P.J. Kostense

Insulin and Risk of Cardiovascular Disease A Meta-Analysis

BACKGROUND Our purposes were to estimate the strength of the longitudinal relationship between hyperinsulinemia and cardiovascular diseases (CVD) from the available literature and to identify study characteristics that modify this relationship. METHODS AND RESULTS Articles were identified by means of a MEDLINE and Embase search and citation tracking. Eligible studies were prospective population-based cohort studies and nested case-control studies on the relationship between, on the one hand, fasting or nonfasting insulin levels and, on the other hand, myocardial infarction, death from coronary heart disease, and/or ECG abnormalities. Data were extracted pertaining to insulin measurements, type of outcome studied, adjustment for confounding, sex, mean age of the study population, follow-up period, insulin assay, and ethnic background (white or nonwhite). Associations of insulin and CVD were reexpressed in a uniform manner, an estimate of relative risk (RR) and 95% CI, to be used in meta-regression analyses. Twelve of 17 potentially eligible articles provided sufficient information. Overall, a weak positive association was found. The meta-analysis resulted in an estimated summary RR (95% CI) of 1.18 (1.08 to 1.29) for differences in insulin level, equivalent to the difference between the 75th and the 25th percentiles of the general population in The Netherlands. Ethnic background and type of insulin assay modified the relationship between insulin and CVD with borderline significance. CONCLUSIONS Hyperinsulinemia is a weak risk indicator for the occurrence of CVD. The relationship between hyperinsulinemia and CVD was modified by ethnic background and by the type of insulin assay involved.

Hyperhomocysteinemia Is Associated With an Increased Risk of Cardiovascular Disease, Especially in Non–Insulin-Dependent Diabetes Mellitus A Population-Based Study

A high serum total homocysteine (tHcy) level is an independent risk factor for cardiovascular disease. Because it is not known whether the strength of the association between hyperhomocysteinemia and cardiovascular disease is similar for peripheral arterial, coronary artery, and cerebrovascular disease, we compared the three separate risk estimates in an age-, sex-, and glucose tolerance-stratified random sample (n=631) from a 50- to 75-year-old general white population. Furthermore, we investigated the combined effect of hyperhomocysteinemia and diabetes mellitus with regard to cardiovascular disease. The prevalence of fasting hyperhomocysteinemia (>14.0 micromol/L) was 25.8%. After adjustment for age, sex, hypertension, hypercholesterolemia, diabetes, and smoking, the odds ratios (ORs; 95% confidence intervals) per 5-micromol/L increment in tHcy were 1.44 (1.10 to 1.87) for peripheral arterial, 1.25 (1.03 to 1.51) for coronary artery, 1.24 (0.97 to 1.58) for cerebrovascular, and 1.39 (1.15 to 1.68) for any cardiovascular disease. After stratification by glucose tolerance category and adjustment for the classic risk factors and serum creatinine, the ORs per 5-micromol/L increment in tHcy for any cardiovascular disease were 1.38 (1.03 to 1.85) in normal glucose tolerance, 1.55 (1.01 to 2.38) in impaired glucose tolerance, and 2.33 (1.11 to 4.90) in non-insulin-dependent diabetes mellitus (P=.07 for interaction). We conclude that the magnitude of the association between hyperhomocysteinemia and cardiovascular disease is similar for peripheral arterial, coronary artery, and cerebrovascular disease in a 50- to 75-year-old general population. High serum tHcy may be a stronger (1.6-fold) risk factor for cardiovascular disease in subjects with non-insulin-dependent diabetes mellitus than in nondiabetic subjects.

