Metabolic tests to determine risk for type 1 diabetes in clinical trials.

AIMS: Evaluate the reproducibility and relationship of various metabolic tests conducted as part of the Diabetes Prevention Trial-type 1 diabetes. METHODS: Coefficients of variation, intraclass correlation coefficients, and Pearson correlations between the same metabolic tests performed at different times as well as the different tests were determined. RESULTS: Fasting samples on the same day had a coefficient of variation of < 10 for C-peptide, 11 for insulin, and 2 for glucose. Testing on separate days approximately doubled the variance. Stimulated insulin values had less variance than fasting values and there was only a moderate correlation between fasting and stimulated values on each test. While highly correlated, C-peptide values from mixed meal tolerance tests are significantly lower than that obtained during oral glucose tolerance tests (OGTTs). Neither peak nor area under the curve C-peptide on the oral glucose tolerance test was different between those with abnormal and normal glucose tolerance. Those with abnormal as compared with normal glucose tolerance had lower 30-min C-peptide and a longer time to peak C-peptide. CONCLUSIONS: A large, multi-centre trial, with tests performed over a decade-long period, can provide robust data. C-peptide data from oral glucose tolerance tests and mixed meal tolerance tests differ; therefore, the same stimulation test should be used to evaluate changes in beta cell function over time. Worsening glucose tolerance is associated with lower C-peptide at 30 min and a delay in peak secretion on the oral glucose tolerance test. This Diabetes Prevention Trial-type 1 diabetes data can be used in planning parameters for future studies, including evaluation of new algorithms to determine risk of disease.

Factors affecting improved glycaemic control in youth using insulin pumps.

AIMS: The purpose of this study was to evaluate factors associated with insulin pump therapy resulting in lower HbA(1c) levels in young people with Type 1 diabetes mellitus. METHODS: Insulin pumps were downloaded from 150 youth (81 male), ages 5-20 years. Consecutive insulin pump downloads, 3 months apart, were available for 85 (43 male) of the 150 youth and changes in pump use were correlated with changes (≥0.5%, ≥ 6 mmol/mol) in HbA(1c) levels. RESULTS: Using cross-sectional data, lower HbA(1c) values correlated with use of more frequent daily insulin boluses (r=-0.46, P<0.0001) and more frequent blood glucose checks/day (r=-0.35, P<0.0001). Young people with HbA(1c) levels <7.5% (58 mmol/mol) vs. values of 7.5-9.0% (58-75 mmol/mol) or ≥ 9.0% (75 mmol/mol) tested blood glucose more frequently/day (P<0.0001), bolused more frequently/day (P<0.0001), reported more grams of carbohydrates eaten/day (P<0.05) and had a higher per cent bolus insulin/day (P<0.05) compared with the ≥9.0% of youth. Using longitudinal data, 48 of 85 patients had a change in HbA(1c) level of ≥0.5% (6 mmol/mol) between downloads (24 improved). Increased bolus insulin (OR=1.15, P=0.03) and time of temporary basal rate use (OR=1.017, P=0.01) predicted ≥0.5% (6 mmol/mol) decrease in HbA(1c) in logistic regression. CONCLUSIONS: This study emphasizes the importance of blood glucose testing, of bolus insulin administration and of an increase in the time of temporary basal rate use in relation to improving glycaemic control.

The effects of different conditions of organ culture on the survival of the mouse pancreas.

The effects of different conditions of organ culture on the viability of murine pancreatic tissues and, particularly, of pancreatic islets, was assessed by morphologic and histochemical analyses. High oxygen tension (1300 mm Hg), found previously to allow successful allogeneic thyroid transplantation, was toxic to pancreatic tissue. Low temperature (22 degrees C) was associated with better islet preservation than high temperature (37 degrees C). Hydrocortisone did not reduce the survival of pancreatic islets and did appear to preserve the acinar components. Fetal and neonatal pancreas responded similarly to the various organ culture conditions. These results have potential importance in guiding future transplantation experiments.

Early exposure to cow's milk and solid foods in infancy, genetic predisposition, and risk of IDDM.

