Is self-monitoring of blood glucose appropriate for all type 2 diabetic patients? The Fremantle Diabetes Study.
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Blood Glucose↗
Biomedical subjects
Stephan Martin
Publications and source records attributed to Stephan Martin.
[Nonpharmacological diabetes therapy].
Insulin resistance caused by obesity and lack of physical activity plays a major role for the development of type 2 diabetes. If the reduced insulin action cannot be compensated by overproduction of insulin, glucose regulation disorder is developing. In addition, other trigger factors such as television viewing, sleep, alcohol or smoking are discussed. During the past years an intensification of pharmacological therapy was believed to be the major goal for the treatment of type 2 diabetes, now the value of nonpharmacological treatment improves. While in the past only nutrition was in the view of lifestyle research, recently a number of studies on the value of physical activity were published. In this paper an overview of recent studies showing the therapeutic potential of nonpharmacological therapies will be given. It will also be shown that these measures will not only optimize hyperglycaemia but also all other cardiovascular risk factors.
Adolescent↗
The DREAM trial.
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Clinical Trials as Topic↗
Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.
OBJECTIVE: We performed a prospective case-cohort study in initially healthy, middle-aged men and women from the MONICA/KORA Augsburg studies conducted between 1984 and 2002 to assess the role of IL-18 in comparison with IL-6 and CRP in the prediction of incident coronary heart disease (CHD). METHODS AND RESULTS: Concentrations of IL-18 were measured in 382 case subjects with incident CHD and 1980 noncases. Mean follow-up was 11 years. Baseline concentrations of IL-18 were slightly higher in cases than in noncases (172.4 [1.0] versus 161.3 [1.0] pg/mL, respectively; P=0.114), but were clearly elevated for C-reactive protein (CRP) and IL-6 in cases compared with noncases. In multivariable analyses, accounting for classical cardiovascular risk factors and inflammatory markers, no statistically significant association was seen between increased concentrations of IL-18 and incident CHD both in men (hazard ratio [HR] and 95% confidence intervals [CIs] comparing extreme tertiles, 1.20; 95% CI, 0.85 to 1.69), and in women (HR, 1.25; 95% CI, 0.67 to 2.34). However, in this population increased concentrations of CRP and IL-6 were found to be independent predictors of future CHD events, even after multivariable adjustment. CONCLUSIONS: Elevated concentrations of CRP and IL-6, but not IL-18, were independently associated with risk of CHD in subjects from an area with moderate absolute risk.
Adult↗
Chemokines and incident coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.
OBJECTIVE: The chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), interleukin-8 (IL-8/CXCL8), and interferon-gamma-inducible protein-10 (IP-10/CXCL10) have been reported to be involved in the development of atherosclerosis and type 2 diabetes. The aim of this study was to assess whether elevated systemic levels of these chemokines precede coronary events. METHODS AND RESULTS: We investigated MCP-1, IL-8, and IP-10 serum levels in a case-cohort design based on data from 381 individuals (294 men, 87 women) with and 1977 individuals (1006 men, 971 women) without incident coronary heart disease (CHD) from the prospective, population-based MONICA/KORA Augsburg study (1984 to 2002). The mean follow-up time was 11.0 years. Baseline concentrations were significantly higher in cases compared with noncases (P < or = 0.001 for all chemokines). MCP-1 and IL-8 remained associated with CHD risk after adjustment for age, sex, and survey with hazard ratios (95% confidence intervals) comparing extreme tertiles of 1.39 (1.05 to 1.84) for MCP-1 and 1.48 (1.10 to 1.99) for IL-8. However, adjustment for further cardiovascular and immunologic risk factors attenuated the observed associations, and they became nonsignificant. CONCLUSIONS: Elevated systemic levels of the chemokines MCP-1, IL-8, and IP-10 precede CHD but do not represent independent risk factors. Thus, the associations are less pronounced than previously shown for type 2 diabetes.
