Quantification of concordance and discordance between apolipoprotein-B and the currently recommended non-HDL-cholesterol goals for cardiovascular risk assessment in patients with diabetes and hypertriglyceridemia.

AIMS: In patients with diabetes and hypertriglyceridemia, LDL-cholesterol (LDL-C) provides an inaccurate reflection of LDL particle burden. The relative value of non-HDL-cholesterol (non-HDL-C) and apolipoprotein-B (Apo-B) in estimating cardiovascular risk is controversial. We assessed the discordance between non-HDL-C and Apo-B targets in patients with diabetes with TG 200-499 mg/dl. METHODS: Data from 1430 determinations of LDL-C, non-HDL-C, and Apo-B in ambulatory patients with diabetes were analyzed. Rates of discordance were calculated, based on the currently recommended LDL-C, non-HDL-C, and Apo-B goals. RESULTS: In patients with non-HDL-C goal of <130 mg/dl, there was a discordance with Apo-B level goal of <90 mg/dl, in 31% of samples. In patients with non-HDL-C goal of <100 mg/dl, 6% of samples had Apo-B ≥80 and 18% had Apo-B <80 mg/dl. Using the Apo-B goal of <70 mg/dl, these numbers were 37% and 3.5% respectively. There was also a significant gender difference, i.e. under-estimation of risk by suggested non-HDL-C cut-offs, in females, compared to males. CONCLUSIONS: In patients with diabetes and hypertriglyceridemia, a considerable discordance exists between non-HDL-C and Apo-B. Our data suggest a need for prospective studies to compare the relative merits of non-HDL-C and Apo-B targets in the assessment of cardiovascular risk.

Management of patients with diabetes and "abnormal" blood pressure: selection of antihypertensive agents.

OBJECTIVE: To characterize the association of diabetes and hypertension and to discuss management strategies. METHODS: Published studies are summarized and various hypotheses are reviewed. RESULTS: Hypertension is a major determinant of the increased cardiovascular, peripheral vascular, and renal complications associated with diabetes. Recent evidence indicates that insulin resistance is one of the multiple key components of the pathophysiologic elements underlying the increased prevalence of hypertension associated with diabetes. In patients with diabetes, management of hypertension is frequently complicated by the coexistence of other macrovascular risk factors, including dyslipidemia, obesity, visceral adiposity, and poor glycemic control. The choice of antihypertensive agents in both type I and type II diabetes must be based on the selective metabolic, hormonal, and hemodynamic advantages and disadvantages of these agents in individual patients. CONCLUSION: Long-term trials are needed to determine the benefits, if any, of various angiotensin-converting enzyme inhibitors, calcium channel antagonists, and alpha1-adrenergic receptor antagonists in preventing the cardiovascular and the renal complications of diabetes.

Efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia.

PURPOSE: Patients with type I and type II diabetes mellitus have an increased risk of coronary heart disease. In many diabetics, hypercholesterolemia is present and further exacerbates this risk. We investigated the efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia. PATIENTS AND METHODS: In this 24-week, multi-center, double-blind, placebo-controlled study, 94 patients (45 men, 49 women), 18 to 70 years of age, with type I or type II diabetes mellitus and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol [LDL-C] levels > 150 mg/dL and above the 75th percentile for the US population by age and gender) were randomized to receive pravastatin 20 mg hs or matching placebo. Two patients were randomized to treatment with drug for every 1 randomized to placebo. The dose could be doubled after 10 weeks, and cholestyramine or colestipol could be added after 18 weeks, as needed, to attempt to lower the LDL-C levels to below the 50th percentile for the US population. RESULTS: Significant reductions in LDL-C (-27.6%), total cholesterol (-22.1%), very-low-density lipoprotein cholesterol (-22.6%), and triglycerides (-12.8%) (P < or = 0.001 versus placebo for all reductions), and significant increases in high-density lipoprotein cholesterol (4.4%) (P < or = 0.05 versus placebo) were noted in the pravastatin treatment group (average dose 29.5 mg) at 16 weeks. The beneficial lipid-lowering effects of pravastatin were maintained throughout the 24 weeks of the study. Pravastatin was well tolerated, and the frequency of side effects was similar in the pravastatin and placebo groups. No clinically significant changes in the control of diabetes, as assessed by fasting blood glucose levels and glycosylated hemoglobin measurements, were seen during this study. CONCLUSION: The results of this study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with type I or type II diabetes mellitus and hypercholesterolemia.

Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes.

OBJECTIVE: To evaluate the determinants of elevated fibrinogen levels and the impact of hyperfibrinogenemia on vascular complications in diabetes. RESEARCH DESIGN AND METHODS: Plasma fibrinogen, glucose, HbA1, and lipids were measured in 116 ambulatory type I and type II diabetic patients with (n = 59) or without (n = 57) clinical evidence of micro- or macrovascular complications. In 56 of these patients, factor VII activity and CRP also were measured. Univariate and multivariate data analyses were conducted. RESULTS: Overall mean +/- SE fibrinogen levels in patients (339 +/- 7.3 mg/dl) were elevated markedly compared with control subjects (248 +/- 9.1 mg/dl). Fibrinogen levels were elevated disproportionately in patients with type II diabetes (P less than 0.0001), hypertension (P = 0.0001), obesity (P less than 0.0001), and vascular complications (P less than 0.0001). Fibrinogen was correlated significantly with age (P less than 0.001), cholesterol (P = 0.002), CRP (P less than 0.001), and factor VII activity (P = 0.032), but not with plasma glucose, triglycerides, HDL cholesterol, or disease duration. Stepwise multiple regression analyses revealed that type II diabetes and presence of vascular complications were major determinants of fibrinogen. For vascular complications, fibrinogen emerged as one of only three independent predictors, the other two being diabetes duration and hypertension.

Coronary artery disease is the major determinant of excess mortality in patients with insulin-dependent diabetes mellitus and persistent proteinuria.

The goal of this review was to assess the magnitude of coronary artery disease (CAD) mortality and its determinants in insulin-dependent diabetes mellitus (IDDM) patients with persistent proteinuria. By reanalyzing data from two previously published studies of patients with nephropathy, it was found that these patients had extremely high CAD mortality rates in comparison with IDDM patients without proteinuria, but only after the age of 35 yr. In addition, the risk of CAD death was associated with high serum cholesterol levels but was unrelated to systemic blood pressure, smoking habits, and obesity. Further studies of the determinants of CAD in patients with IDDM and proteinuria are urgently needed. Except for efforts to lower serum cholesterol, it is not known whether any other measure can be undertaken to reduce the extremely high mortality due to CAD that afflicts IDDM patients with persistent proteinuria, in particular those patients whose renal failure might have been "successfully" postponed by antihypertensive therapy.

Different effects of duration on prevalence of anti-adrenal medullary and pancreatic islet cell antibodies in type I diabetes mellitus.

Autoimmunity is a known factor in the pathogenesis of islet cell destruction, but little is known of its role in the pathogenesis of the neuronal complications of diabetes. We carried out a cross-sectional study of 94 subjects with Type I diabetes mellitus (DM) to examine the relationship between duration and presence of complement fixing anti-adrenal medullary antibodies (CF-ADM). CF-ADM were present in 19% of subjects (n = 62) with duration of DM less than or equal to 16 years and 3% of subjects (n = 32) with duration of DM greater than 16 years. All subjects with CF-ADM+ and duration of DM 0-5 years (n = 7) were islet cell antibody positive (ICA+). Among subjects with duration of DM 6-16 years who were CF-ADM+, 4 of 5 subjects were ICA- and 1 of 5 subjects was ICA+. The only CF-ADM+ subject with duration of DM greater than 16 years was ICA-. Absorption of ADM+ and ICA+ sera with upper phase glycolipid extract blocks ICA but not ADM binding to tissue. This study suggests: 1) CF-ADM positivity is associated with ICA positivity in subjects with duration of DM 0-5 years. CF-ADM positivity persists after 5 years duration of DM when islet cell antibodies have disappeared. Therefore, the antigenic target of the adrenal medulla and pancreatic islets may be different. 2) There is an increased prevalence of CF-ADM in subjects with duration of DM 0-16 years (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-fetoprotein associated with islet cell tumors.