Prevalence and Determinants of Glucose Intolerance in a Dutch Caucasian Population: The Hoorn Study

OBJECTIVE To study the prevalence and determinants of glucose intolerance in a general Caucasian population. RESEARCH DESIGN AND METHODS A random sample of 50- to 74-year old Caucasians (n = 2,484) underwent oral glucose tolerance tests. Multiple regression analyses were performed to study the association of 2-h postload plasma glucose values with potential determinants. RESULTS Prevalence of known and newly detected diabetes and impaired glucose tolerance was 3.6, 4.8, and 10.3%, respectively. In women, but not in men, the association of body mass index with 2-h glucose was fully accounted for by the waist-to-hip ratio. Maternal history of diabetes was twice as prevalent as paternal history, but paternal history only was associated with 2-h glucose. In addition, paternal history was a stronger determinant in men than in women. An independent positive association with 2-h plasma glucose was found for alcohol use of > 30 g/day in women and for intake of total protein, animal protein, and polyunsaturated fatty acids in men. An independent inverse association with 2-h plasma glucose was demonstrated for height (both sexes), alcohol use of ≤ 30 g/day (both sexes), energy intake (in men), and, unexpectedly, current smoking (in men). CONCLUSIONS The prevalence of diabetes in elderly Caucasians was 8.3%. In men, dietary habits may unfavorably influence glucose tolerance independent of obesity.

Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in a general Caucasian population: the Hoorn Study.

SummaryWe studied the intra-individual variation in plasma glucose, specific serum insulin and serum pro-insulin concentrations, measured by two 75-g oral glucose tolerance tests in an age, sex, and glucose tolerance stratified random sample from a 50–74-year-old Caucasian population without a history of diabetes mellitus. The intra-individual variation was assessed by the standard deviation of the test-retest differences (SDdif). For subjects with normal (n=246), impaired glucose tolerance (n=198), and newly detected diabetes (n=80) classified at the first test, the following (SDdif/median level of individual average scores) were found: fasting glucose: 0.4/5.4, 0.5/5.9 and 0.7/7.2 mmol/l; 2-h glucose: 1.3/5.6, 1.8/8.5 and 2.3/12.8 mmol/l; fasting insulin: 23/76, 32/89 and 30/ 116 pmol/l; 2-h insulin: 190/303, 278/553 and 304/626 pmol/l; fasting proinsulin: 4/8, 6/13 and 9/18 pmol/l; 2-h proinsulin: 19/49, 23/84 and 33/90 pmol/l, respectively. In both glucose, proinsulin and insulin concentrations the total intra-individual variation was predominantly determined by biological variation, whereas analytical variation made only a minor contribution. The SDdif can easily be interpreted, as 95% of the random test-retest differences will be less than 2 · SDdif, or in terms of percentage, less than (2 · SDdif/median level of individual average scores) · 100. Therefore, for subjects with normal glucose tolerance, 95% of the random test-retest differences will be less than 15% (fasting glucose), 46% (2-h glucose), 61% (fasting insulin), 125% (2-h insulin), 100% (fasting proinsulin) and 78% (2-h proinsulin) of the median value of the individual average scores. No substantial independent association of either age, gender or obesity with the intra-individual variation in glucose, proinsulin, or insulin concentrations was found.

Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes 5-Year Follow-Up of the Hoorn Study

BACKGROUND A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 (non-insulin-dependent) diabetes mellitus compared with nondiabetic subjects is not known. A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects. We therefore prospectively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality. METHODS AND RESULTS Between October 1, 1989, and December 31, 1991, serum was saved from 2484 men and women, 50 to 75 years of age, who were randomly selected from the town of Hoorn, The Netherlands. Fasting serum tHcy concentration was measured in 171 subjects who died (cases; 76 of cardiovascular disease) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. The prevalence of hyperhomocysteinemia (tHcy >14 micromol/L) was 25. 8%. After adjustment for major cardiovascular risk factors, serum albumin, and HbA(1c), the odds ratio (95% CI) for 5-year mortality was 1.56 (1.07 to 2.30) for hyperhomocysteinemia and 1.26 (1.02 to 1. 55) per 5-micromol/L increment of tHcy. The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 (0.87 to 2.06) in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects (P=0.08 for interaction). CONCLUSIONS Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects.

