insulin in response to an orally administered mixed meal is undiminished with age in non-diabetic adults.

Objective: To evaluate the long-term effect on blood glucose levels of successful transplantation of part or all of an intact human pancreas in patients with insulin-dependent diabetes mellitus (IDDM)., Design: Cohort study., Setting: Referral medical center., Patients: Thirty-seven patients with adequate data, representative of a group of 62 patients with functioning grafts (that is, insulin-independent) at 2 years after transplantation. The 62 patients came from a total of 178 patients in the University of Minnesota series as of July 1987, for a 2-year success rate of 35% (95% Cl, 27.8% to 41.8%). These patients were compared to two diabetic control groups (18 patients with IDDM under standard insulin treatment in a university diabetes clinic and 11 patients with IDDM whose pancreas grafts had failed) and to two nondiabetic groups (14 nondiabetic patients who received immunosuppressive drugs after kidney transplantation and 196 healthy control subjects)., Measurements: Glycosylated hemoglobin was measured by the high-pressure liquid chromatography method, as total A1 (Hb A1) and the A1C subfraction (Hb A1C); results were expressed as a percentage of total hemoglobin., Main Results: Before pancreas transplantation, the 37 patients in the study group had a mean Hb A1 of 10.8%, consistent with moderate to marked hyperglycemia and not statistically different from the levels in the diabetic control groups. All 37 patients had values above the therapeutic target range of 5.4% to 7.4%. However, at 1 and 2 years after transplantation, the mean Hb A1 value had fallen sharply to 6.7% and 6.5%, respectively, well within target range (Cl of the difference, 3.4% to 4.8%; P less than 0.001). These levels did not differ from the mean Hb A1 in the nondiabetic kidney transplant recipients but were slightly above the 6.2% value for the 196 healthy controls (Cl of the difference at 1 year, 0.2% to 0.8%). Serial values were available on 6 subjects for 5 years; these values were all well within target range. As expected, Hb A1C values were parallel to those of Hb A1., Conclusions: Pancreas transplantation, in our successful cases, lowered glycosylated hemoglobin to normal or near-normal levels that were sustained for as long as 5 years. These results compare favorably with those in our patients on standard treatment, and also with those in similar patients on intensive control reported by others. Further effort to improve transplant methods appears to be warranted.

Epidemiologic data suggest that having a parent with Type 2 (non-insulin-dependent) diabetes mellitus increases the risk for Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 diabetes and Type 2 diabetes. We contrast genetic risk factors in three sets of families, consisting of (1) a single Type 1 diabetic child (proband) and non-diabetic parents, (2) multiple Type 1 diabetic siblings and non-diabetic parents, and (3) at least one Type 1 diabetic child and at least one Type 2 diabetic parent. Previous studies have demonstrated that HLA region genes, which elevate the risk in Type 1 diabetes, have no significant effect with respect to the risk for developing Type 2 diabetes. An earlier report cited a contribution by the haptoglobin locus to genetic susceptibility for Type 2 diabetes. We provide evidence that a high risk HLA antigen (HLA-DR3) is decreased to a greater extent in Type 1 patients with a Type 2 parent than in Type 1 patients in which the parents are not diabetic. The role of HLA-DR4 is maintained in these families, with an unexpectedly significant increased rate of transmission of the HLA-DR4 allele from Type 2 parent to Type 1 offspring. The role of haptoglobin in these families does not appear to be important, either with respect to association with diabetes or with respect to linkage with a secondary susceptibility locus. These results indicate that families with a Type 2 parent and Type 1 child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility.

Pancreas grafts, when not rejected, can sustain an insulin-independent state in type I diabetic recipients for indefinite periods. To what extent the metabolic control achieved approaches that of normal individuals, the relationships between graft endocrine and exocrine function, the effect of reversible rejection episodes on subsequent graft function, and the correlation between the results of serial tests of graft function were determined by studies at 1 month, 1 year, and 2 years in a cohort of 39 recipients (29 females, 10 males; mean age (+/- SD), 33 +/- 5 years; mean duration of diabetes, 22 +/- 6 years) of bladder-drained pancreas transplants performed between November 1984 and December 1988. Fifteen patients received a pancreas transplant alone, 8 a pancreas after a kidney, and 16 a simultaneous pancreas/kidney transplant. Graft endocrine function was tested by a 24-hr metabolic profile of blood glucose levels before meals, at 1 and 2 hr after meals, and during the night (14 values in all), by intravenous and oral blood glucose tolerance tests, and by glycosylated hemoglobin levels (HA1 and HA1c). Graft exocrine function was assessed by urine amylase activity (U/hr). The results of the tests in the recipients were subjected to paired comparisons between timepoints and at each timepoint to the results of the same tests in 55 normal nondiabetic control individuals. The means of the mean 24-hr profile glucose (mg/dl) values were significantly lower (P less than 0.05) at 1 and 2 years posttransplant (116 +/- 27 and 115 +/- 15, respectively) than at 1 month (128 +/- 31) in the recipients, but the mean of the mean values in the normal controls (100 +/- 7) was even lower (P less than 0.05). Mean values of individual timepoints during the profile were significantly lower for 6 of the 14 values in the controls than in the recipients. The mean IVGTT K value of the normal controls (-1.9 +/- 0.4%) was significantly lower than the 1-month and 2-year values of the recipients (-1.5 +/- 0.5% and -1.3 +/- 0.6%, respectively), but the comparison with the 1-year value (-1.6 +/- 0.6%) was not significant. The mean glucose levels at zero minutes and between 120 and 300 min of the OGTTs were significantly lower at both 1 and 2 years than at 1 month in the recipients, and the values in the control group were also significantly lower than in the recipients at 1 month but not at 1 and 2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