Using a case-control study design, we examined the hypothesis that early exposure to cow's milk and solid foods increased the risk of IDDM. An infant diet history was collected from 164 IDDM subjects from the Colorado IDDM Registry with a mean birth year of 1973, and 145 nondiabetic population control subjects who were frequency matched to diabetic subjects on age, sex, and ethnicity. Early exposure was defined as exposure occurring before 3 mo of age. After controlling for ethnicity, birth order, and family income, more diabetic subjects were exposed early to cow's milk (OR 4.5, 95% CI 0.9-21.4) and solid foods (OR 2.5, CI 1.4-4.3) than control subjects. To examine this association while accounting for the genetic susceptibility to IDDM, we defined individuals as high and low risk by an HLA-DQB1 molecular marker. Early exposure to cow's milk was not associated with elevated risk for IDDM in low-risk individuals. Relative to unexposed low-risk individuals, early exposure to cow's milk was strongly associated in individuals with a high risK marker (OR 11.3, CI 1.2-102.0). Similar findings were observed for early exposure to solid foods. These data indicate that early exposure to cow's milk and solid foods may be associated with increased risk of IDDM. The inclusion of HLA-encoded risk in the analyses demonstrates the combined effect of genetic and environmental factors.

Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies.

Islet cell antibodies (ICAs) are predictive of type I diabetes in first-degree relatives, but this immunohistochemical assay has proven difficult to standardize. As an alternative, we assessed the use of radioassays for antibodies against three molecularly characterized islet autoantigens, including ICA512bdc (amino acid residues 256-979 of the IA-2 molecule, incorporating the intracellular domain). We measured insulin autoantibodies (IAAs), GAD autoantibodies (GAAs), and ICA512bdc autoantibodies (ICA512bdcAAs) by radioassay, in addition to ICAs, in 882 first-degree relatives of patients with type I diabetes, 50 of whom later developed diabetes with a median follow-up of 2.0 years (maximum 11.3 years). The cutoff for each radioassay was determined by testing >200 control subjects. When autoantibody frequencies among the relatives were analyzed according to relationship to the proband, the offspring of diabetic fathers had a higher frequency of ICA5I2bdcAAs (P = 0.008), IAAs (P = 0.0001) and GAAs (P = 0.0001) than the offspring of diabetic mothers. ICA512bdcAAs and IAAs both showed a significant association with HLA-DR4-DQ8 (P = 0.0005). Among relatives developing diabetes, 98% had one or more of IAAs, GAAs, or ICA512bdcAAs, and 80% had two or more of these autoantibodies, compared with none of the control subjects. Using survival analysis to allow for different lengths of follow-up, there was a significant increase in the risk of diabetes with the number of these autoantibodies present, comparing zero, one, two, and three autoantibodies (P < 0.0001, log-rank test), and by Cox regression analysis, this was independent of ICAs and age. For relatives with two or more of these autoantibodies, the risk of diabetes within 3 years was 39% (95% CI, 27-52) and the risk within 5 years was 68% (95% CI, 52-84). Relatives with all three autoantibodies had a risk within 5 years estimated to be 100%. The presence of low first-phase insulin release further increased the risk for relatives with one or two autoantibodies. We conclude that the presence of two or more autoantibodies (out of IAAs, GAAs, and ICA512bdcAAs) is highly predictive of the development of type I diabetes among relatives.

High-normal blood pressure and early diabetic nephropathy.

The relationship between high-normal blood pressure (BP) levels and early diabetic nephropathy is currently unknown. Blood pressure levels were checked longitudinally for a mean of 6.6 years in 230 subjects to determine their relationship to early diabetic nephropathy as monitored by microalbuminuria. High-normal BP level correlated with the presence of microalbuminuria. Microalbuminuria was 2.8 times as common in subjects with high-normal BP levels compared with those subjects with BP levels below the 90th percentile for their age. The elevated microalbumin excretion was primarily associated with high-normal diastolic BP levels. Our data suggest that either microalbuminuria or high-normal BP levels can precede the other. In a logistics model, diastolic BP and mean HbA1 (over 6.6 years) entered the model at similar levels, followed by duration of diabetes. When the influence of mean HbA1 was removed using logistic regression, the diastolic BP level remained a significant associated factor for the presence of microalbuminuria.

Slicing the pie. Correlating HbA--values with average blood glucose values in a pie chart form.

