Overt Diabetes Mellitus Research Articles

Integration of local and central laboratory functions in a worldwide multicentre study: Experience from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study

Measurement of glucose in multiple Field Laboratories requires rigorous standardization when patients and caregivers are masked, unless predefined thresholds are met. Local misclassification of participants at the thresholds can introduce recruitment bias and adversely affect the integrity of study findings. To describe the challenges and the approach to meeting them in measuring glucose, HbA1c, and C-peptide in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO is an observational epidemiologic study of 25 000 pregnant women from 15 centres in 10 countries, designed to clarify unanswered questions on associations of maternal glycemia, less severe than overt diabetes mellitus, with risks of adverse pregnancy outcome. Glucose tolerance (75 g two-hour OGTT) is assessed locally at 24-32 weeks' gestation, with results masked if fasting and two-hour plasma glucose are </=5.8 mmol/L and </=11.1 mmol/L, respectively. For analysis of outcomes HAPO utilizes measurements of glucose, C-peptide, and HbA1c on frozen samples in a Central Laboratory; measurement of HbA1c on stored, frozen blood also creates special challenges. A common external quality assessment scheme was used to standardize glucose measurements between Field Centre and Central Laboratories before and during data collection. Agreement between Field Centres and the Central Laboratory in rates above the masking thresholds has been excellent (Kappa = 0.79, P < 0.001), with rates of 1.8 and 1.7% respectively. Percent technical error for Central Laboratory OGTT measurements of glucose, C-peptide, and HbA1c, were 2.0, 4.2, and 2.0, respectively. It is not possible to assess if comparable results could have been obtained with a less rigorous approach to standardization. HAPO has been successful in ensuring comparability of glucose measurement between its Central Laboratory and Field Centre laboratories and in measuring its key metabolites with accuracy and precision. Recruitment bias based on glucose measurement has been avoided.

Insulin-dependent diabetes mellitus as long term complication of haemolytic-uraemic syndrome

Haemolytic-uraemic syndrome (HUS) is a rare cause of insulin-dependent diabetes mellitus during the acute stage. We previously reported the case of a 3-year-old girl having presented with typical HUS with diarrhea, microangiopathic anaemia, thrombocytopenia and acute renal failure (17 days of anuria). Transient hyperglycaemia (highest level: 513 mg/dl) was observed, requiring continuous intravenous insulin infusion for 9 days. Subcutaneous insulin injections were stopped after 24 days. Oral glucose tolerance test performed 4 months after normalization of blood glucose was normal. HLA DQ genotype (DQA1-DQB1.AZH/DQA3-DQB3.1) was not at risk for type 1 diabetes and there were no auto-antibodies (ICA and IAA). The 3-years follow-up was marked by persistent arterial hypertension, proteinuria and slight renal insufficiency despite angiotensin-converting enzyme inhibitor treatment. Ten years after HUS occurred (the patient had been lost to follow-up for 7 years), she came back with complaints of headache but neither polyurodipsia nor weight loss. She was found to have arterial hypertension. Chronic renal impairment had moderately progressed with decreased glomerular filtration rate (63 ml/min/1.73 m2) and proteinuria (2 g/24 hours). Fasting blood glucose was 189 mg/dl and reached 315 mg/dl during an oral glucose tolerance test. HbA1c level was 8.2% (N<6.2%) and diabetes mellitus was diagnosed without any signs of autoimmunity (IAA, ICA, GADA and IA2B were negative). Good glycaemic control was obtained with 0.5 U/kg/day of insulin. In conclusion, transient beta-cell dysfunction complicating HUS acute stage may evolve to overt non-autoimmune diabetes mellitus (microangiopathic process?), even after a long free interval. This case emphasizes the need for a long-term follow-up of patients with HUS.

Characteristics of patients with abnormal glucose challenge test and normal oral glucose tolerance test results: Comparison with normal and gestational diabetic patients