Symptoms and well-being in relation to glycemic control in type II diabetes

OBJECTIVE To describe the cross-sectional relation between glycemic control and physical symptoms, emotional well-being, and general well-being in patients with type II diabetes. RESEARCH DESIGN AND METHODS The study population consisted of 188 patients with type II diabetes between 40 and 75 years of age. Patients were treated with blood glucose-lowering agents or had either a fasting venous plasma glucose level ≥7.8 mmol/l or an HbA1c level > 6.1%. Multiple regression analyses were performed. Dependent variables were scores on the Type II Diabetes Symptom Checklist, the Profile of Mood States, the Affect Balance Scale, and questions regarding general well-being. The primary determinant under study was HbA1c. In addition, age, sex, neuroticism (indicating a general tendency to complain), insulin use, and comorbidity were included as determinants in all analyses. Other potential determinants taken into consideration were hypoglycemic complaints, marital status, diabetes duration, cardiovascular history, blood pressure, BMI, waist-to-hip ratio, perceived burden of treatment, and smoking. None of these potential determinants had to be included to correct confounding of the relation between HbA1c and well-being scores. RESULTS Higher HbA1c levels were significantly associated with higher symptom scores (total score, hyperglycemic score, and neuropathic score), with worse mood (total score, displeasure score, depression, tension, fatigue), and with worse general well-being. The relative risks varied between 1.02 and 1.36 for each percentage difference in HbA1c. The relation between HbA1c and some mood states was modified by neuroticism: in the less neurotic patient (i.e., one who is less inclined to complain), the relation was more evident. CONCLUSIONS These data suggest that better glycemic control in type II diabetes is associated with fewer physical symptoms, better mood, and better well-being, in a nonhypoglycemic HbA1c range.

Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease

Context The value of adding HLA genetic typing to serologic testing for celiac disease is not well defined. Contribution In this prospective study of patients referred for evaluation of celiac disease, the test performance of combinations of genetic typing and serologic testing was similar to that of either strategy alone. Caution The small number of cases of celiac disease precluded meaningful comparisons of testing strategies. Implications The combination of genetic typing and serologic testing is about as accurate as either strategy alone. Neither is a substitute for small-bowel biopsy in the diagnosis of celiac disease. The Editors The high prevalence and clinical heterogeneity of celiac disease necessitate noninvasive tests for diagnosis. Specifically, tests are needed to select which patients should undergo small-bowel biopsy. Although celiac disease serologic tests, especially IgA tissue antitransglutaminase antibodies (TGA) and IgA antiendomysium antibodies (EMA), are often used for this purpose because of their reported high sensitivity (1), they may perform less well in the clinical setting (2). Most studies have not defined the usefulness of serologic tests prospectively (37), and in addition, some authors doubt the high sensitivity of these tests (8, 9). Susceptibility to celiac disease is related to the presence of distinct HLA-DQ heterodimersthe DQ2 heterodimer encoded by the alleles HLA-DQA1*05 and HLA-DQB1*02, and the DQ8 heterodimer encoded by the alleles HLA-DQA1*03 and HLA-DQB1*0302 (1014). One way to improve the selection of patients to undergo small-bowel biopsy may be to combine serologic tests with HLA-DQ typing (15, 16). We designed a prospective study to define the value of specific serologic tests, HLA-DQ typing, or both in diagnosing celiac disease. Methods The institutional review board of the VU University Medical Center, Amsterdam, the Netherlands, approved the study protocol. All participants received oral and written information according to the usual recommendations for medical research and the Declaration of Helsinki (17) and gave written informed consent. Patients The study was performed in an academic, mixed secondary and tertiary referral center that serves a population of about 200000 people. In the design phase of the study (19992000), the staff of departments of internal medicine and gastroenterology reviewed the literature and agreed that serologic tests could not substitute for small-bowel biopsy in the diagnostic work-up of celiac disease. Therefore, the policy was to perform small-bowel biopsy when celiac disease was suspected. Adults suspected of having celiac disease who were attending the endoscopy department for small-bowel biopsy were requested to give blood samples for serum antibody testing and HLA-DQ typing. We excluded patients younger than 18 years of age, those with known celiac disease, and patients who declined to undergo endoscopy. Endoscopy We performed upper gastrointestinal endoscopy with Olympus video endoscopes (GIF-NT140/160, Olympus Nederland, Zoeterwoude, the Netherlands) and obtained 4 oriented biopsy specimens from the distal duodenum (18). Serum Antibody Tests We performed serologic tests after obtaining small-bowel biopsy specimens in all patients to avoid referral bias. All serologic tests were determined anonymously without knowledge of the clinical status or histologic result. We determined IgA and IgG antigliadin antibodies (AGA-IgA and AGA-IgG, respectively) by using enzyme-linked immunosorbent assay (ELISA). We tested for EMA according to the method of Lerner and colleagues (19) by indirect immunofluorescence assay using monkey esophagus (16). Finally, TGA was determined by ELISA, essentially as described by Dieterich and colleagues (20), with guinea pig TGA (gp-TGA) (Sigma-Aldrich, Poole, United Kingdom; coating 10 g/mL in Tris hydrochloride [pH, 7.5] with 5-mmol/L of CaCl2) as the substrate (20). Sera were diluted and preincubated (30 minutes at room temperature) with 1% bovine serum albumin to avoid nonspecific binding (16, 21). The cutoff values for the titers of AGA and gp-TGA tests are based on measurements in control groups (blood donors, patients without celiac disease, and the general population age 2 to 4 years), and optimization was done by a receiver-operating characteristic curve analysis in well-defined patient groups. Because the recombinant human TGA (rh-TGA) assay became available when the study was already ongoing, we retrospectively reevaluated all samples from patients with an abnormal result on serologic testing or histologic examination by using rh-TGA as substrate (Roboscreen, Leipzig, Germany; coating 5 g/mL and same conditions as those for gp-TGA). When serologic test results did not match histologic findings, we measured total serum IgA and repeated the serologic tests. In cases of IgA deficiency, we evaluated TGA-IgG antibodies. We defined seropositivity as 1 or more positive measured antibody test results and seronegativity as negative results on all 4 tests. HLA-DQ Typing Whole blood was obtained for HLA-DQA1 and HLA-DQB1 genotyping. Polymerase chain reactionamplified exon 2 amplicons were generated for low- to medium-resolution typing in a combined, single-stranded conformation polymorphismheteroduplex assay by a semiautomated electrophoresis and gel-staining method on the PhastSystem (Amersham Pharmacia Biotech, Uppsala, Sweden). Alleles DQA1*05 and DQB1*02 (encoding the HLA-DQ2 heterodimer) and alleles DQA1*03 and DQB1*0302 (encoding the HLA-DQ8 heterodimer) could be reliably characterized in homozygous and heterozygous states. This method has been validated by using a panel of reference DNA against the Dynall Allset sequence-specific primers high-resolution typing kits (Dynal A.S., Oslo, Norway) (16, 22). Histologic Studies A gastrointestinal pathologist who was masked to clinical data evaluated the biopsy material, and an independent pathologist reviewed the samples when histologic examination was abnormal. Consensus was reached on the final diagnosis. Villous (crypt) anatomy and density of intraepithelial lymphocytes were assessed uniformly by using hematoxylineosin and immunohistologic anti-CD3 staining, respectively. Appendix Figures 1 and 2 show the histologic grading of abnormalities, based on the most severe change found according to the modified Marsh classification (23, 24). Appendix Figure 1. Small-bowel histologic findings (Marsh 0 to II). A. B. C. Appendix Figure 2. Small-bowel histologic findings (Marsh IIIa to IIIc). A. B. C. Diagnosis and Follow-up of Celiac Disease The diagnosis of celiac disease was based on the European Society for Paediatric Gastroenterology, Hepatology and Nutrition criteria, revised in 1989 and published in 1990, by identifying characteristic histologic findings (Marsh III) on small-bowel biopsy and unequivocal clinical resolution after a gluten-free diet was initiated (25). Thus, by this definition and for this study, the diagnosis of celiac disease did not require follow-up biopsy. However, we assessed histologic response in most patients and serologic response in all patients who were found to have celiac disease. We defined a serologic response as the disappearance of initially positive celiac disease antibody test results and histologic response as the regression of villi to Marsh 0 to II on a repeated biopsy at least 12 months after a gluten-free diet was initiated (24). Statistical Analysis We compared results of serologic tests and HLA-DQ typing with the diagnosis of celiac disease as previously defined. We performed statistical analysis by using SPSS software, version 11.0 (SPSS, Chicago, Illinois). To calculate exact binomial CIs, we used StatXact software, version 7.0.0 (Cytel Software, Cambridge, Massachusetts). We used 2 2 tables (Bayes theorem) to calculate sensitivities and specificities, predictive values, and likelihood ratios. We used the t test and Fisher exact test to compare continuous data and categorical data, respectively. We calculated posttest probabilities (and CIs) of celiac disease for different diagnostic tests or a combination thereof by using the method recommended by Altman (26). Role of the Funding Source The study received no funding. Results Patients Between January 2001 and January 2004, 502 consecutive patients (originally from community practices in the Amsterdam area) were referred from outpatient internal medicine and gastroenterology clinics for endoscopy and small-bowel biopsy for the diagnosis of celiac disease. Another 16 inpatients were referred from the internal medicine and gastroenterology inpatient wards. No referred patient was under the care of the investigators. We excluded 55 (10.6%) patients because they declined to participate in the study after the small-bowel biopsy. Age, sex, body mass index, ethnicity, and indications for referral did not statistically significantly differ between those included in and those excluded from the study (data not shown). The available serologic data (n = 20), HLA-DQ data (n = 4), and histologic examinations (n = 55) suggested the absence of celiac disease in excluded patients. Therefore, 463 patients were included in the study: 346 (75%) were unrelated Dutch Caucasian persons and 117 (25%) were not Caucasian (Indian, Chinese, North African [Arab], and Central African [black], in descending order of frequency). All patients were on a normal diet at the time of inclusion. Table 1 summarizes the general characteristics and indications for small-bowel biopsy of patients without and with celiac disease. Table 1. Characteristics of and Indications for Referral in Patients without and with Celiac Disease Patients with Celiac Disease Of the 463 patients enrolled, 16 (3.46% [95% CI, 1.99% to 5.55%]) fulfilled the diagnostic criteria for celiac disease (Figure) (25) within a median follow-up interval of 22 months (range, 11 to 44 months). Biopsy readings of the 2 pathologists were concor

