Lessons learned from more than 1,000 pancreas transplants at a single institution.

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.

The role of obesity in the association of cardiovascular risk factors and glucose intolerance in small Japanese and North American communities.

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.

Reversal of lesions of diabetic nephropathy after pancreas transplantation.

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.

Risk factors for kidney damage in the adult population of Wadena, Minnesota. A prospective study.

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.

Anti-islet autoantibodies detected by monoclonal antibody 1A2: further studies suggesting a role in the pathogenesis of IDDM.

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.

Are specific serum insulin levels low in impaired glucose tolerance and type II diabetes?: measurement with a radioimmunoassay blind to proinsulin, in the population of Wadena, Minnesota.

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.

A reassessment of fasting plasma glucose concentrations in population screening for diabetes mellitus in a community of northern European ancestry: the Wadena City Health Study.

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)

HLA-DQB1-associated susceptibility that distinguishes Hashimoto's thyroiditis from Graves' disease in type I diabetic patients.

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.

Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys.

Pancreas transplantation prevents or retards development of early diabetic glomerular lesions in renal allografts transplanted to patients with insulin-dependent diabetes mellitus (IDDM), but its effect on established renal lesions in native kidneys of such patients is unknown. Renal biopsy samples were taken before and 5 years after pancreas transplantation from 13 non-uraemic IDDM patients and compared with baseline and 5-year biopsy samples from 10 persistently hyperglycaemic IDDM patients who did not undergo transplantation. The two groups were similar in age, duration of diabetes, metabolic control, renal function, and blood pressure. Glomerular structures were measured by standard morphometric techniques. Haemoglobin A1 concentrations fell to within the normal range after pancreas transplantation but did not change in the comparison group. Glomerular basement membrane width did not significantly change in either group. Glomerular volume decreased and mesangial fractional volume increased in the pancreas transplant recipients but there was no significant change in total mesangial volume over 5 years. By contrast, both glomerular volume and mesangial fractional volume increased in the comparison patients, resulting in increased total mesangial volume. Diabetic glomerular lesions in patients with their own kidneys were not ameliorated by pancreas transplantation, despite 5 years of normoglycaemia. Pancreas transplantation can correct severe metabolic instability and thus improve quality of life, but it cannot yet be recommended for the treatment of established lesions of diabetic nephropathy.

Glomerulosclerosis in type 2 (non-insulin-dependent) diabetes mellitus: relationship to glycaemia in the University Group Diabetes Program (UGDP).

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.

HLA-associated susceptibility to type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study.

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.

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.

Cardiovascular disease risk factors and glucose tolerance. The Wadena City Health Study.

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.

Association between stimulated plasma C-peptide and age: the Wadena City Health Study.

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.

Long-term glucose control in patients with pancreatic transplants.

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.

Shared genetic susceptibility of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin.

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.