OBJECTIVE: The purpose of this study was to define the correlation between HbA1c values and the percentage of home blood glucose (HBG) measurements within given ranges in a pie chart in three age-groups of subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: HbA1c values were compared with HBG measurements in subjects who did at least three blood glucose tests per day over 30 days in three age groups: 5-11, 12-16, and 17-35 years. The blood glucose values were arbitrarily divided into three groups, defined as the percentage of HBG measurements within, above, and below target range. Each range was then compared with the corresponding HbA1c value. Longitudinal data were also collected for 279 of the subjects after a mean of 139 days. RESULTS: A strong correlation (P = 0.001) was found between HbA1c values and the average blood glucose, and also with the percentage of HBG measurements within, above, and below target range in each of the three age-groups (P < 0.001). Analyses of longitudinal data showed a strong correlation of the changes in HbA1c values to the changes in blood glucose values. CONCLUSIONS: These data showed that a pie-shaped graph of the HBG data can be useful as a clinical parameter in helping patients and families attain desired HbA1c values.

Accuracy of a filter paper method for measuring glycosylated hemoglobin.

OBJECTIVE: To compare glycosylated hemoglobin (GH) results obtained by filter paper fingerstick collection and mailed for assay by affinity chromatography with results from a venous sample assayed by ion-exchange chromatography (HbA1) in a local laboratory. RESEARCH DESIGN AND METHODS: Fifty-eight volunteer subjects with insulin-dependent diabetes mellitus (IDDM), aged 5-24 yr, included patients at a referral-based IDDM clinic and subjects in an ongoing research study. We obtained two blood samples from each subject. One was collected by fingerstick onto filter paper, the other by venipuncture into a vacutainer. We sent filter paper samples to the Diabetes Research Laboratory (Univ. of Missouri, Columbia, MO) for analysis. Vacutainer samples were sent to the Clinical Chemistry Department of the Clinical Laboratory, University of Colorado Health Sciences Center. RESULTS: Results were highly correlated (r = 0.89, P = 0.0001). Fifty-nine percent were classified identically when results were normalized to SD units and grouped to suggest levels of clinical concern. CONCLUSIONS: The filter paper method is a convenient, accurate measure of glycosylated hemoglobin in young people with IDDM. It should be considered a credible alternative research and clinical tool.

Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study.

OBJECTIVE: We undertook this study to test whether Bacillus Calmette-Guerin (BCG) vaccine preserves beta-cell function and increases the remission rate in children with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a randomized double-blind placebo-controlled trial offered to children referred to the Barbara Davis Center for Childhood Diabetes or the Baystate Medical Center with a diagnosis of new-onset type 1 diabetes. There were 94 children aged 5-18 years who received either BCG or saline intradermally within 4 months of onset of symptoms and who were then evaluated at 3-month intervals for 2 years. The primary end point was remission, defined as insulin independence for 4 weeks. Secondary end points were C-peptide levels (fasting and in response to a mixed meal challenge), insulin dose, and HbA1c. RESULTS: Of the patients, 47 were randomized to each arm; 7 in the placebo group and 9 in the BCG group did not complete 1 year of the study and are not included in the analysis. One patient from each group achieved remission. Fasting and stimulated C-peptide levels did not differ by treatment arm but declined in both groups and were lower initially and during the entire 2-year period in younger children. Insulin requirements and HbA1c levels did not differ in the two groups. CONCLUSIONS: Vaccination with BCG at the time of onset of type 1 diabetes does not increase the remission rate or preserve beta-cell function.

The impact of the diabetes control and complications trial and humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes.

OBJECTIVE: This study was performed to determine the effects of the Diabetes Control and Complications Trial (DCCT) report in 1993 and the introduction of Lispro (Humalog) insulin in 1996 on glycemic control and on the number of severe hypoglycemic episodes in type 1 diabetic patients of various ages. RESEARCH DESIGN AND METHODS: Diabetes care parameters and HbA1c data from 884 subjects with type 1 diabetes were entered into our database at the time of clinic visits from 1993 through 1998. In addition, a questionnaire was sent to all patients to validate the number of insulin injections per day, the incidence of severe hypoglycemic episodes (as defined by the DCCT), and the use of Humalog insulin. Data were divided into four age-groups: < 5, 5-12, 13-18, and > 18 years of age. RESULTS: Longitudinal HbA1c levels declined significantly after the DCCT report in 1993-1996 (P < 0.001), but the number of severe hypoglycemic events increased (P < 0.001). A second decline in HbA1c levels was observed after the introduction of Humalog insulin in 1996 (P < 0.001). However, severe hypoglycemic episodes did not change (P = 0.26). CONCLUSIONS: Administration of Humalog resulted in an additional reduction in HbA1c levels beyond the reduction in HbA1c values after the DCCT report. In contrast to the increase in severe hypoglycemic events after the DCCT results, the number of severe hypoglycemic episodes did not increase after the introduction of Humalog, despite a further decrease in HbA1c values.