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)

Reestablishment of the euglycemic state by successful transplantation of the pancreas might halt or reverse diabetic neuropathy. To test this possibility we evaluated neurologic function by clinical examination, nerve conduction studies, and autonomic-function tests in patients with insulin-dependent (Type I) diabetes mellitus before and after successful pancreatic transplantation. Sixty-one patients were studied before and 12 months after transplantation, 27 again after 24 months, and 11 again after 42 months. A control group of patients with Type I diabetes treated with insulin underwent the same studies at similar intervals--48 patients before and after 12 months had elapsed, 21 again after 24 months, and 12 again after 42 months. In the control group, neuropathy tended to worsen during the follow-up period. The scores on the clinical examination indicated increased impairment after 12 months. Composite indexes of the degree of abnormality found on neurophysiologic testing of the function of peripheral motor, sensory, and autonomic nerves indicated decreased autonomic function after 12 months. The examination score and the three index values worsened slightly but not significantly in the patients followed for 24 and 42 months. In contrast, in the patients who had received pancreatic transplants, the neuropathy tended to improve. There was significant improvement in the motor and sensory indexes 12 months after transplantation and in the sensory index 24 months after transplantation. The other measures improved slightly but not significantly at these times, as did all four measures in the patients studied 42 months after transplantation. We conclude that the progression of diabetic polyneuropathy may be halted through the restoration of a euglycemic state by successful pancreatic transplantation.

Pancreatic tissue obtained by hemipancreatectomy from healthy living related donors has been transplanted into recipients with Type I diabetes mellitus. To determine the metabolic consequences of this procedure for the donors, we carried out oral glucose-tolerance testing and 24-hour monitoring of serum glucose levels and urinary C-peptide excretion as a measure of insulin secretion in 28 donors, both before and one year after hemipancreatectomy. The mean fasting serum glucose level was significantly higher one year after the procedure (mean +/- SD, 5.4 +/- 0.9 vs. 4.9 +/- 0.5 mmol per liter; P less than 0.003), as was the serum glucose value two hours after the administration of glucose (8.7 +/- 2.9 vs. 6.5 +/- 1.0 mmol per liter; P less than 0.001). The fasting serum insulin level was significantly lower one year after hemipancreatectomy (33.0 +/- 21.6 vs. 38.4 +/- 21.6 pmol per liter; P less than 0.05), as was the area under the insulin curves during the oral glucose-tolerance test (52,554 +/- 22,320 vs. 76,230 +/- 33,354 pmol per liter per minute; P less than 0.04). The mean 24-hour serum glucose-profile value was higher at one year, and the 24-hour urinary C-peptide excretion was lower in the 17 donors who underwent these studies. Seven of the 28 donors had abnormal glucose tolerance one year after hemipancreatectomy; however, insulin secretion in these 7 donors was indistinguishable from that in the 21 donors who had normal glucose tolerance. All 28 donors had fasting serum glucose concentrations lower than 7.8 mmol per liter, and their mean 24-hour plasma glucose levels remained within the normal range. We conclude that in healthy donors hemipancreatectomy results in a deterioration of insulin secretion and glucose tolerance, as measured one year later. Further study is required to ascertain whether the development of clinical diabetes mellitus is a risk inherent in hemipancreatectomy.

