Fear of hypoglycaemia in adults with Type 1 diabetes: results from Diabetes MILES - The Netherlands.

AIMS: To examine sociodemographic, clinical and psychological factors associated with fear of hypoglycaemia in adults with Type 1 diabetes. METHODS: Data were obtained from Diabetes MILES - The Netherlands, an online self-report national survey. This cross-sectional analysis focused on participants with Type 1 diabetes who completed the 18-item Hypoglycaemia Fear Survey - Second Version Worry subscale (HFS-II-W; possible total score range 0-72, higher scores indicating higher fear) (n = 288). To explore correlates of fear of hypoglycaemia, a hierarchical linear regression analysis was performed in participants with full data on sociodemographic, clinical and psychological factors (n = 232; younger and more highly educated than those excluded). RESULTS: HFS-II-W mean score was 11.1 ± 11.1. Gender, age, education and having a partner (model 1) were not associated with fear of hypoglycaemia. In model 2, history of severe hypoglycaemia (irrespective of number of events) was associated with (greater) fear of hypoglycaemia, whereas diabetes duration, pump therapy and HbA1c were not. Type D personality was positively correlated (model 3), as were symptoms of depression, but not anxiety (model 4). Adding loneliness (model 5) did not improve the model. The fully adjusted analysis showed that fear of hypoglycaemia was associated with depressive symptoms (ß = 0.38, P < 0.001) and history of hypoglycaemia (1-2 events: ß = 0.30, P < 0.001; ≥ 3 events: ß = 0.19, P = 0.002). Total explained variance was 23%. CONCLUSIONS: Depressive symptoms and history of hypoglycaemia are associated with fear of hypoglycaemia in adults with Type 1 diabetes. These factors may help to identify people with excessive fear, who may particularly benefit from interventions to reduce hypoglycaemia risk and worries.

An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age.

AIMS/HYPOTHESIS: The appearance of autoantibodies (Abs) before diabetes onset has mainly been studied in young children. However, most patients develop type 1 diabetes after the age of 15 years. In first-degree relatives aged under 40 years, we investigated the frequency of seroconversion to (persistent) Ab positivity, progression to diabetes and baseline characteristics of seroconverters according to age. METHODS: Abs against insulin (IAA), glutamate decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured during follow-up of 7,170 first-degree relatives. RESULTS: We identified 379 (5.3%) relatives with positivity for IAA, GADA, IA-2A and/or ZnT8A (Ab(+)) at first sampling and 224 (3.1%) at a later time point. Most seroconversions occurred after the age of 10 years (63%). During follow-up, Abs persisted more often in relatives initially Ab(+) (76%) than in seroconverters (53%; p < 0.001). In both groups diabetes developed at a similar pace and almost exclusively with Ab persistence (136 of 139 prediabetic individuals). For both groups, progression was more rapid if Abs appeared before the age of 10 years. Baseline characteristics at seroconversion did not vary significantly according to age. CONCLUSIONS/INTERPRETATION: Seroconversion to (persistent) Ab(+) occurs regardless of age. Although the progression rate to diabetes is higher under age 10 years, later seroconverters (up to age 40 years) have similar characteristics when compared with age-matched initially Ab(+) relatives and generate an important minority of prediabetic relatives, warranting their identification and, eventually, enrolment in prevention trials.

Modest opposite associations of endogenous testosterone and oestradiol with left ventricular remodelling and function in healthy middle-aged men.

In healthy middle-aged men, endogenous testosterone does not seem to increase risk for cardiovascular disease (CVD). One explanation might be a differential effect of testosterone, and another, interference with oestradiol with respect to specific cardiovascular functions. To investigate these possibilities, we evaluated in a cross-sectional population of 1223 healthy men, aged 46 (6) years, associations between endogenous testosterone, oestradiol and left ventricular structure and function (echocardiography). Testosterone was inversely associated with ejection fraction (EF) and with more sensitive systolic tissue Doppler imaging indices. Oestradiol was positively associated with EF. These associations were confirmed by linear regression analyses, and consistent for calculated free as well as for total sex steroid concentrations. Standardized regression coefficients were -0.13 for testosterone (P < 0.01) and 0.12 for oestradiol (P < 0.01) for the association with EF, in a model which included height, waist circumference, triglycerides, glucose, systolic blood pressure, drug-treated hypertension, heart rate, haematocrit, current smoking, serum sampling time, age and excessive alcohol use. The study suggests an opposite link, albeit modestly, of testosterone and oestradiol with left ventricle systolic function in healthy middle-aged men. The finding provides a partial explanation for the overall neutral effect on CVD of testosterone in healthy middle-aged men.

Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men.

OBJECTIVE: To assess and compare the effects of short-term aromatase inhibition on glucose metabolism, lipid profile, and adipocytokine levels in young and elderly men. DESIGN AND METHODS: Ten elderly and nine young healthy men were randomized to receive letrozole 2.5 mg daily or placebo for 28 days in a crossover design. RESULTS: Both in young and elderly men, active treatment significantly increased serum testosterone (+128 and +99%, respectively) and decreased estradiol levels (-41 and -62%, respectively). Fasting glucose and insulin levels decreased in young men after active intervention (-7 and -37%, respectively) compared with placebo. Leptin levels fell markedly in both age groups (-24 and -25%, respectively), while adiponectin levels were not affected by the intervention. Lipid profile was slightly impaired in both groups, with increasing low density lipoprotein-cholesterol levels (+14%) in the younger age group and 10% lower levels of APOA1 in the elderly. A decline in IGF1 levels (-15%) was observed in the younger age group. No changes in weight or body mass index were observed in either young or old men. CONCLUSIONS: Short-term aromatase inhibition appears to affect glucose metabolism in young men, and lipid metabolism, including leptin secretion, in young and elderly men. Furthermore, the short period of exposure suggests that these changes might be mediated by direct effects of sex steroids rather than by changes in body composition.

Incretin mimetics and enhancers for the treatment of type 2 diabetes mellitus.

Recently, new therapeutic strategies based on the incretin system have been developed for the treatment of type 2 diabetes mellitus. The present mini-review aims to provide a short overview of the background of this incretin system and the therapeutic potential of incretin mimetics and enhancers (DPP-4 inhibitors). The function of the incretin system, which shows gradual failure in type 2 diabetes, can be restored by incretin mimetics or DPP-4 inhibitors, with subsequently an improve of glycaemic control without an increase of risk for hypoglycaemia, as long as not combined with glucose-lowering agents like sulfonylureas or insulin. Incretin mimetics have additional important weight-reducing properties, though associated with gastro-intestinal adverse events. DPP-4 inhibitors appear to be 'weight neutral' and show a safe profile in a limited number of available clinical studies of short duration.

Is the effect of testosterone on body composition modulated by the androgen receptor gene CAG repeat polymorphism in elderly men?

OBJECTIVE: The androgen receptor (AR) gene contains a CAG repeat polymorphism coding for a polyglutamine chain, the length of which is inversely correlated with AR transcriptional activity. We explored whether this polymorphism modulates the activities of testosterone (T) related to body composition in elderly men. DESIGN: We performed cross-sectional analyses using data from a 4-year follow-up study in community-dwelling men aged 75-89 years (n=159). METHODS: Body composition was assessed by dual-energy X-ray absorptiometry and its relation with T and the AR gene CAG repeat length was assessed by multiple linear regression analyses, adjusting for confounding and exploring effect modification. RESULTS: AR gene CAG repeat length was not directly related to body composition, either with or without adjustment for confounding variables like age, weight, total T or sex hormone binding globulin (SHBG) levels. However, exploration of effect modification showed that CAG repeat length modulated the relation between T and body composition (standardized regression coefficients of interaction term: beta=0.12, P<0.01 and beta=-0.09, P<0.05 for fat-free mass and fat mass respectively). These results were confirmed using similar models and data of mean T, SHBG and weight of the 2 years' preceding body composition assessment instead of data of the same year (beta=0.09, P<0.05 and beta=-0.09, P<0.05 respectively). CONCLUSION: These findings suggest that the AR gene CAG polymorphism contributes, albeit modestly, to the between-subject variation of T action on body composition in community-dwelling elderly men.

Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome.