Clinical characteristics of IDDM in Hispanics and non-Hispanic whites. Little evidence of heterogeneity by ethnicity.

OBJECTIVE: To compare the clinical characteristics of IDDM in HD and NHWD subjects in order to evaluate potential heterogeneity of IDDM by ethnicity. RESEARCH DESIGN AND METHODS: HD subjects (n = 73) and NHWD subjects (n = 97) were recruited from the Colorado IDDM Registry. The registry included individuals who were Colorado residents, less than 18 yr old at diagnosis, placed on insulin within 2 wk of diagnosis, and had diabetes not secondary to other conditions. Residual beta-cell function was measured as the 1-h C-peptide response to a Sustacal challenge. RESULTS: HD subjects were similar to NHWD subjects in insulin dose, HbA1, HLA-DR antigens, ICAs, and family history of IDDM. HD subjects were more likely to have a family history of NIDDM than NHWD subjects (11 vs. 3%, P = 0.03). HD girls had higher C-peptide levels (0.27 vs. 0.11 nm/L [0.83 vs. 0.33 ng/ml], P = 0.01), BMI (22.7 vs. 20.9 kg/m2 P = 0.04), subscapular skinfold thickness (18.9 vs. 15.0 mm, P = 0.04), and WHR (0.81 vs. 0.77, P = 0.03) than NHWD females. After controlling for diabetes duration, BMI, sex, and family history of NIDDM, residual beta-cell function was associated significantly with Hispanic ethnicity, although the term accounted for just 3% of the overall variability in C-peptide levels. CONCLUSIONS: Little evidence of heterogeneity by ethnicity of IDDM patients in the Colorado IDDM Registry was found. Ethnic differences in C-peptide levels may be related to differences in body fat distribution in females rather than heterogeneity of the disease.

Increasing trend of outpatient management of children with newly diagnosed IDDM. Colorado IDDM Registry, 1978-1988.

OBJECTIVE: To examine the management of newly diagnosed insulin-dependent diabetes mellitus (IDDM) in Colorado over time and to determine the prevalence of outpatient care at IDDM diagnosis on a statewide basis. RESEARCH DESIGN AND METHODS: The Colorado IDDM Registry was used to assess medical care at the diagnosis of IDDM in 1182 patients less than 18 yr of age between 1978 and 1988. RESULTS: Twenty-three percent of children with IDDM in Colorado reported never being hospitalized during the diagnosis period. Treatment of IDDM at diagnosis (outpatient vs. inpatient) did not differ by age, sex, or ethnicity/race. Patients living in rural counties were less likely to have been treated as outpatients at diagnosis than those living in urban counties. Physicians at specialized diabetes clinics (e.g., The Barbara Davis Center for Childhood Diabetes and The Childrens Hospital) were more likely to treat newly diagnosed children in an outpatient setting than physicians not affiliated with these clinics. The proportion of patients receiving only outpatient care at IDDM diagnosis increased from 6% in 1978 to 35% in 1988. This increase can be attributed to three factors: 1) an increase in the number of Colorado children diagnosed at The Barbara Davis Center, where outpatient care is strongly advocated; 2) a change in treatment practices at The Childrens Hospital away from routine hospitalization at onset; and 3) a steady increase in outpatient care for newly diagnosed diabetic children by physicians who were not affiliated with the aforementioned specialized diabetes clinics. CONCLUSIONS: The relatively new practice of outpatient care at diagnosis of IDDM increased between 1978 and 1988 in Colorado, in both specialized diabetes clinics and physicians' practices not affiliated with specialized clinics.

Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes.