The purpose of this study was to evaluate the characteristics and outcomes of patients who had abnormal glucose challenge test results and subsequent normal oral glucose tolerance test results and to assess whether such patients are at a greater risk than normal pregnant patients for adverse perinatal outcome. In this retrospective cohort study that was conducted between June and December 2003, 101 pregnant women (group A) had an abnormal glucose challenge test result and a normal oral glucose tolerance test result. Data were also collected on 2 control groups: 100 pregnant women with normal glucose challenge test results (group B) and all 76 pregnant women who were diagnosed with gestational diabetes mellitus during this period of time (group C). Patients with multiple pregnancies, chronic hypertension, pregestational diabetes mellitus, or any other maternal or fetal problems that were diagnosed before 24 weeks (when the glucose challenge test was performed) were excluded from the study groups. The following data were collected and analyzed: maternal age, maternal weight and height, parity and gravidity, diabetes mellitus in first-degree relatives, medical and obstetric history, ethnicity, complications during the third trimester of pregnancy, birth weight, gestational age at delivery, mode of delivery, Apgar scores, cord blood gas results, maternal complications of labor and during the postpartum period, and infant admission to the neonatal intensive care unit. For comparison between groups, we used the Student t test, 1-way analysis of variance, the chi-square test, and stepwise logistic regression. Patients in groups A and C were significantly older compared with group B (29.2 +/- 5.6 years and 30.4 +/- 5.5 years, respectively, vs 24.8 +/- 5.5 years; P < .01), had a lesser rate of primiparity (48% and 31%, respectively, vs 24%; P < .05), had greater body mass index (30.8 +/- 5 kg/m2 and 31.3 +/- 6 kg/m2, respectively, vs 29.2 +/- 4.4 kg/m2; P < .01), had a greater rate of previous gestational diabetes mellitus (6% and 20%, respectively, vs 0%; P < .05), and had a greater rate of first-degree family members with diabetes mellitus (21% and 21%, respectively, vs 3%; P < .01). None of the outcome parameters was statistically significant when group A was compared with group B. Patients with an abnormal glucose challenge test result and a subsequent normal oral glucose tolerance test result have different maternal characteristics and backgrounds compared with patients in whom both test results are normal, yet both groups have normal outcomes. We should continue to consider patients who have an abnormal glucose challenge test result and subsequent normal oral glucose tolerance test result as low-risk; however, these findings may represent an indication of an increased likelihood for the development of overt diabetes mellitus later in life.

Apparent Resolution of Type 2 Diabetes Mellitus after Initiation of Potent Antiretroviral Therapy in a Man from Africa with HIV Infection

We describe a 52-year-old African man with human immunodeficiency virus infection and type 2 diabetes mellitus whose diabetes resolved as viral replication was suppressed with protease inhibitor-based antiretroviral therapy. This case suggests that human immunodeficiency virus infection itself can precipitate overt diabetes mellitus.

Safety of Growth Hormone Treatment in Children Born Small for Gestational Age: The US Trial and KIGS Analysis

Background: Recently, growth hormone (GH) therapy for children with short stature born small for gestational age (SGA) has been approved in the USA and Europe. There have been few reports examining adverse events during GH treatment of these children. Aims: (i) To examine glucose tolerance and insulin sensitivity during GH treatment of children born SGA in a US trial. (ii) To determine and compare adverse events reported in children born SGA with those reported in children with idiopathic short stature (ISS) enrolled in KIGS – Pfizer International Growth Database. Methods: In the US SGA trial, an oral glucose tolerance test was performed and fasting plasma glucose, insulin and glycosylated haemoglobin (HbA_1C) concentrations were measured at baseline and after 12 months of GH therapy. Insulin sensitivity was calculated using the homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). In the KIGS analysis, a retrospective audit of spontaneously logged cumulative adverse events in children born SGA and those with ISS was undertaken. Adverse events are reported per 1,000 patients. Values are expressed as mean with 10th–90th percentiles. Results: In the US trial, 84 patients had complete data sets for analysis. Median birth weight was 1.78 kg (SDS, –2.5) and birth length 43 cm (SDS, –2.2) at a median gestational age of 36.5 weeks; 79% were Caucasian. At entry, median age of the patients analysed was 6.6 years, and 65% were male. Median height was 104.3 cm (SDS, –2.97), median weight 15.95 kg (SDS, –2.21) and body mass index 14.66 kg/m² (SDS, –0.67). No patients developed impaired glucose tolerance or overt diabetes mellitus. The 0-min glucose concentration was 81 mg/dl at baseline and 86 mg/dl at 1 year, while the 120-min glucose concentration was 90 mg/dl at baseline and 96 mg/dl at 1 year. The 0-min insulin concentrations were 2.9 mU/l at baseline and 5.3 mU/l at 1 year, while the 120-min insulin levels were 7.7 mU/l at baseline and 11 mU/l at 1 year. The proportions of HbA_1C were 5.2 and 5.4% at baseline and 1 year, respectively. HOMA and QUICKI values were 0.59 and 0.42, respectively, at baseline, and 1.13 and 0.38 at 1 year. In KIGS, there were 1909 children born SGA aged 9.1 (3.9–13.3) years with a birth weight SDS of –2.6 (–4.0 to –1.5), birth length SDS of –2.7 (–4.3 to –1.3) and height SDS of –2.71 (–3.9 to –1.8) prior to treatment. GH doses ranged from 0.032 to 0.037 in the USA and from 0.022 to 0.023 mg/kg/day in the remaining countries in KIGS. Neither total (187 vs. 183) nor serious (14 vs. 10) adverse events occurred more commonly in the SGA group than in the ISS group. Although respiratory adverse events occurred more commonly in children born SGA (34.3 vs. 16.8; p < 0.05), endocrine (12.0 vs. 2.7; p < 0.05) and hepatobiliary (6.2 vs. 1.1; p < 0.05) adverse events occurred more commonly in children with ISS. Conclusions: As expected, a reduction in insulin sensitivity occurred during GH treatment of children born SGA; however, glucose tolerance remained normal. No adverse events were reported more commonly in children born SGA than in those with ISS. Minor differences in adverse events reporting within organ systems between children born SGA and those with ISS are probably due to variable under-reporting of adverse events. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA.