Case-Control Studies↗
High prevalence of undiagnosed impaired glucose regulation and diabetes mellitus in patients scheduled for an elective coronary angiography.
BACKGROUND: Impaired glucose regulation (IGR) and diabetes mellitus (DM) are amongst the main risk factors for developing coronary heart disease (CHD). The aim of this study was to investigate previously unknown glucose metabolism disorder in patients scheduled for an elective coronary angiography. METHODS: A total of 141 patients scheduled for coronary angiography without signs of acute myocardial ischemia or previous history of a glucose metabolism disorder were prospectively included in the study. An oral glucose tolerance test (OGTT) was performed in each patient. RESULTS: IGR was diagnosed in 40.4% (95% confidence interval 32.3-49.0) and undetected DM in 22.7% (16.1-30.5) of patients undergoing an elective coronary angiography. Depending on the severity of CHD, the percentage of IGR and DM increased up to 45.3% (34.6-56.5) and 26.7% (17.8-37.4) in the subgroup with the need of percutaneous angioplasty, while the corresponding proportions in the group without CHD were 30.3% (15.6-48.7) and 12.1% (3.4-28.2). The percentage of undiagnosed DM increased with the number of epicardial vessels involved. Using the recommended fasting plasma glucose value of > or = 126 mg/dl for the diagnosis of DM, we would have missed 71.9% of the patients with undiagnosed DM. If all patients with a fasting plasma glucose of > or = 90 mg/dl had been subjected to OGTT, 93.8% of DM would have been identified. CONCLUSIONS: Prevalences of DM and IGR are higher than expected in patients with CHD. An OGTT should be considered for all patients with a fasting plasma glucose > or = 90 mg/dl undergoing a coronary angiography.
Aged↗
Inflammation in metabolic syndrome and type 2 diabetes: Impact of dietary glucose.
Chronic overnutrition combined with a lack of exercise is the main cause for the rapidly increasing prevalence of overweight and obesity. It seems accepted that adipositis (macrophage infiltration and inflammation of adipose tissue in obesity) and systemic low grade inflammation affect the pathogenesis of the metabolic syndrome or type 2 diabetes mellitus (T2DM). Therefore, modern weight reduction programs additionally focus on strategies to attenuate the inflammation state. Exercise is one major factor, which contributes to the reduction of both the incidence of T2DM and inflammation, and the immunomodulatory effects of exercise are supported by similarly beneficial effects of dietary changes. In this context, glucose is the most extensively studied nutrient and current investigations focus on postprandial glucose-induced inflammation, one possible reason why hyperglycemia is detrimental. Indeed, glucose may modulate the mRNA expression and serum concentrations of immune parameters but these alterations rapidly normalize in normoglycemic subjects. In case of an impaired metabolic state, however, postprandial hyperglycemia increases magnitude and duration of systemic inflammatory responses, which probably promotes the development of T2DM and of cardiovascular disease.
Cytokines↗
Systemic immune mediators and lifestyle changes in the prevention of type 2 diabetes: results from the Finnish Diabetes Prevention Study.
The Finnish DPS (Diabetes Prevention Study) demonstrated that lifestyle intervention, aimed at increasing physical activity, improving diet, and decreasing body weight, reduced the incidence of type 2 diabetes in individuals with overweight and impaired glucose tolerance by 58%. Here, we studied which immunological markers at baseline predicted subsequent type 2 diabetes and whether there are immunologically defined subsets of subjects who are more or less responsive to the protective effects of lifestyle intervention. We randomly assigned 522 participants to a control group (n = 257) or a lifestyle intervention group (n = 265). Immunological parameters at baseline included high-sensitivity C-reactive protein (CRP), serum amyloid A, interleukin-6, regulated on activation normal T-cell expressed and secreted (RANTES), macrophage migration inhibitory factor (MIF), and soluble intercellular adhesion molecule. In the control group, CRP was the best immunological predictor for progression to overt type 2 diabetes. In the intervention group, progression to type 2 diabetes was significantly higher in subjects with the highest RANTES concentrations and was lower in subjects with the highest MIF levels. Ratios of RANTES to MIF in the upper tertile were highly predictive of incident type 2 diabetes in the intervention group (P = 0.006), whereas the association was less pronounced in the control group (P = 0.088). Thus, systemic concentrations of immune mediators appear to be associated with the progression to type 2 diabetes and the prevention of type 2 diabetes by lifestyle changes.