OBJECTIVE: The purpose of this study was to compare measurements of glucose obtained via iontophoretic extraction with the GlucoWatch automatic glucose biographer (Cygnus, Inc., Redwood City, CA) with capillary blood glucose values that were determined 1) in a controlled outpatient clinic setting and 2) in a home setting. RESEARCH DESIGN AND METHODS: There were 76 GlucoWatch biographers used on 28 different young adults (21 women and 7 men) with type 1 diabetes (age 30.9 +/- 6.9 years and duration of diabetes 18.4 +/- 8.1 years [mean +/- SD]) in a controlled outpatient clinic setting. Some subjects participated on multiple days. Subjects wore two GlucoWatch biographers, each on the forearm (ventral aspect). Comparisons were made to HemoCue blood glucose analyzer (Aktiebolgat Leo, Helsingborg, Sweden) capillary blood glucose measurements. In addition, GlucoWatch biographers (one each day for 3 consecutive days) were used by 12 subjects (8 women, 4 men) in a home setting. Comparisons were made to capillary blood glucose values determined using the One Touch Profile meter (Johnson & Johnson, New Brunswick, NJ). RESULTS: GlucoWatch biographer glucose values correlated well with capillary blood glucose values determined using the HemoCue analyzer in the clinic setting (r = 0.90, 1,554 paired data points) and using the One Touch Profile meter in the home setting (r = 0.85, 204 paired data points). When 36 subjects wore two biographers simultaneously, the correlation between the two biographers was r = 0.94. The error grid analysis demonstrated that > 96% of biographer glucose values determined in the clinic or home setting were in the clinically acceptable A and B regions. CONCLUSIONS: This study confirms the accuracy and precision of glucose values as determined using the GlucoWatch biographer in clinic and home settings.

Colorado IDDM Registry. Incidence and validation of IDDM in children aged 0-17 yr.

The purpose of this study was to determine the incidence of insulin-dependent diabetes mellitus (IDDM) among children aged 0-17 yr for age, sex, season, and urban and rural residence of onset in Colorado. Retrospective registration of new-onset cases was conducted from 1978 to 1980, and then prospective registration continued through 1983 with the use of physician reporting with hospital validation. The annual incidence of IDDM was 15.2/100,000 per year (95% confidence interval [CI] 14.1, 16.3), with little difference between the sexes. The highest incidence was in the 10- to 14-yr age-group for both sexes. There was a seasonal peak of winter onset in those aged 10-17 yr, with similar patterns between sex and ethnic groups. No temporal trend over the 6 yr was seen, although an excess of cases was seen for 15- to 17-yr-old boys in 1980-1982. Rates were similar for urban and rural areas of the state. Case ascertainment was estimated to be 93.2% complete (95% CI 91.5, 95.5). Incidence was similar in Colorado to other populations in the United States at similar latitudes. These data serve as a baseline for evaluation of changes in incidence over time, by region, and for the identification of possible outbreaks.

Colorado IDDM Registry: lower incidence of IDDM in Hispanics. Comparison of disease characteristics and care patterns in biethnic population.

The Colorado IDDM Registry identifies newly diagnosed cases of insulin-dependent diabetes mellitus (IDDM) throughout the state. Hispanics in Colorado are a racial mixture of American Indian and White populations. Because American Indians have a low risk of IDDM, and differing frequencies of HLA antigens and haplotypes are reported for Hispanics and non-Hispanics, we compared incidence rates and disease characteristics. Eligible participants were less than 18 yr of age and Colorado residents at time of diagnosis, diagnosed between 1 January 1978 and 31 December 1983, and on insulin within 2 wk of diagnosis. Subjects were reported by their physicians, and statewide validation of reporting was conducted through review of hospital discharge indexes. Incidence rates for Hispanics (n = 76) were significantly lower than those for non-Hispanics (n = 628), although 95% confidence intervals overlapped for children aged 10-17 yr. Age-adjusted rates were significantly lower in Hispanic than non-Hispanic males, whereas age-adjusted rates for females did not differ. The cumulative risk of IDDM was less for Hispanic males aged 0-17 yr than for non-Hispanic males (P less than .001); cumulative risk among females was males (P less than .001); cumulative risk among females was not different (P = .10). Clinical onset characteristics and medical care at diagnosis were similar. After diagnosis, hospitalizations per 100 person-yr appeared higher in Hispanics, but ketoacidosis and insulin reactions per 100 person-yr were similar. Difference in rate of hospitalizations may have been due to lower response rates among older non-Hispanics.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethnic differences in human leukocyte antigen markers of susceptibility to IDDM.

OBJECTIVE: To determine whether genetic differences explain the lower risk of developing insulin-dependent diabetes mellitus (IDDM) for Hispanic versus non-Hispanic white children in Colorado. RESEARCH DESIGN AND METHODS: Hispanic (n = 62) and non-Hispanic white (n = 82) subjects with IDDM identified from the Colorado IDDM Registry and healthy, nondiabetic control subjects were recruited. Human leukocyte antigen (HLA) serologic typing and sequence-specific oligonucleotide typing of DQA1 and DQB1 alleles were performed. RESULTS: HLA and allele associations with IDDM were similar in both ethnic groups. HLA-DR3 and HLA-DR4 were more common in IDDM subjects in both ethnic groups. Subjects with DQBl alleles encoding aspartic acid (Asp) in position 57 were less likely to have IDDM, irrespective of ethnic background. HLA-DR3 was less common among Hispanic subjects than non-Hispanic white control subjects (4.4 vs. 17.5%, Hispanics vs. non-Hispanic whites, P = 0.04). CONCLUSIONS: These data suggest that the lower prevalence of HLA-DR3 in the Hispanic population, a pattern consistent with the presence of Amerindian admixture, may explain the lower rate of IDDM in the Hispanic population.