The University of Minnesota has the largest experience with pancreas transplantation of any institution, with 130 cases since 1966, including 116 in 98 patients between July 1978 and June 1985. Currently, 30 patients are insulin-independent, 19 for greater than one year, the longest for seven years. One-year patient and graft survival rates overall are 87% and 30%, respectively. Of 98 recipients, 49 had had previous kidney transplants, while 49 had not, and currently most of the pancreas recipients do not have uremia and have not had a kidney transplant but have early complications of diabetes. A total of 44 of the grafts were procured from related and 72 from cadaver donors. Although 32 of the 116 grafts (28%) failed for technical reasons, the most common cause of graft failure has been rejection. Various immunosuppressive regimens have been used in attempts to reduce the rejection rate, and one combination, low-dose cyclosporine-azathioprine-prednisone (triple therapy), has been particularly effective, with a one-year functional survival rate of 73% in recipients of technically successful grafts from human leukocyte antigen-mismatched cadaver or related donors (N = 20). The pancreas graft survival rates have improved gradually (43% for 1984 to 1985, N = 30; versus 27% for 1978 to 1983, N = 86) for transplants from both related and cadaver donors. Metabolic studies from most recipients with functioning grafts (insulin-independent) show normal or nearly normal results. Preliminary observations on secondary complications suggest a more favorable course in recipients whose grafts have functioned long term than in those whose grafts failed early.

Forty-nine pancreas transplants were performed in 45 patients between July 23, 1978 and May 14, 1982, 18 from related donors. Currently (June 1982), 13 patients have functioning grafts and are insulin independent between 1 and 46 months after transplantation, 5 for more than 1 year. Nineteen patients lost graft function between 1 and 7 months. Sixteen grafts failed for technical reasons. Eight patients died between 1 and 21 months from infections or preexisting complications or for unknown reasons, three with functioning grafts. Actuarial 1-year graft survival is 24% and patient survival is 84%. A variety of techniques were used to handle exocrine secretions of 41 hemipancreas segmental grafts, 4 extended segmental grafts, and 4 whole pancreas grafts. Currently, 3 of 14 duct-open, 0 of 2 duct-ligated, 0 of 4 prolamine-injected, 6 of 19 silicone rubber-injected, and 4 of 10 jejunal anastomosed pancreatic grafts are functioning. Of 33 technically successful allografts, 5 in 12 conventionally immunosuppressed and 8 in 21 cyclosporin A (Cy A)-immunosuppressed recipients are functioning. Most technically successful grafts that failed were not biopsied or removed. In those that were biopsied, fibrosis was a dominant feature in all but one patient. In this patient endocrine and exocrine tissue was normal except for the absence of insulin-positive (beta) cells in the islets and an increase in glucagon-positive (alpha) cells, in contrast to the normal appearance of alpha and beta cells in islets at the time of the pancreas transplant. Currently, we perform pancreas transplants in diabetic patients who have previously received kidney transplants and therefore already require immunosuppression. For nonuremic patients, we perform pancreas transplant only if it is judged that their complications of diabetes exceed, or predictably will exceed, the potential side effects of chronic immunosuppression.

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)

Between December, 1966 and October, 1981, 183 pancreas transplants were performed in attempts to correct the metabolic defect in 171 insulin-dependent diabetic patients. Nearly half of the transplants have been performed in the last two years. Currently, 20 patients have functioning grafts and are insulin independent. Twelve grafts (including six current ones) functioned for more than a year (the longest for four years). A variety of techniques have been used to drain or suppress the secretions of the exocrine pancreas; the most frequent method is injection of the pancreatic duct with a synthetic polymer. In most patients carbohydrate metabolism has been normal or nearly normal while the graft was functioning. Although the technical problems are not entirely solved, the major cause of graft failure has been rejection. The need for antirejection therapy has limited the application of pancreas transplantation to diabetic renal allograft recipients or to non-uraemic patients whose complications of diabetes are, or predictably will be, worse than the side- effects of chronic immunosuppression. If consistently effective methods to suppress the immune response of the recipient to donor histocompatibility antigens are developed, pancreas transplantation could be applied to a wider variety of diabetic patients.

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.

Between July 1978 and April 1987, a total of 182 pancreas transplants were performed at the University of Minnesota. For the first 100 cases (through October 1984), a variety of surgical techniques and immunosuppressive regimens were used, and 1 year patient and graft functional (insulin-independent) survival rates were 88% and 27%, respectively. From November 1984 to April 1987, a triple therapeutic drug regimen of cyclosporine, azathioprine, and prednisone was used for maintenance immunosuppression, and bladder drainage (BD) (n = 39; 38 cadaver (CAD) and 1 related (REL) donor grafts) and enteric drainage (ED) (n = 40; 21 CAD and 19 REL donor grafts) techniques were compared in 59 nonuremic, nonkidney (NUNK) transplant recipients, 21 recipients of previous kidney (PK) transplants and 8 uremic recipients of simultaneous pancreas and kidney (SPK) transplants. The survival rates were higher in recipients of BD CAD and ED REL than of ED CAD grafts (58% and 59% versus 29% at one year for all, and 84%, 84% and 40% for technically successful cases), but patient survival rates were similar (90%, 93% and 90% at one year). BD allows for early diagnosis of rejection based on urine amylase monitoring, and REL grafts are less prone to incite rejection; thus, we are currently performing only BD for grafts from CAD donors, while both techniques are used for REL donor grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