Unexpected high prevalence of metabolic disorders and chronic disease among young male draftees--the Swiss Army XXI experience.

What are the benefits of laboratory screening examinations entailed in the new army recruitment concept (Swiss Army XXI)? PRINCIPLES/METHODS: Between January 1 and June 30, 2004, a total of 7714 of 11,322 (68%) draftees from 6 Swiss army recruitment centres underwent clinical examination and laboratory testing. In 1.7% of the draftees we found elevated levels of the C-reactive protein (CRP) as evidence of infection or inflammation. Although we found no case of acute hepatitis, 16 draftees had active hepatitis B and 1 patient had active hepatitis C. Diseases, which were found by laboratory screening, and which forbid service in the army, included Crohn's disease, terminal renal insufficiency and essential thrombocytosis. In conditions such as anaemia (0.1%) or latent iron deficiency (7.2%), the cause may have to be elucidated before the start of military training. In other draftees (9.8%), we found elevated alanine-amino-transferase (ALAT) levels as a hint to possible alcohol abuse, which might impair the ability to serve in special units of the army. Finally, elevated levels of ferritin (0.1%), glucose (0.4%), and cholesterol (1.4%) may indicate iron overload/haemochromatosis, impaired glucose tolerance or even overt diabetes mellitus and hypercholesterolaemia. The results of our studies indicate that laboratory evaluation may confirm findings of the medical examination and may help to explain unspecific symptoms. Draftees with severe diseases and conditions caused by serious underlying disease can be excluded from military services early on the basis of laboratory testing. Future cost benefit analyses will have to show whether laboratory screening and consecutive early preventive measures are also advantageous to society as a whole and will reduce public health costs.

Unexpected high prevalence of metabolic disorders and chronic disease among young male draftees--the Swiss Army XXI experience.

What are the benefits of laboratory screening examinations entailed in the new army recruitment concept (Swiss Army XXI)? PRINCIPLES/METHODS: Between January 1 and June 30, 2004, a total of 7714 of 11,322 (68%) draftees from 6 Swiss army recruitment centres underwent clinical examination and laboratory testing. In 1.7% of the draftees we found elevated levels of the C-reactive protein (CRP) as evidence of infection or inflammation. Although we found no case of acute hepatitis, 16 draftees had active hepatitis B and 1 patient had active hepatitis C. Diseases, which were found by laboratory screening, and which forbid service in the army, included Crohn's disease, terminal renal insufficiency and essential thrombocytosis. In conditions such as anaemia (0.1%) or latent iron deficiency (7.2%), the cause may have to be elucidated before the start of military training. In other draftees (9.8%), we found elevated alanine-amino-transferase (ALAT) levels as a hint to possible alcohol abuse, which might impair the ability to serve in special units of the army. Finally, elevated levels of ferritin (0.1%), glucose (0.4%), and cholesterol (1.4%) may indicate iron overload/haemochromatosis, impaired glucose tolerance or even overt diabetes mellitus and hypercholesterolaemia. The results of our studies indicate that laboratory evaluation may confirm findings of the medical examination and may help to explain unspecific symptoms. Draftees with severe diseases and conditions caused by serious underlying disease can be excluded from military services early on the basis of laboratory testing. Future cost benefit analyses will have to show whether laboratory screening and consecutive early preventive measures are also advantageous to society as a whole and will reduce public health costs.