Medical care patterns at the onset of insulin-dependent diabetes mellitus: association with severity and subsequent complications.

The hospitalization of a child at the onset of insulin-dependent diabetes mellitus (IDDM) has become routine in many parts of the world, although controversy exists about its necessity. We examined the patterns of medical care use and the prognosis for acute complications after diagnosis for children with newly diagnosed IDDM in Colorado from 1978 to 1982. We reasoned that if children cared for entirely in outpatient settings at diagnosis had no more frequent acute complications after diagnosis than hospitalized children, we would be encouraged to further explore other potential benefits of outpatient care at onset. Twelve percent of 305 children studied statewide received only outpatient care during the first 2 wk after diagnosis, and, prognostically, their subsequent hospitalization and ketoacidosis rates were 2-3.7 times lower than those of children who received any inpatient care. No differences were noted for severe insulin reaction rates. Children classified as "severe" at onset, or with parents of lower education and income, or aged 10-14 yr at onset, regardless of care setting, had 2-4 times higher subsequent acute complication rates after onset than children without these characteristics. These findings, together with data on nights hospitalized and average length of stay in hospital at onset, suggest that a 42% reduction in total nights hospitalized could occur if children with "mild" or "normal" severity at onset were treated largely in the outpatient setting.

Low vitamine A and zinc concentrations in Mexican-American migrant children with growth retardation.

Nutritional evaluations were undertaken on 102 Mexican-American preschool children who were below the 3rd percentile for height, weight, or head circumference. Serum vitamin A concentrations were low in 36 of 102 children (35%). Hair zinc concentrations were low in 28 of 96 children (29%) and plasma zinc concentrations were low in 35 of 94 children (37%). Children with only low height had a mean hair zinc level of 87.5 microgram/g, whereas those with only low weight had a mean level of 108.6 microgram/g and those with only low head circumference had a mean level of 100.1 microgram/g. There was no correlation of height percentiles with plasma zinc, hair zinc, or serum vitamin A. However, further studies are needed to determine if there is a relationship between growth retardation and zinc and/or vitamin A status in this population.

Cholesterol metabolism following portacaval shunt in the pig.

Portacaval shunting resulted in lower serum cholesterol and low density lipoprotein levels in comparison with values for littermate control pigs. Triglyceride levels were lower in the shunted animals only while receiving a low fat diet. The reductions in serum cholesterol and triglyceride levels of shunted pigs while receiving a standard pig diet were shown to be related to reduced hepatic synthesis of cholesterol and triglycerides.

Portacaval shunt as treatment for hypercholesterolemia. Metabolic and morphological effects in a swine model.

Since 1973 the portacaval shunt has been used as a treatment for homozygous familial hypercholesterolemia. Favorable results have been reported, but the mechanism or reduction of cholesterol is not clear. The objective of this research was to evaluate mechanisms of lipid alterations after portacaval shunting in Yucatan miniature swine. The animals were fed a high-fat diet, similar in composition to the average American diet, with or without added cholesterol. Controls were fed the atherogenic diet (+ cholesterol) for 8 months. Pigs were fed atherogenic or American diets for 8 months, then surgery (shunt or sham) was performed. They were continued on the diets for another 8 months. The vascular system was examined for the distribution and severity of atherosclerotic disease. Blood lipids and numerous biochemical indices were measured. Progression of atherosclerosis was slowed by portacaval shunting. Low density lipoprotein (LDL) concentrations were positively and high density lipoprotein (HDL) concentrations were negatively correlated with severity of atherosclerosis. Serum insulin concentrations were positively correlated with atherosclerosis. Cholesterol synthesis was increased by the shunting and decreased by cholesterol feeding. The cholesterol-fed swine is not an adequate model for familial hypercholesterolemia, but the results are consistent with inhibition of the atherosclerotic process and the involvement of lipoproteins and insulin in the mechanisms.