P.A. Grootenhuis

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.

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.

Development of a Type 2 Diabetes Symptom Checklist: a Measure of Symptom Severity

The aim of the present study was to develop a Type 2 diabetes symptom checklist for use in clinical and epidemiological research, which can measure differences in symptom severity between patients and detect changes over time within patients. Face and content validity of items and dimension structure were based on literature and experiences of diabetologists. Two Likert scales were used to measure symptom frequency and perceived burden. Reliability, responsiveness and validity were studied in 185 Type 2 diabetic patients. Factor‐analysis confirmed the predesigned dimension structure with 34 items, distributed over 6 dimensions. The internal consistency with Cronbach α coefficients between 0.76 and 0.95 and test‐retest reliability with Pearson product‐moment correlation coefficients between 0.79 and 0.94 were satisfactory. The ability to detect change over time (responsiveness) was estimated in stable subjects, using sample size calculations. A minimal detectable mean change of 0.07‐0.58 points in total score on the 10‐point scale within a group of 100 subjects suggests an impressive responsiveness. Significant differences in symptom severity score were found between patients with different co‐morbidity status and treatment modes, indicating satisfactory construct validity of the dimension structure. The Type 2 Diabetes Symptom Checklist was found to be a useful diabetes‐specific symptom severity assessment method for clinical and epidemiological studies.

A semiquantitative food frequency questionnaire for use in epidemiologic research among the elderly: validation by comparison with dietary history.

A self-administered semiquantitative food frequency questionnaire including 75 food items and providing information on the habitual intake of 31 nutritional parameters, based on the intake of protein, fat, carbohydrate, fiber and 11 vitamins and minerals, was developed for use in epidemiologic research on chronic disease among the elderly, such as diabetes and cardiovascular disease. By means of detailed frequency and quantity questions, specifications of types of food, preparation methods and seasonal variation, the questionnaire was expected to be an improvement on existing instruments. The relative validity of the questionnaire was examined in 74 men and women, aged 50-75, by comparison with a modified dietary history. Systematic differences were absent or negligible for all nutrients, except vitamin C. Bias depending on the level of intake could be ruled out for all but seven nutrients. Pearson correlation coefficients for estimates from the questionnaire and dietary history were on average 0.71 (range: 0.65-0.78) and 0.66 (range: 0.36-0.81) for macronutrients, and vitamins and minerals, respectively. Classifying individual intake estimates into tertiles of the distribution for both methods, on average 62.4 and 54.7% of the intakes were categorized into the same tertile and 3.9 and 5.9% into the opposite tertile for macronutrients, vitamins and minerals, respectively. These results demonstrate an acceptable relative validity for this newly developed questionnaire, as compared to the dietary history method.

Methods for assessing diabetic polyneuropathy: validity and reproducibility of the measurement of sensory symptom severity and nerve function tests.

The usefulness of sensory symptoms in the assessment of diabetic polyneuropathy is unclear. In the present study, we studied the hypothesis that pain is associated with small nerve fibre function, and that sensory alteration is associated with large nerve fibre function. In addition, we assessed the reproducibility and the ability to detect changes in clinical status over time of the nerve function tests currently used in clinical trials. Patients (78) with stable diabetic polyneuropathy were examined on three separate occasions with a test-retest interval of 17 and 52 weeks. Small nerve fibre function was measured using temperature discrimination thresholds for warmth (TDTwarmth) and cold (TDTcold). Large nerve fibre function was measured by testing sensory and motor nerve conduction velocities (SNCV and MNCV) and vibration perception thresholds (VPT). Neuropathic pain was only significantly associated with TDTcold, and with the MNCV of the tibial nerve. Sensory alteration was associated with almost all nerve function tests except the SNCV and MNCV of the ulnar nerve. The measurements of symptom severity and the nerve function tests all proved to be sufficiently reproducible. The standardized smallest detectable difference on group level (SDD) of the measurement of sensory alteration and neuropathic pain were almost the same (9% and 12%, respectively). Among the nerve function tests, the SNCV and MNCV had the smallest SDD (3-4%), and were, therefore, potentially the most responsive instruments. The SDD of the TDT was greater than the VPT (9-14% vs 21-28%, respectively). In conclusion, neuropathic pain was not associated with small nerve fibre function, and sensory alteration was associated with both large and small fibre function. In addition, the standardized measurement of symptom severity, the SNCV and MNCV tests, and the VPT test appear to be useful for monitoring the course of polyneuropathy in clinical trials.