Elevated serum levels of alpha-fetoprotein (AFP) (100-1,000 ng/ml) were found in three patients with islet cell tumors. Serial levels correlated with progression of disease, suggesting that AFP could be a useful tumor marker substance for islet cell tumors. Survey sera from an expanded pool of 23 patients with islet cell tumors and nine with carcinoid tumors did not identify additional cases, however, suggesting that elevated AFP levels in these classes of Apudomas are uncommon. Nonetheless, the distinction from other AFP-producing tumors such as hepatocellular carcinoma is clinically important and warrants an awareness of the rare association of AFP with these tumors.

Diminished A-cell secretion in the early phase of type I diabetes mellitus.

The A-cell function in "true pre-type I diabetes" or in early phase of type I diabetes has not been reported. We studied A-cell reserve in response to intravenous arginine infusion in six individuals characterized by type I diabetes-associated immunologic defects and absent first-phase insulin secretory response to intravenous glucose prior to development of diabetes. The peak glucagon response in these patients was markedly impaired (153 +/- 39 pg/mL, mean +/- SEM) compared to a group of 23 normal, healthy controls (301 +/- 18; P less than 0.01) and a group of 11 healthy, discordant monozygotic twins of type I diabetic patients (250 +/- 25, P less than 0.05). The glucagon concentrations in response to oral glucose were completely suppressed to undetectable levels in three of the patients studied. In view of the well-known observations of insulitis in the prediabetic phase in man and in experimental models of type I diabetes and anti-islet cytoplasmic antibodies directed against all islet cells, our observations suggest an impairment of A-cells during the evolution of type I diabetes.

Acquired defect in interleukin-2 production in patients with type I diabetes mellitus.

Deficient production of interleukin-2 has been reported in Type I diabetes, but its cause has not been elucidated. We therefore measured interleukin-2 production in 27 patients with Type I diabetes, 20 patients with Type II diabetes (6 requiring insulin), 5 monozygotic twin pairs discordant for Type I diabetes, and 10 nondiabetic persons with islet-cell antibodies. Interleukin-2 production was decreased in patients with Type I diabetes as compared with controls (35.8 +/- 2.5 vs. 61.6 +/- 4.6 percent, P less than 0.001). Interleukin-2 production did not differ between patients with Type II diabetes and controls, regardless of whether the patients used insulin. Twins with Type I diabetes had decreased interleukin-2 production as compared with normal controls (33.2 +/- 5.4 vs. 61.6 +/- 4.6 percent, P less than 0.001) and with their nondiabetic twins (33.2 +/- 5.4 vs. 54.5 +/- 3.4 percent, P less than 0.005). Interleukin-2 production in nondiabetic twins and in nondiabetic persons with islet-cell antibodies was normal. There was no correlation between glycosylated hemoglobin levels and interleukin-2 production in any diabetic group. We conclude that patients with Type I diabetes have an acquired defect in interleukin-2 production, whereas patients with Type II diabetes do not, and that this defect is not correlated with an ongoing autoimmune process, with hyperglycemia, or with insulin administration or oral hypoglycemic therapy. Thus, the defect appears to be related to marked beta-cell destruction, although not to the metabolic consequences thereof or the responsible autoimmune process.

Progressive autoimmune beta cell insufficiency: occurrence in the absence of high-risk HLA alleles DR3, DR4.

In a prospective screening program for type I diabetes mellitus, we identified a unique family in which several members (mother and three siblings) expressed an unusual set of HLA-DR alleles (DR2+, DR3/4-) and were in different phases of immunologically mediated islet beta cell dysfunction. Immunologic and/or clinical manifestations of type I diabetes were absent in all siblings not sharing both HLA haplotypes in common with the proband. This article illustrates: the clinical utility of prospective family screening for predictive markers, such as islet cell antibodies, progressive autoimmune beta cell destruction can occur in the absence of the "high-risk" alleles HLA-DR3 and DR4, and HLA identity with the proband, rather than specific HLA alleles, i.e., presence of DR3, DR4 and absence of DR2, is an essential factor.