Rates and risks for co-morbid depression in patients with Type 2 diabetes mellitus: results from a community-based study

Aims/hypothesisThere is accumulating evidence that depression is common in people with Type 2 diabetes. However, most prevalence-studies are uncontrolled and could also be inaccurate from selection-bias, as they are conducted in specialized treatment settings. We studied the prevalence and risk factors of co-morbid depression in a community-based sample of older adults, comparing Type 2 diabetic patients with healthy control subjects.MethodsA large (n=3107) community-based study in Dutch adults (55–85 years of age) was conducted. Pervasive depression was defined as a CES-D score greater than 15. Diagnosis of Type 2 diabetes was obtained from self-reports and data from general practitioners.ResultsA number of 216 patients (7%) were identified as having Type 2 diabetes. The prevalence of pervasive depression was increased in people with Type 2 diabetes and co-morbid chronic disease (20%) but not in patients with Type 2 diabetes only (8%), compared with the healthy control subjects (9%). Regression analyses in diabetic patients yielded that being single, being female, having functional limitations, receiving instrumental support and having an external locus of control were associated with higher levels of depression.Conclusions/interpretationThe Results suggest that the prevalence of pervasive depression is increased in patients with Type 2 diabetes and co-morbid disease(s), but not in patients with Type 2 diabetes only. Functional limitations that often accompany co-morbid chronic disease could play an essential role in the development of depression in Type 2 diabetes. These findings can enable clinicians and researchers to identify high-risk groups and set up prevention and treatment programs.