Abnormal Glucose Regulation and Treatment Strategies for Insulin Resistance HIV-Infected Patients

HIV-infected patients receiving highly active antiretroviral therapy often demonstrate abnormalities in glucose regulation, in association with changes in fat distribution[1,2]. In the majority of cases, these abnormalities are best characterized by insulin resistance and impaired glucose tolerance, rather than overt diabetes mellitus and fasting hyperglycemia. Insulin resistance may result from direct effects of antiretroviral therapy, changes in fat distribution or abnormal regulation of fat metabolism and adipocytokines. Use of insulin sensitizing agents may be rationale to reduce cardiovascular risk and improve related metabolic and body fat abnormalities in HIV-infected patients.

The combined effect of augmentation index and carotid intima-media thickness on cardiovascular risk in young and middle-aged men without cardiovascular disease

Carotid artery intima-media thickness (IMT) has been used as a surrogate marker of atherosclerosis and is related to cardiovascular risk. Indices of arterial stiffness are also associated with cardiovascular risk and atherosclerosis. The aim of this study was to assess the prognostic value of the combination of surrogate markers of cardiovascular disease measured non-invasively in subjects without cardiovascular disease. In this cross-sectional study, 81 young and middle aged males (39.2+/-6.3 years) without evidence of overt cardiovascular disease or diabetes mellitus were enrolled. High-resolution B-mode ultrasonography and pulse wave analysis were used to measure carotid artery IMT and augmentation index (AI), a measure of arterial stiffness. Framingham risk score (FRS) was used as an estimate of the risk for development of cardiovascular disease. Regional differences were observed in the carotid arteries' IMT regarding their relationship with FRS: combined (average from all sites) IMT and IMT in the carotid bulb (CB), but not in the common (CC) and internal carotid artery (IC), and AI showed significant increases of FRS by their tertiles. However, subjects with both AI and IMT at any site in the highest tertile (AI>15%, CC>0.65 mm, CB>0.8 mm, IC>0.65 mm) had an increased FRS compared to subjects with one or none of these parameters in the highest tertile. In conclusion, young and middle-aged men without overt cardiovascular disease with both high IMT and AI are in high cardiovascular risk, as assessed by FRS. Epidemiological studies are needed to further validate this combination.

Overt Diabetes Mellitus in a Patient with Combined Primary Aldosteronism and Cushing's Syndrome

Although there are some case reports of combined aldosterone and cortisol producing adrenal tumor, overt diabetes mellitus has been rarely described. A 55-year-old hypertensive woman had hypokalemia and overt hyperglycemia without Cushingoid clinical features. The body mass index was 18.2 kg/m2, fasting blood glucose was 302 mg/dl and hemoglobin A1c was 11.6%. Endogenous insulin secretion was well preserved, whereas insulin sensitivity measured by short insulin tolerance test was markedly impaired. A solitary left aldosterone- and cortisol-producing adrenal tumor was diagnosed. We described a rare case of overt diabetes mellitus in a patient with combined primary aldosteronism and Cushing's syndrome.

Increased insulin resistance and β cell activity in patients with Crohnʼs disease

Pancreatitis and exocrine pancreatitic insufficiency have been described as extraintestinal manifestations of inflammatory bowel disease. In this study, we investigated whether the endocrine pancreatic function is also disturbed in patients with inflammatory bowel disease. Seventeen patients with Crohn's disease and 13 healthy volunteers participated in the study. We analyzed the plasma insulin response in a 75-g oral glucose tolerance test. Glucose and insulin levels were determined at time 0 (fasting levels) and 30, 60, 90, 120, 180, 240, and 300 min after glucose uptake. Insulin resistance and beta cell function (BCF) were analyzed by calculating respective indices. Fasting and oral glucose-tolerance test glucose levels appeared to be similar in patients with Crohn's disease and in the controls. Impaired fasting glucose, impaired glucose tolerance, and/or overt diabetes mellitus were not observed in the volunteers. Insulin as well as the index for BCF were significantly increased in patients with Crohn's disease. In addition, insulin resistance was shown to be significantly elevated in Crohn's disease. Patients with Crohn's disease reveal an increased insulin secretion caused by an enhanced BCF, which may be induced by an up-regulated enteropancreatic axis. This hypersecretion may override the insulin resistance given by the chronic inflammatory state.