First-degree relatives of patients with type I diabetes mellitus. Islet-cell antibodies and abnormal insulin secretion.

In a prospective study to evaluate the prevalence and predictive potential of circulating islet-cell antibodies, we have screened 1723 "normal" first-degree relatives (parents, siblings, and offspring) of patients with insulin-dependent diabetes mellitus. The prevalence of islet-cell antibodies on initial screening was 0.9 per cent (16 of 1723). Over a maximal follow-up period of two years, insulin-dependent diabetes mellitus developed in 2 of 16 relatives with islet-cell antibodies and in 1 of 1707 without antibodies. In addition, 6 of 12 nondiabetic relatives with islet-cell antibodies had abnormally low insulin responses--below the third percentile in 6 and below the first percentile in 4--on their initial intravenous glucose challenge. Thus, prospective islet-cell antibody screening of high-risk first-degree relatives, in combination with intravenous glucose-tolerance testing, is capable of identifying immunologically abnormal persons with profoundly diminished beta-cell function, who are presumably at increased risk of insulin-dependent diabetes mellitus.

Alterations in plasma lipids in the presence of mild glucose intolerance in the offspring of two type II diabetic parents.

Plasma lipids and oral glucose tolerance were determined in 67 normal control subjects (age range 19-67 yr) and 150 individuals (17-69 yr) who were offspring of two type II diabetic parents. Age- and weight-adjusted analyses of covariance were performed for lipids and for glucose and insulin responses. For both men and women, the mean concentrations of total, low-density-, and high-density-lipoprotein-cholesterol and of triglycerides in the offspring with normal glucose tolerance (N = 109) were similar to respective controls. For offspring with abnormal glucose tolerance (N = 41), the mean levels of total cholesterol, LDL-cholesterol, and triglycerides were significantly elevated (P = 0.02 or less) in women but not in men. The mean HDL-cholesterol levels were 20% lower and LDL/HDL-cholesterol ratios 60% greater in women with abnormal glucose tolerance, whereas no significant differences existed for any of the lipid fractions in men, compared with respective controls. Both men and women with abnormal glucose tolerance had a comparable magnitude of hyperglycemia as well as hyperinsulinemia. These observations indicate that significant alterations in plasma lipids exist in individuals with mild, asymptomatic glucose intolerance and there are important sex differences in lipid metabolism in the early stage of diabetes, despite comparable degrees of glucose intolerance and insulin responses.

Pre-type I diabetes. Linear loss of beta cell response to intravenous glucose.

Twenty-one intravenous (i.v.) glucose tolerance tests were performed on nine subjects before the onset of overt type I diabetes mellitus. Islet cell antibodies (6 of 9 subjects) and elevated levels of Ia-positive T-lymphocytes (3 of 3 subjects studied) were detected during the prediabetic period. Elevations of fasting blood glucose and peak glucose during oral glucose tolerance tests were not observed until the year before onset of clinically overt diabetes. During the prediabetic period, there was a progressive loss of early-phase insulin release to i.v. glucose (rate of decline, 20-40 microU/ml insulin release/yr; correlation coefficient, 0.9).

Pre-type 1 (insulin-dependent) diabetes: common endocrinological course despite immunological and immunogenetic heterogeneity.

In an ongoing prospective study 32 individuals have been evaluated for insulin secretory dynamics, islet cell antibodies and HLA antigens, during the preclinical phase of Type 1 diabetes mellitus. Twenty-four out of the 32 subjects were islet cell antibody-positive. To date, 14 subjects (10 islet cell antibody-positive, four islet cell antibody-negative) have progressed to develop overt diabetes. Several patterns of HLA-DR expression were noted (DR3/DR4, DR3/DR3, DR3/x, DR3/DR1, DR4/x, DR4/DR7, DR5/DR7, DR1/DR7 and DR1/DR2). Irrespective of differences in islet cell antibody status or HLA-DR alleles, pre-diabetic individuals exhibited a similar slow course of progressive beta-cell dysfunction.