OBJECTIVE: To investigate whether leukocyte count, fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 activity (PAI-1) are increased in subjects with the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and the World Health Organisation (WHO). DESIGN: Cross-sectional study. SUBJECTS: A total of 520 overweight and obese subjects: 379 women and 141 men, visiting the weight management clinic of a University Hospital. SUBJECTS AND MEASUREMENTS: Waist circumference, triglycerides, HDL cholesterol, blood pressure and fasting glucose were determined, and the presence or absence of the metabolic syndrome according to the NCEP-ATPIII criteria was assessed. In 349 subjects, data on the waist-to-hip ratio (WHR) and albumin excretion rate were available and the WHO criteria were applied. Insulin resistance was defined using the HOMA-IR index. RESULTS: Subjects with the metabolic syndrome according to the NCEP-ATPIII criteria had significantly higher levels of leukocyte count (P < 0.001) and PAI-1 (P < 0.001), while no significant differences were found for fibrinogen or vWF (P > 0.05). Using the WHO criteria, similar results were found except for vWF, where higher levels were found in subjects with the metabolic syndrome. When subjects were classified according to the number of components of the metabolic syndrome, levels of leukocyte count, vWF and PAI-1 activity were significantly different (P < 0.05). In logistic regression analysis PAI-1, gender and leukocyte count were independent determinants of the metabolic syndrome (P < 0.001). CONCLUSION: Evidence for being a true component of the metabolic syndrome is strong for PAI-1, less for leukocyte count and weak for vWF and fibrinogen.

A 16-year survey of Takayasu's arteritis in a tertiary Belgian center.

AIM: To evaluate the clinical features, angiographic findings and evolution of Takayasu's arteritis in a Belgian tertiary center, and to compare the findings with published series of Western patients. METHODS: Retrospective analysis of 15 patients with Takayasu's arteritis, satisfying the American College of Rheumathology criteria, in the period 1986 to 2002. Published series of Western patients were identified by means of a Medline search and citation-tracking. RESULTS: Diagnosis was often delayed, with a median period of 9 months. Patients presented with a variety of symptoms and clinical signs and had on average 4.5 arterial segments involved at angiography. Twelve patients received corticosteroid treatment and 4 of them additional immunosuppressive drugs. Five patients underwent angioplasty and/or stenting and 8 patients had open surgical procedures. During follow-up, there were 2 cardiac deaths and 2 other patients died from intracranial hemorrhage. Comparison with published series of other Western patients did not reveal major differences of anatomical distributions of the lesions, but left the impression that more aggressive use of immunosuppressive drugs might have improved the outcome. CONCLUSION: Takayasu's arteritis results in an important morbidity and mortality. More aggressive medical therapy may be advantageous, but this would require adequate investigation in a controlled trial for which a multicenter effort is needed because of the rarity of the disease.

Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus.

AIMS/HYPOTHESIS: The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel in the pancreatic beta cell. Mutations at nt -3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 of the gene for the sulphonylurea receptor (SUR1) associate with Type II (non-insulin-dependent) diabetes mellitus in several independent populations. We investigated whether these gene variants associate with changes in the pattern of glucose-stimulated insulin secretion. METHODS: Subjects who had normal glucose tolerance (n = 67) and subjects with an impaired glucose tolerance (n = 94), originating from two independent studies, were included in the study. Beta-cell function and insulin sensitivity were assessed by the hyperglycaemic clamp. RESULTS: Frequencies of the exon 16 -3t allele in the normal and impaired glucose tolerant groups were 46% and 44% respectively (p = NS). The more rare exon 18 T allele showed frequencies of 5 and 7% respectively (p = NS). We observed an approximately 25% reduced second-phase insulin secretion in carriers of the exon 16 -3t allele in both groups (p < 0.05). Estimates of insulin sensitivity did not show differences between carriers and non-carriers. The variant in exon 18 and the combined presence of variants in exon 16 and exon 18 were not associated with differences in insulin secretion or insulin sensitivity in our study groups. CONCLUSION/INTERPRETATION: The diabetes associated exon 16 -3t variant of the SUR1 gene associates with a functional change of the beta cell as reflected by reduced second-phase insulin secretion in response to a standardized hyperglycaemia in normal and impaired glucose tolerant subjects.

Leptin and variables of body adiposity, energy balance, and insulin resistance in a population-based study. The Hoorn Study.