This single-meal pilot study compared the plasma glucose and serum insulin response to defined-formula diets with two levels of carbohydrate (CHO) (55% and 30% of the kilocalories) with and without added soy polysaccharide (10 g) in subjects with type 2 diabetes mellitus. Subjects received each of the four liquid-formula test meals in a randomly assigned order: 1) high CHO, low fiber (HC, LF), 2) high CHO, high fiber (HC, HF), 3) low CHO, low fiber (LC, LF), and 4) low CHO, high fiber (LC, HF). On the day of each test meal the formula was consumed, eight blood samples were drawn for plasma glucose and serum insulin measurements, and a 4-h urine collection was obtained for measuring glucose excretion. Our results showed that area increments under glucose and insulin curves were significantly lower with both low-CHO formulas (p less than 0.001). The addition of soy polysaccharide to the liquid formula did not result in statistically different area increments for glucose or insulin.

Diabetic nephropathy develops in less than half of all patients with diabetes. To study heredity as a possible risk factor for diabetic kidney disease, we examined the concordance rates for diabetic nephropathy in two sets of families in which both probands and siblings had diabetes mellitus. In one set, the probands (n = 11) had no evidence of diabetic nephropathy, with normal creatinine clearance and a urinary albumin excretion rate below 45 mg per day. In the other set, the probands (n = 26) had undergone kidney transplantation because of diabetic nephropathy. Evidence of nephropathy was found in 2 of the 12 diabetic siblings of the probands without nephropathy (17 percent). Of the 29 diabetic siblings of probands with diabetic nephropathy, 24 (83 percent) had evidence of nephropathy (P less than 0.001), including 12 with end-stage renal disease. No significant differences were noted between the sibling groups with respect to the duration of diabetes, blood pressure, glycemic control, or glycosylated hemoglobin levels. Logistic regression analysis found nephropathy in the proband to be the only factor significantly predictive of the renal status of the diabetic sibling. We conclude that diabetic nephropathy occurs in familial clusters. This is consistent with the hypothesis that heredity helps to determine susceptibility to diabetic nephropathy. However, this study cannot rule out the possible influences of environmental factors shared by siblings.

To determine the effect of renal transplantation on visual status, we studied 134 eyes of 67 diabetic patients prospectively for one to seven years, with a mean of three years, after surgery. The best-corrected visual acuity and retinopathy status were determined at the time of surgery and annually thereafter. Useful visual acuity (greater than or equal to 6/15 [20/5o]) was present in 49% (66) of the eyes at the time of the baseline examination and in 51% (69) at the final determination. Of the 134 eyes 40% (54) were legally blind (less than or equal to 6/60 [20/200]) before surgery. Sixty-eight percent (91) of the eyes showed no significant visual change during the period of follow-up, 15% (20) showed significant improvement, and 17% (23) deteriorated significantly after surgery. With regard to the retinovitreous findings, 13% (12) of the eyes had non-proliferative retinopathy, 20% (26 had active proliferative retinopathy, and 67% (90) had inactive or involutional retinopathy. The results of this study showed stable or improved visual function in 83% (111) of the eyes after renal transplantation. Transplantation before dialysis becomes necessary may ben an important consideration in an attempt to reduce the high incidence of visual impairment in diabetic patients with renal failure.

Of 89 pancreas transplants performed in 77 diabetic patients (43 with and 34 without previous kidney transplants), 53 were from cadaver and 36 from related donors. To date, 64 patients (83%) are alive and 27 (35%) have functioning grafts (14 greater than 1 year), including 0 out of 3 duct-ligated, 3 out of 15 open-duct, 17 out of 32 enteric-drained, and 7 out of 39 duct-injected. Of technically successful allografts, 8 out of 16 (50%) in the azathioprine- and 17 out of 47 (36%) in the cyclosporin-treated recipients are functioning (eight cyclosporin patients also take azathioprine). Seven of the nine (78%) non-kidney-transplants recipients of technically successful pancreas allografts from HLA-identical siblings have functioning grafts. Causes of graft failure include allograft rejection, fibrosis secondary to duct injection, or selective beta-cell destruction independent of rejection. Of the 24 recipients who are currently insulin-dependent, 14 have normal or near-normal glucose tolerance test results, while 10 have abnormal results, even though they are otherwise euglycaemic. The patient population to whom pancreas transplantation is applied is gradually changing, and non-uraemic, non-kidney-transplant patients currently comprise the majority of our cases (17 out of 24 in 1983; nine of the 17 currently have functioning grafts). We now prefer the enteric drainage technique.(ABSTRACT TRUNCATED AT 250 WORDS)