Randomized study of two different target levels of glycemic control within the acceptable range in type 2 diabetes - Effects on well-being at 1 year

OBJECTIVE A randomized trial with 1-year follow-up was conducted in 23 general practices to study the relationship between target values for glycemic control and well-being in type 2 diabetes RESEARCH DESIGN AND METHODS A total of 176 patients with type 2 diabetes, aged 40–75 years, were included. General practitioners were encouraged to make decisions according to a standardized step-up regimen until the target levelof glycemic control was reached. The random allocation to a strict or a less strict target level of glycemic control (fasting capillary glucose <6.5 or <8.5 mmol/;1), change in HbAlc and fasting glucose, and initiating insulin or treatment with oral hypoglycemic agents were studied as putative determinants of scores on a type 2 diabetes symptom checklist, a profile ofmood states, an affect balance scale, and general well-being. Adjustments were made for baseline scores on the outcome at issue. RESULTS Positive affect (an odds ratio [OR] [95% CI] of 0.39 [0.19–0.83]) and perceived treatment burden (OR 0.48[0.23–0.98]) were unfavorably altered in the group randomly allocated to stricter target levels (fasting capillary glucose <6.5 mmol/l). Patients who had a decrease in HbA1c of 1% or more tended to have comparatively favorable mood (OR displeasure score 0.35 [0.13–0.94]) and general well-being scores at 1 year (ORs of having unfavorable scores ranged from 0.4 to 0.5, NS). CONCLUSIONS Perceived treatment burden and positive effect are unfavorably affected by random allocation to a strict target level for glycemic control. Improved glycemic control is associated with favorable mood and possibly general well-being in type 2 diabetes.

Determinants of specific serum insulin concentrations in a general Caucasian population aged 50 to 74 years (the Hoorn study)

The aim of this study was to investigate anthropometric and life‐style determinants of insulinaemia. Specific fasting serum insulin (FI) was analysed in a general Caucasian population aged 50–74 years, not known to have diabetes mellitus (n = 2226, sample 1). The analysis was repeated some weeks later in a subgroup of sample 1 in which two individual measurements of FI were available (n = 540, sub‐sample 2). Specific serum insulin 2 h after ingestion of 75 g glucose (2hI), also measured on two occasions, was analysed in this same subgroup after excluding 59 subjects with fasting plasma glucose >7 mmol l−1 (n = 481, sub‐sample 3). Multiple regression analyses were performed, stratified for sex, with 10log insulin as the dependent variable. All determinants were adjusted for each other. FI was positively associated with BMI and waist–hip ratio (men and women) and inversely associated with intake of fibre (women), moderate alcohol use (men), and current smoking (women). 2hI was positively associated with BMI and waist–hip ratio (men and women), and intake of fat (women). 2hI was inversely associated with physical activity and moderate alcohol use (men and women), and current smoking (men). Family history of diabetes was not associated with insulinaemia. In conclusion, various life‐style factors are related to insulinaemia, independent of obesity.

Complaints of neuropathy related to the clinical and neurophysiological assessment of nerve function in patients with diabetes mellitus

To determine the value of a detailed evaluation of neuropathic sensory complaints in assessing diabetic polyneuropathy, a questionnaire listing different sensory symptoms was compared with a clinical and neurophysiological examination of the peripheral nerves. Thirty-seven insulin dependent and thirty-one non-insulin dependent diabetic patients who were consecutively referred because of suspected polyneuropathy were investigated. In all patients both clinical and neurophysiological examination confirmed the diagnosis of polyneuropathy. Only the scores of the clinical examination were significantly correlated with the scores of the sensory symptoms (r = 0.31, P < 0.01). Using a factor analysis, a dimension of complaints of sensory alteration could be distinguished from a dimension of complaints of neuropathic pain (alpha coefficients 0.88 and 0.86, respectively). Tingling sensations turned out to be an expression of the dimension of complaints of sensory alteration. The scores of clinical and neurophysiological examinations were only significantly correlated with the dimension of sensory alteration (r = 0.38, P < 0.002; r = 0.37, P < 0.02, respectively). We conclude that only symptoms of numbness and tingling sensations in hand and feet are associated with objectively assessed diabetic polyneuropathy.

Dissimilar association of conventional immuno-reactive versus specific insulin with cardiovascular risk factors: a consequence of proinsulinaemia?

In this study involving 365 non-diabetic elderly Caucasians, we examined the relationship of immuno-specific insulin (ISI), total immuno-reactive insulin (IRI), proinsulin (PI) and proinsulin-insulin ratio (PI:ISI) to serum high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean blood pressure (MBP) and pulse pressure. In a multiple regression analysis, adjusted for age, sex and obesity, a 1.3-fold stronger inverse association with HDL-C levels was found for IRI than for ISI, with a 1.6-fold better fit of the regression equation. The positive association of insulin with TG was 1.6-fold stronger for IRI compared to ISI, with a 2.5-fold better fit. In contrast, the positive association of IRI with the various blood pressure parameters was 1.5-1.9-fold weaker than for ISI, with a 2.1-3.8-fold worse fit. Both PI:ISI ratio and PI were independently associated with TG levels, but not with HDL-C. The PI:ISI ratio but not PI, was associated with blood pressure, but dependent on glycaemia. In conclusion, compared to ISI, IRI overestimates the association of insulin with serum lipids and underestimates the association of insulin with blood pressure. The use of non-specific insulin assays may explain the inconsistencies in the findings of previous epidemiological studies.