Anthropometry↗
IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants' data from 21 studies.
Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.
Case-Control Studies↗
Circulating levels of interleukin-18 independent of body fat and fat-free mass: results from the MONICA/KORA study.
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Adipose Tissue↗
Chronic inflammation and hemodialysis reduce immune competence of peripheral blood leukocytes in end-stage renal failure patients.
Immunoincompetence is a profound problem in end-stage renal failure patients undergoing hemodialysis, and chronic inflammation with altered serum levels of inflammation markers has been reported. Gene expression patterns have had little relevance for leukocyte research so far because of limitations in transcript levels and stability. Using a new stimulation system we induced the expression of immune-relevant transcripts in whole blood preparations ex vivo and stabilized transcript levels by preventing RNA degradation and uncontrolled gene induction. Using quantitative real-time PCR we could show that basal TGF-beta mRNA expression is about 2-fold decreased in end-stage renal failure patients, while expression of TNF-alpha becomes 2-fold increased, further doubling during hemodialysis. By short term stimulation with phytohemagglutinin (PHA) for 2 h we tested for the immune competence of peripheral blood leukocytes and demonstrated that hemodialysis decreases TNF-alpha-mediated immune responsiveness more than 3-fold. This study shows by induction and stabilization of immune-relevant transcripts that chronic inflammation and hemodialysis are crucial factors for disturbed immune competence of end-stage renal failure patients.
Adult↗
Performance of screening questionnaires and risk scores for undiagnosed diabetes: the KORA Survey 2000.
BACKGROUND: Validation of published screening questionnaires and risk scores for undiagnosed diabetes has typically not been performed in independent population samples. METHODS: Oral glucose tolerance tests were performed in 1353 participants (aged 55-74 years) without known diabetes in the Cooperative Health Research in the Region of Augsburg (KORA) Survey 2000, Augsburg, Germany. Sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) for undiagnosed diabetes were calculated for various screening questionnaires. RESULTS: Four screening tests (Rotterdam Diabetes Study, Cambridge Risk Score, San Antonio Heart Study, and Finnish Diabetes Risk Score) were applied to the KORA data. The AUCs were 61% (95% confidence interval [CI], 56%-66%) for the Rotterdam Diabetes Study, 65% (95% CI, 60%-69%) for the Finnish Diabetes Risk Score (P=.10 vs Rotterdam), and 67% (95% CI, 62%-72%) for the Cambridge Risk Score (P<.001 vs Rotterdam). A predictive model including fasting glucose level (San Antonio Heart Study) yielded an AUC of 90% (P<.01 vs all 3 questionnaires); however, this was not significantly different from fasting glucose level alone (AUC, 89%; P=.46). The sensitivities, specificities, and predictive values of questionnaires were substantially lower than originally described, which was mainly due to population variation of risk factors compared with the KORA sample (age, body mass index, antihypertensive medication, and smoking). CONCLUSIONS: Currently proposed questionnaires yielded low validity when applied to a new population, most likely due to differences in population characteristics. Performance of diabetes risk questionnaires or scores must be assessed in the target population where they will be applied.
Adult↗
Elevated levels of interleukin-18 predict the development of type 2 diabetes: results from the MONICA/KORA Augsburg Study, 1984-2002.
