Citations

Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in linkage disequilibrium with at-risk DR4 and DR3 alleles, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the greatest risk. A double transgenic mouse expressing both DR3 and DQ8 was generated to investigate potential major histocompatibility complex class II interactions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolerance to GAD65, in which the T-cell response to GAD65 was restricted by HLA DR. Although the mice also showed spontaneous insulitis, they did not progress to overt diabetes. Mice expressing either transgene (DQ8 or DR3) alone showed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. Therefore, in a fashion analogous to human diabetes, the murine model demonstrated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.

Retinopathy is an important sequela of diabetes mellitus, but clinical risk factors for this condition have rarely been assessed in a geographically defined population. In this population-based study, the 1135 Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort) were followed through their complete medical records in the community to January 1, 1982. Because most of the cases of diabetic retinopathy in Rochester residents developed in patients with non-insulin-dependent diabetes mellitus (NIDDM), risk factors for diabetic retinopathy were examined in this group (N = 1031). A proportional hazards model identified the following risk factors for diabetic retinopathy in NIDDM: elevated initial fasting blood glucose level, marked obesity, and earlier age at onset of diabetes. Stratified analyses indicated that duration of diabetes was also significantly associated with an increased risk of retinopathy. Two secular trends, increasing detection of “mild” NIDDM and decreasing risk of diabetic retinopathy, had a major effect on retinopathy risk assessment. These data also suggest that insulin therapy is not an independent risk factor for diabetic retinopathy.

Among the 1135 Rochester residents discovered to have diabetes in the period 1945–69, the prevalence of retinopathy was 2.6% at the time of initial diagnosis. Among those free of retinopathy at diagnosis of diabetes, the subsequent incidence of any retinopathy was 17.4 per 1000 person-years and for proliferative retinopathy alone was 1.6 per 1000 person-years, based on 12,000 person-years of follow-up. The incidence rate of retinopathy was almost three times greater among residents with insulin-dependent (IDDM) than with non-insulin-dependent diabetes (NIDDM); however, the actual number of retinopathy cases was over four times greater among the more numerous residents with NIDDM. By 20 yr after diagnosis of diabetes, the cumulative incidence of retinopathy approached 70% among IDDM subjects and was 30% and 36%, respectively, among the obese and nonobese NIDDM residents. The epidemiologic patterns for proliferative retinopathy were qualitatively similar to those for nonproliferative retinopathy. The risk of blindness was greater among those with proliferative than with nonproliferative retinopathy but was substantial even for those without retinopathy. Most blindness was caused by factors other than isolated diabetic retinopathy.

OBJECTIVE—Management of diabetes is frequently suboptimal in primary care settings, where providers often fail to intensify therapy when glucose levels are high, a problem known as clinical inertia. We asked whether interventions targeting clinical inertia can improve outcomes. RESEARCH DESIGN AND METHODS—A controlled trial over a 3-year period was conducted in a municipal hospital primary care clinic in a large academic medical center. We studied all patients (4,138) with type 2 diabetes who were seen in continuity clinics by 345 internal medicine residents and were randomized to be control subjects or to receive one of three interventions. Instead of consultative advice, the interventions were hard copy computerized reminders that provided patient-specific recommendations for management at the time of each patient’s visit, individual face-to-face feedback on performance for 5 min every 2 weeks, or both. RESULTS—Over an average patient follow-up of 15 months within the intervention site, improvements in and final HbA1c (A1C) with feedback + reminders (ΔA1C 0.6%, final A1C 7.46%) were significantly better than control (ΔA1C 0.2%, final A1C 7.84%, P < 0.02); changes were smaller with feedback only and reminders only (P = NS vs. control). Trends were similar but not significant with systolic blood pressure (sBP) and LDL cholesterol. Multivariable analysis showed that the feedback intervention independently facilitated attainment of American Diabetes Association goals for both A1C and sBP. Over a 2-year period, overall glycemic control improved in the intervention site but did not change in other primary care sites (final A1C 7.5 vs. 8.2%, P < 0.001). CONCLUSIONS—Feedback on performance aimed at overcoming clinical inertia and given to internal medicine resident primary care providers improves glycemic control. Partnering generalists with diabetes specialists may be important to enhance diabetes management in other primary care settings.

OBJECTIVE—The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. RESEARCH DESIGN AND METHODS—Participants included 231 patients with diabetes (type 1, n = 83; type 2, n = 148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). RESULTS—Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS ≥5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. CONCLUSIONS—These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.

OBJECTIVE—Increasing obesity within the general population has been accompanied by rising rates of diabetes. The extent to which obesity has increased among people with diabetes is unknown, as are the potential consequences for diabetes outcomes. RESEARCH DESIGN AND METHODS—Community medical records (hospital and ambulatory) of all Rochester, Minnesota, residents aged ≥30 years who first met standardized research criteria for diabetes from 1970 to 1989 (n = 1,306) were reviewed to obtain data on BMI and related characteristics as of the diabetes identification date (±3 months). Vital status as of 31 December 1999 and date of death for those who died were obtained from medical records, State of Minnesota death tapes, and active follow-up. RESULTS—As of the identification date, data on BMI were available for 1,290 cases. Of the 272 who first met diabetes criteria in 1970–1974, 33% were obese (BMI ≥30), including 5% who were extremely obese (BMI ≥40). These proportions increased to 49% (P < 0.001) and 9% (P = 0.012), respectively, for the 426 residents who first met diabetes criteria in 1985–1989. BMI increased significantly with increasing calendar year of diabetes identification in multivariable regression analysis. Analysis of survival revealed an increased hazard of mortality for BMI ≥41, relative to BMI of 23–25 (hazard ratio 1.60, 95% CI 1.09–2.34, P = 0.016). CONCLUSIONS—The prevalence of obesity and extreme obesity among individuals at the time they first met criteria for diabetes has increased over time. This is disturbing in light of the finding that diabetic individuals who are extremely obese are at increased risk of mortality compared with their nonobese diabetic counterparts.