OBJECTIVE: Leptin is thought to play a key role in the control of body weight. There is a complex interrelationship between leptin and insulin or insulin resistance, but it is unknown how leptin is regulated. We therefore explored, in a large population-based study of 2,484 Caucasian subjects aged 50-74 years, the relationship between leptin and variables of body adiposity, energy balance, and insulin resistance. RESEARCH DESIGN AND METHODS: Leptin was measured by means of a radioimmunoassay. Multiple linear regression analyses were performed with leptin as dependent variable and age, sex, BMI, waist circumference, daily energy intake, physical activity, smoking, hypertension, fasting triglyceride concentrations, HDL cholesterol, fasting plasma glucose, and fasting plasma insulin concentrations as independent variables (determinants) RESULTS: Leptin concentrations were found to be four times higher in women than in men. Effect modification between sex and potential determinants was expected, and the analyses were performed separately for women and men. BMI was the strongest determinant of leptin in women and waist circumference the strongest determinant in men. BMI, waist circumference, insulin, and triglyceride concentrations were independently and significantly (P < 0.05) associated with leptin, while inverse associations were shown for smoking and daily energy intake (borderline significance). CONCLUSIONS: This study confirms the relationship between insulin and leptin and, in addition, suggests a relationship between triglyceride concentrations and leptin independent of sex, BMI, waist circumference, and insulin.

Variants in the sulphonylurea receptor gene: association of the exon 16-3t variant with Type II diabetes mellitus in Dutch Caucasians.

AIMS/HYPOTHESIS: We have analysed to what extent two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) are associated with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands. Furthermore, we estimated haplotype frequencies in control and diabetic populations, including data extracted from three other studies. METHODS: Subjects with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were randomly selected from two population-based studies, the Hoorn and Rotterdam studies. DNA was typed for variants in exon 16 (-3c-->t variant in the splice acceptor site) and exon 18 (Thr759Thr, ACC-->ACT). RESULTS: The genotype frequencies in both populations were similar. We observed an association of the exon 16-3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in NGT and Type II diabetes, respectively, p = 0.01). There was no association between Type II diabetes and the variant in exon 18 or the combination of both variants (p > 0.5). A strong linkage disequilibrium between the exon 16 and exon 18 variants was observed in the diabetic groups but not, or less pronounced, in the control groups from the different studies. Haplotype estimation shows that several different risk haplotypes exist in different Caucasian populations. CONCLUSION/INTERPRETATION: The exon 16-3t allele of the SUR1 gene is associated with Type II diabetes in the Netherlands. Based on estimated haplotype frequencies in different Caucasian populations we conclude that multiple haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes in Caucasians.

Performance of a predictive model to identify undiagnosed diabetes in a health care setting.

OBJECTIVE: To develop a predictive model to identify individuals with an increased risk for undiagnosed diabetes, allowing for the availability of information within the health care system. RESEARCH DESIGN AND METHODS: A sample of participants from the Rotterdam Study (n = 1,016), aged 55-75 years, not known to have diabetes completed a questionnaire on diabetes-related symptoms and risk factors and underwent a glucose tolerance test. Predictive models were developed using stepwise logistic regression analyses with the absence or presence of newly diagnosed diabetes as the dependent variable and various items with a plausible connection to diabetes as the independent variables. The models were evaluated in another Dutch population-based study, the Hoorn Study (n = 2,364), in which the participants were aged 50-74 years. Performances of the predictive models were compared by using receiver-operator characteristics (ROC) curves. RESULTS: We developed three predictive models (PMs), PM1 contained information routinely collected by the general practitioner, while PM2 also contained variables obtainable by additional questions. The third predictive model, PM3, included variables that had to be obtained from a physical examination. These latter variables did not have additive predictive value, resulting in a PM3 similar to PM2. The area under the ROC curve was higher for PM2 than for PM1, but the 95% Cls overlapped (0.74 [0.70-0.78] and 0.68 [0.64-0.72], respectively). CONCLUSIONS: Using only information normally present in the files of a general practitioner, a predictive model was developed that performed similarly to one supplemented by information obtained from additional questions. The simplicity of PM1 makes it easy to implement in the current health care setting.

Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene.