We investigated prospectively the association between serum levels of interleukin (IL)-18 and the risk of type 2 diabetes in a case-cohort study conducted in middle-aged men and women who represented 7,936 participants of the three MONItoring of trends and determinants in CArdiovascular disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) surveys. Levels of IL-18 were measured in stored samples of 527 case subjects with incident type 2 diabetes and 1,698 noncase subjects. Elevated levels of IL-18 were associated with a significantly increased risk of type 2 diabetes after adjustment for age, sex, survey, BMI, systolic blood pressure, ratio of total cholesterol to HDL cholesterol, physical activity, alcohol intake, smoking status, and parental history of diabetes. Hazard ratios and 95% confidence intervals comparing quartile extremes were 1.73 (1.25-2.40). Further adjustment for C-reactive protein and IL-6 had no impact on the observed associations. However, the risk of developing type 2 diabetes was highest among subjects with elevated levels of both IL-18 and CRP or IL-18 and IL-6, respectively. In conclusion, elevated levels of IL-18 are associated with a considerably increased risk of type 2 diabetes. This association is independent of a generalized proinflammatory state, but subjects with elevated levels of several inflammatory markers seem to be particularly prone to develop type 2 diabetes.
Aging↗
Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4).
Chemokines are crucial immune mediators in many physiological and pathophysiological conditions. Chemokines have been hypothesized to be involved in macrophage infiltration into adipose tissue in obesity and might therefore play an important role in the development of obesity-related disorders like type 2 diabetes. Out of 1,653 individuals aged 55-74 years participating in a population-based survey in southern Germany (the Kooperative Gesundheitsforschung in der Region Augsburg [KORA] [Cooperative Health Research in the Region of Augsburg] Survey S4, 1999-2001), 236 individuals with type 2 diabetes, 242 subjects with impaired glucose tolerance (IGT), and 244 normoglycemic control subjects were studied for circulating concentrations of interleukin (IL)-8; RANTES (regulated on activation, normal T-cell expressed, and secreted); interferon-gamma-inducible protein-10 (IP-10), and eotaxin. Systemic concentrations of RANTES were higher in individuals with IGT or type 2 diabetes than in control subjects, whereas IL-8 levels were elevated in type 2 diabetic patients only (P < 0.001 for all comparisons). IP-10 and eotaxin were not significantly associated with IGT or type 2 diabetes. Adjustment for age, sex, BMI, hypertension, LDL cholesterol, HDL cholesterol, uric acid, C-reactive protein, and IL-6 did not alter these findings. Our findings indicate that RANTES and IL-8 may be involved in the development of type 2 diabetes independent of metabolic syndrome-related risk factors and of each other. There is no general upregulation of chemokine production in type 2 diabetes, but rather an association of the disease with specific members of the chemokine family.
Aged↗
Evaluation of diagnostic relevance of mRNA levels in peripheral blood: predictive value for mortality in hemodialysis patients.
In clinical practice, diagnosis and risk prediction are usually based on the analysis of serum or plasma proteins whereas gene expression analysis is not used on a routine basis. In order to compare the diagnostic and predictive relevance of serum protein and peripheral blood mRNA levels, we determined cytokine levels of end-stage renal failure patients undergoing hemodialysis. These patients face a high mortality mainly due to acceleration of atherosclerosis and subsequent severe vascular events. mRNA expression of the pro-inflammatory cytokine TNF alpha was significantly elevated in hemodialysis patients and further increased after 2 h of dialysis treatment. In contrast, gene expression of the anti-inflammatory cytokine TGF beta was significantly decreased. Patients who died during the observation period of 36 months had significantly increased mRNA levels of TNF alpha and decreased TGF beta mRNA expression at baseline. Survival analysis indicated that increased TNF alpha mRNA levels (P < 0.02) and TNF alpha/TGF beta mRNA ratios (P < 0.001) predict mortality. The corresponding cytokines in serum showed some association with disease, but serum concentrations neither changed during hemodialysis nor predicted mortality. This study shows that gene expression patterns of circulating leukocytes may present an important new diagnostic tool to predict clinical outcome in patients with inflammatory vascular diseases.
Adult↗
Combined activation of innate and T cell immunity for recognizing immunomodulatory properties of therapeutic agents.