OBJECTIVE The American Diabetes Association (ADA) has recommended that the fasting plasma glucose (FPG) level used to diagnose diabetes be changed from 7.8 mmol/l (the level recommended by the National Diabetes Data Group [NDDG] in 1979) to 7.0 mmol/l. We examined the impact of this change on rates of progression to overt diabetes from different levels of FPG. RESEARCH DESIGN AND METHODS Using the laboratory database of Mayo Clinic, we assembled a cohort of 8,098 nondiabetic Olmsted County residents 40 years of age or older on 1 July 1983. Subjects were followed for a median of 9 years. RESULTS Among 7,567 individuals with follow-up FPG data, 778 (10.3%) progressed to ADA diabetes and 513 (6.8%; P < 0.0001) progressed to NDDG diabetes. The risk of developing ADA diabetes was 7, 19, and 39% for individuals with initial FPG values in the ranges of <5.6, 5.6–6.0, and 6.1–6.9 mmol/l, respectively. For progression to NDDG diabetes, the respective risks were 3, 11, and 25%. A clear gradient of risk was observed within the “normal” range of FPG (<5.6 mmol/l). Among the 793 individuals who developed ADA diabetes, 222 (29%) developed NDDG diabetes simultaneously and 291 (37%) developed NDDG diabetes later. In all FPG subgroups, progression to ADA diabetes occurred ∼7 years sooner than progression to NDDG diabetes. CONCLUSIONS The baseline level of FPG is a major predictor of an individual's risk of developing diabetes. The proposed change in the diagnostic criteria for diabetes will lead to earlier diagnosis among individuals who are destined to develop the disease.

OBJECTIVE Fasting hyperinsulinemia in the presence of normoglycemia usually indicates insulin resistance and is characteristic of populations at high risk for developing NIDDM. Hyperinsulinemia predicts the development of impaired glucose tolerance and NIDDM in Pima Indians, a population with a high incidence of NIDDM. Insulin concentrations in population-based samples of children who have different risks of developing NIDDM later in life have not been reported previously. RESEARCH DESIGN AND METHODS We compared fasting insulin concentrations in two populations of nondiabetic children, 6–19 yr of age: Pima Indians from southern Arizona and Caucasians from Minnesota. RESULTS Insulin concentration varied with age, sex, glucose concentration, and relative weight. Mean fasting insulin concentration was 140.3 pM in Pima Indian males, 94.4 pM in Caucasian males, 171.5 pM in Pima Indian females, and 107.1 pM in Caucasian females. For each sex, the mean fasting insulin concentration, controlled for age, glucose, and relative weight, was significantly higher in the Pima Indians than in the Caucasians (P < 0.001). CONCLUSIONS From a young age, Pima Indian children have higher fasting insulin concentrations than Caucasian children. As hyperinsulinemia predicts subsequent NIDDM, these data suggest that the susceptibility to NIDDM is manifest at a young age as fasting hyperinsulinemia.

Abstract Hepatic resection is the only treatment for patients with colorectal cancer metastatic to the liver that has resulted in long-term survival. This apparent efficacy of hepatectomy has prompted efforts to expand the surgical approach for disease progression within the liver. A review of personal experience and of the literature was performed in an attempt to define the role of surgery for disease progression. Twenty-one patients who underwent hepatic resection between 1983 and 1991 for isolated disease progression in the liver were retrospectively reviewed. The median follow-up of patients still alive was 1·7 years (range 4 months to 4·5 years). The median survival from the date of repeat hepatic resection was 3·4 years with an estimated actuarial survival rate of 43 per cent at 4 years. These patients experienced no significant morbidity and the mortality rate was 5 per cent. Hepatic resection of metastatic colorectal carcinoma can produce long-term survival without prohibitive risk. These findings support an aggressive surgical approach for metastatic progression in the liver from colorectal carcinoma.

Abstract Nine consecutive patients underwent surgery for liver and lung metastases from colorectal cancer (Dukes' stage B in five, C in one and ‘D’ in three) between 1980 and 1991. A total of 21 procedures were performed: 16 thoracotomies with six lung lobectomies and 17 lung wedge resections, ten laparotomies with nine hepatectomies and six liver wedge resections. No operative or hospital deaths occurred and the mean(s.d.) postoperative hospital stay was 10(7) days per procedure. Perioperative blood transfusions for all nine patients amounted to a total of 7 units. The median survival after completion of liver and lung surgery was 27 (range 10–62) months. Median survival from resection of the first liver or lung metastasis was 30 (range 12–62) months and from excision of the primary colorectal tumour 46 (range 30–78) months. Two patients were alive and well 11 and 62 months after liver and lung resections; seven have died with metastases. This controversial aggressive treatment resulted in longer survival times than most alternative therapies in these highly selected and well motivated young patients, with no hospital mortality and only moderate morbidity.