Friedreich's ataxia is associated with GAA trinucleotide repeat expansions in the frataxin gene. In the general population, these trinucleotide expansions are variable in length, and three types of expansions are seen: short, intermediate, and long repeats. Friedreich's ataxia patients are generally homozygous for the long repeats and exhibit diabetes as pronounced comorbidity. Ristow et al. recently reported an association between the intermediate-length normal allele in the frataxin gene and type 2 diabetes. We have investigated in 94 subjects with impaired glucose tolerance (IGT) as to whether the length of the GAA trinucleotide repeat polymorphism in the frataxin gene associates with parameters reflecting beta-cell function. A hyperglycemic clamp at 10 mmol/l glucose for 3 h was used to quantitate beta-cell characteristics. Carriers of one or two intermediate repeat alleles (n = 32) had a 50% higher median first- phase insulin response to glucose than the noncarriers. Furthermore, they needed less time to reach peak insulin. An analysis of the distribution of the various repeat lengths in elderly type 2 diabetic (n = 179) and control subjects (n = 183), with the same age and ethnic background, did not provide evidence for an association of the intermediate-length repeat allele with type 2 diabetes in Dutch Caucasians.

Hyperproinsulinaemia in impaired glucose tolerance is associated with a delayed insulin response to glucose.

In subjects with impaired glucose tolerance hyperproinsulinaemia has been shown to be predictive for progression to Type II (non-insulin-dependent) diabetes mellitus. These findings are often interpreted as early indicators of an impaired beta-cell function. The aim of our study was to assess the potential determinants of hyperproinsulinaemia in subjects with impaired glucose tolerance. The study group consisted of 110 subjects, 45-74 years of age with mean 2 h plasma glucose concentrations between 8.6 and 11.1 mmol/l following two oral glucose tolerance tests. Subsequently, the hyperglycaemic clamp technique (10 mmol/l, with a priming infusion of 20% glucose solution, 150 mg/kg) was used to assess the beta-cell function (time needed to reach the insulin peak) and insulin sensitivity (M/I value: glucose metabolised divided by insulin response, 150-180 min). Results showed that the intact-proinsulin:insulin ratio increased with increasing time needed to reach the insulin peak (0.065, 0.079 and 0.101; time needed to reach the insulin peak < or = 5 min, 5 to 15 min, > 15 min; p < 0.05). The split-proinsulin:insulin ratio showed a similar association with the time needed to reach the insulin peak. These associations were independent of age, sex, body mass index and waist:hip ratio. In conclusion, this study shows that relative hyperproinsulinaemia is associated with an impaired beta-cell function in a study group of subjects with impaired glucose tolerance selected after two oral glucose tolerance tests.

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.

Low prevalence of antibodies to GAD65 in a 50- to 74-year-old general Dutch population. The Hoorn Study.

OBJECTIVE: To assess the prevalence of antibodies to GAD65 (GAD65-A) in relation to glucose tolerance disturbances and to blood glucose-lowering therapy in a general Dutch population. RESEARCH DESIGN AND METHODS: A population sample of 2,350 Dutch subjects, age 50-74 years, agreed to undergo an oral glucose tolerance test (OGTT). They were classified as having normal glucose tolerance, impaired glucose tolerance, newly detected diabetes, or known diabetes. GAD65-A levels were measured in serum by means of a standardized radioligand assay and subsequently were expressed as indexes. The prevalence rates were defined as the proportions of individuals of each category of glucose tolerance exceeding the value of the index at the 99th percentile of the entire study population. RESULTS: The prevalence rates and the 95% CIs of GAD65-A were 0.7% (0.4-1.2%) in cases of normal glucose tolerance, 2.4% (0.9-5.3%) in impaired glucose tolerance, 0% (0-3.3%) in newly detected diabetes, according to the World Health Organization (WHO) criteria, and 3.5% (0.7-10.0%) in known diabetes. A total of 2 out of 3 subjects with GAD65-A indexes above the 99th percentile and 10 out of 18 subjects with GAD65-A indexes above the 85th percentile received insulin therapy for their diabetes, which showed an association between GAD65-A and insulin therapy CONCLUSIONS: Low prevalence rates of latent autoimmunity to GAD were found in 50- to 74-year-old Dutch subjects with normal and abnormal glucose tolerance, and GAD65-A was associated with insulin use in known diabetic subjects.

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.