Complex syndromes such as atherosclerosis and type 2 diabetes are disorders that are associated with inflammatory processes involving innate and adaptive immunity. Emerging knowledge about the pathological consequences of immune imbalances in a wide range of disease settings is expected to help to identify novel therapeutic targets. However, current test systems for immunomodulatory drugs tend to be too simplistic, as they rely only on cells of the innate- or the adaptive-immune system, or they are complex, in vivo models, which are not suitable for screening purposes. Using a modified mixed lymphocyte culture (MMLC) assay for combined analysis of innate and adaptive immunity, we show that this assay is very sensitive for the presence of low concentrations of immunomodulatory agents. Low-dose lipopolysaccharide stimulation of cells from two unrelated donors yields a strong cytokine response including interleukin (IL)-12 and IL-18, which induce interferon-gamma as a potential analysis parameter. As the MMLC assay is based on the mutual interaction of cells of the innate and adaptive immunity, it enables the monitoring of cytokine release under almost physiological conditions and might be of interest for the characterization of known and novel drugs concerning their immunomodulatory potency.
Adjuvants, Immunologic↗
IL-10 induces gene expression in macrophages: partial overlap with IL-5 but not with IL-4 induced genes.
The hypothesis that IL-10, in addition to down-regulating pro-inflammatory activities of macrophages, induces an alternative state of macrophage reactivity was tested. We therefore conducted a systematic search for genes induced by IL-10 using the method of suppression subtractive hybridisation. Of an initial 1,300 candidate clones obtained, several screening rounds led to the identification of 51 clones which were reproducibly at least twofold up-regulated in mouse J774 macrophages in response to treatment with IL-10. Of these, 41 genes were homologous to known genes involved in cell metabolism or immunoregulation, five contained novel sequences and another five were homologous to ESTs without known function. One major finding was that about 25% of the IL-10 genes were also found expressed in response to IFNgamma, and several of these also reappeared in IL-4 or IL-5 induced mRNA species. Hence, Th1 and Th2 type cytokines may elicit a common basal activation response in macrophages. The second major finding was that 57% of IL-10 induced genes reappeared in IL-5 induced mRNA but no more than 18% were also found in IL-4 induced mRNA of J774 cells. We conclude that the gene expression response to IL-10 in macrophages is partially different from the response to IL-5 and is substantially different from the response to IL-4, which suggests an unexpected diversity of biological phenotypes induced by different Th2 type cytokines.
Animals↗
Oral DNA vaccination with a plasmid encoding soluble ICAM-1 modulates cytokine expression profiles in nonobese diabetic mice.
Adhesion molecules are important for leukocyte extravasation and for the delivery of costimulatory signals in T cell activation. We therefore interfered in the immune process leading to islet inflammation in diabetes prone NOD mice by oral vaccination with plasmid DNA encoding soluble ICAM-1. Female NOD mice were treated orally with ICAM-1, TGF-beta, or control plasmid DNA and received a single injection of cyclophosphamide for synchronization and acceleration of the disease process in the pancreas. Quantitative RT-PCR analysis of pancreatic mRNA showed that cyclophosphamide induced the expression of Th1 cytokines (IFN-gamma and IL-12p40) in vehicle- or control plasmid-treated mice. Treatment with ICAM-1 and TGF-beta DNA resulted in increased levels of IL-10 mRNA in the pancreas, indicating an anti-inflammatory regulatory immune response. Histological analysis of pancreatic islets showed that the DNA treatment did not alter islet infiltration in response to cyclophosphamide. Hence vaccination with the ICAM-1 plasmid had not suppressed leukocyte migration but rather modulated lymphocyte activity, similarly as seen for the TGF-beta-encoding plasmid. Neither of the three plasmids caused recognizable changes in cytokine expression in the small intestine, Peyer's patches, or mesenteric lymph nodes. We conclude that oral vaccination with DNA encoding immunoregulatory molecules such as ICAM-1 and TGF-beta represents an approach for modulating the ongoing inflammatory process in the pancreas of diabetes prone NOD mice.
Administration, Oral↗