Diabetes, pulse pressure and cardiovascular mortality: the Hoorn Study

Objective Type 2 diabetic patients have an increased arterial stiffness and a very high risk of cardiovascular death. The present study investigated the relationship between pulse pressure, an indicator of vascular stiffness, and risk of cardiovascular mortality among type 2 diabetic and non-diabetic individuals. Second, we determined the relationship between pulse pressure and its main determinant (i.e. age), and the influence of diabetes and mean arterial pressure on this relationship. Design and methods We studied a cohort of 2484 individuals including 208 type 2 diabetic patients. Mean age and median follow-up for non-diabetic and diabetic individuals, respectively, were 61 and 66 years, and 8.8 and 8.6 years. One-hundred and sixteen non-diabetic and 34 diabetic individuals died of cardiovascular causes. Relative risks of cardiovascular mortality were estimated by Cox proportional hazards regression adjusted for age, gender and mean arterial pressure. Results Pulse pressure was associated with cardiovascular mortality among the diabetic, but not among the non-diabetic individuals [adjusted relative risk (95% confidence interval) per 10 mmHg increase, 1.27 (1.00–1.61) and 0.98 (0.85–1.13), P interaction = 0.07]. Further adjustment for other risk factors gave similar results. The association, at baseline, between age and pulse pressure was dependent on the presence of diabetes (P interaction = 0.03) and on the mean arterial pressure (P interaction < 0.001) (i.e. there was a stronger association when diabetes was present and when mean arterial pressure was higher). Conclusions We conclude that, in type 2 diabetes, pulse pressure is positively associated with cardiovascular mortality. The association between age and pulse pressure is influenced by the presence of type 2 diabetes and by the height of the mean arterial pressure. These findings support the concept of accelerated vascular aging in type 2 diabetes.

Performance of an NIDDM Screening Questionnaire Based on Symptoms and Risk Factors

OBJECTIVE To investigate to what extent a short questionnaire on symptoms and risk factors can be used to identify people at increased risk for undiagnosed NIDDM. RESEARCH DESIGN AND METHODS A general population sample of 2,364 Caucasian subjects, age 50–74 years, not known to have diabetes, completed a questionnaire on diabetes-related symptoms and risk factors. Subsequently, they underwent an oral glucose tolerance test. A backward stepwise multiple logistic regression was carried out with the absence or presence of newly detected diabetes as the dependent variable and the items from the questionnaire as the independent variables. The selected items were included in a new symptom risk questionnaire, which was evaluated in a different population sample of 786 subjects, age 45–74 years, not known to have diabetes and compared with existing questionnaires. RESULTS The newly developed symptom-risk questionnaire contains questions concerning the following items, which were independently and significantly (P < 0.05) associated with the presence of previously undiagnosed diabetes: pain during walking with need to slow down, shortness of breath when walking with people of the same age, frequent thirst, age, sex, obesity, parent or sibling with diabetes, use of antihypertensive drugs, and reluctance to use a bicycle for transportation. The 1993 American Diabetes Association questionnaire, the 1995 Herman et aL (17) questionnaire, and the newly developed symptom-risk questionnaire had sensitivities of 59, 72, and 72%; specificities of 57, 55, and 56%; positive predictive values of 5.6, 6.4, and 6.5%; and negative predictive values of 97, 98, and 98%, respectively. CONCLUSIONS The newly developed symptom-risk questionnaire has good performance characteristics, and the advantage of a variable cutoff makes it a useful screening tool for NIDDM in general practice.