Impaired left ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of Nɛ‐(carboxymethyl) lysine

Myocardial dysfunction in the absence of myocardial ischemia is frequent in patients with diabetes mellitus but the underlying pathomechanism is unclear. We investigated whether accumulation of advanced glycation end products (AGEs) in the diabetic myocardium is related to its functional abnormalities. In 11 male homozygous Zucker diabetic fatty rats (ZDF/Gmi-fa/fa) aged 37 weeks (OBESE) and 11 non-obese, non-diabetic littermates (LEAN), we measured left ventricular function (pressure-volume catheter) and levels of N(epsilon)-(carboxymethyl) lysine (CML), a prototypical AGE, in serum and the left ventricle (competitive enzyme linked immuno-assay). Overt diabetes mellitus (HbA1c > 9%) was present in all OBESE animals but not in LEAN. Systolic left ventricular function was not different between the groups, but the markers of left ventricular relaxation, dP/dt(min) and the relaxation constant tau, were impaired in OBESE. In parallel, CML levels were increased in serum (273 +/- 15 vs. 197 +/- 10 ng/ml, p<0.05) and in the left ventricle (18.4 +/- 1.1 vs. 12.5 +/- 2.0 ng/mg protein, p < 0.05) in OBESE compared to LEAN. There was a linear correlation between tau and the left ventricular CML levels (r = 0.65; p < 0.05). We conclude that type 2 diabetes is associated with predominant left ventricular diastolic dysfunction. Myocardial accumulation of advanced glycation end products may contribute to relaxation abnormalities in type 2 diabetes.

Lifestyle Management of Erectile Dysfunction: The Role of Cardiovascular and Concomitant Risk Factors

The influence and significance of lifestyle factors in erectile dysfunction (ED) have been demonstrated in cross-sectional and prospective, randomized, controlled trials. Recent epidemiologic studies in several countries have shown that modifiable lifestyle or risk factors, including physical activity in particular, are directly related to the occurrence of ED. In this article, we review several recent observational studies, 2 of which include a longitudinal follow-up component in the study design. The levels of physical activity in both of these studies predicted ED prevalence and incidence. Furthermore, the role of lifestyle changes (weight loss, physical activity) were recently demonstrated to be effective in modifying ED in a prospective, randomized Italian trial in moderately obese, sedentary men. Men without overt diabetes mellitus or cardiovascular disease participated in this landmark study. Other studies have shown that aggressive management of cardiovascular risk factors can increase the effectiveness or outcomes associated with pharmacologic management of ED. Taken together, these studies support the value of risk factor modification and lifestyle change in the clinical management in men with ED and concomitant cardiovascular illness.

A Nonsense Mutation in the Arg345 of the Insulin Receptor Gene in a Japanese Type A Insulin-resistant Patient

Defects in insulin receptor function have been associated with insulin resistant states such as obesity and type 2 diabetes mellitus. Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. We have studied a 10-year-old Japanese girl with type A insulin resistance with hirsutism and hyperinsulinemia but without the dysmorphic features characteristic of leprechaunism or Rabson-Mendenhall syndrome. Despite the presence of severe insulin resistance, the patient did not develop overt diabetes mellitus at the time of investigation. Using direct sequencing, we identified a nonsense mutation causing premature termination after amino acid 345 in the alpha subunit of the insulin receptor.

Calcium antagonists

Calcium antagonists were introduced for the treatment of hypertension in the 1980s. Their use was subsequently expanded to additional disorders, such as angina pectoris, paroxysmal supraventricular tachycardias, hypertrophic cardiomyopathy, Raynaud phenomenon, pulmonary hypertension, diffuse esophageal spasms, and migraine. Calcium antagonists as a group are heterogeneous and include 3 main classes—phenylalkylamines, benzothiazepines, and dihydropyridines—that differ in their molecular structure, sites and modes of action, and effects on various other cardiovascular functions. Calcium antagonists lower blood pressure mainly through vasodilation and reduction of peripheral resistance. They maintain blood flow to vital organs, and are safe in patients with renal impairment. Unlike diuretics and β-blockers, calcium antagonists do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. In long-term follow-up, patients treated with calcium antagonists had development of less overt diabetes mellitus than those who were treated with diuretics and β-blockers. Moreover, calcium antagonists are able to reduce left ventricular mass and are effective in improving anginal pain. Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients. In comparison with placebo, calcium antagonist—based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients and in diabetic patients. In several comparative studies in hypertensive patients, treatment with calcium antagonists was equally effective as treatment with diuretics, β-blockers, or angiotensin-converting enzyme inhibitors. From these studies, it seems that a calcium antagonist—based regimen is superior to other regimens in preventing stroke, equivalent in preventing ischemic heart disease, and inferior in preventing congestive heart failure. Calcium antagonists are also safe and effective as first-line or add-on therapy in diabetic hypertensive patients. Heart rate—lowering calcium antagonists (verapamil, diltiazem) may have an edge over the dihydropyridines in post—myocardial infarction patients and in diabetic nephropathy. Thus, calcium antagonists may be safely used in the management of hypertension and angina pectoris.

Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice.

We evaluated the effects of E2F1 on glucose homeostasis using E2F1(-/-) mice. E2F1(-/-) mice show an overall reduction in pancreatic size as the result of impaired postnatal pancreatic growth. Furthermore, these animals have dysfunctional beta cells, linked to impaired PDX-1 activity. Because of the disproportionate small pancreas and dysfunctional islets, E2F1(-/-) mice secrete insufficient amounts of insulin in response to a glucose load, resulting in glucose intolerance. Despite this glucose intolerance, E2F1(-/-) mice do not develop overt diabetes mellitus because they have insulin hypersensitivity, which is secondary to a diminished adipose tissue mass and altered adipocytokine levels, which compensates for the defect in insulin secretion. These data demonstrate that factors controlling cell proliferation, such as E2F1, determine pancreatic growth and function, subsequently affecting metabolic homeostasis.

Impaired pancreatic growth, β cell mass, and β cell function in E2F1 –/– mice

We evaluated the effects of E2F1 on glucose homeostasis using E2F1–/– mice. E2F1–/– mice show an overall reduction in pancreatic size as the result of impaired postnatal pancreatic growth. Furthermore, these animals have dysfunctional β cells, linked to impaired PDX-1 activity. Because of the disproportionate small pancreas and dysfunctional islets, E2F1–/– mice secrete insufficient amounts of insulin in response to a glucose load, resulting in glucose intolerance. Despite this glucose intolerance, E2F1–/– mice do not develop overt diabetes mellitus because they have insulin hypersensitivity, which is secondary to a diminished adipose tissue mass and altered adipocytokine levels, which compensates for the defect in insulin secretion. These data demonstrate that factors controlling cell proliferation, such as E2F1, determine pancreatic growth and function, subsequently affecting metabolic homeostasis.

Selective imidazoline agonist moxonidine plus the ACE inhibitor ramipril in hypertensive patients with impaired insulin sensitivity: partners in a successful MARRIAGE?

Hypertension in combination with clinically overt diabetes mellitus is recognized as a particularly powerful combination of risk factors that greatly increases cardiovascular vulnerability. There is also evidence that presumed pre-diabetic conditions such as insulin resistance, hyperinsulinaemia and compensatory hyperglycaemia may amplify overall cardiovascular risk in patients with hypertension, especially when encountered as part of the condition known as metabolic syndrome X (Reaven's syndrome).The long-term benefits of antihypertensive therapy may be compromised if these drugs exert adverse effects on metabolic parameters such as insulin sensitivity, or if they promote a transition from pre-diabetes to overt diabetes. Class differences in the effects of antihypertensives on metabolic indices may therefore be an important consideration when choosing treatment for patients who exhibit these characteristics.Experience from clinical trials suggests that drugs that target the renin-angiotensin system may have metabolic advantages over drugs such as beta-blockers and diuretics, but this conclusion has not been proved definitively.Moxonidine, which selectively targets imidazoline type-1 receptors in the sympathetic vasomotor centres of the rostral-ventrolateral medulla, is an effective antihypertensive and has been reported to exert favourable metabolic effects in preclinical and clinical studies. The MARRIAGE study (Moxonidine And Ramipril Regarding Insulin And Glucose Evaluation) will extend these preliminary observations by comparing the effects of moxonidine and the ACE inhibitor ramipril - and the combination of both drugs - on metabolic and haemodynamic parameters in patients with hypertension and impaired fasting glycaemia. A description is provided of the design and conduct of MARRIAGE.

Impaired glucose metabolism in patients with heart failure: pathophysiology and possible treatment strategies.

The firm association of diabetes mellitus with congestive heart failure (CHF) has been undoubtedly established. Recent reports support the presence of the reciprocal interrelationships between CHF and glucose abnormalities. The present review provides an overview of some aspects of the multifactorial interrelationships between heart failure and diabetes mellitus. Patients with heart failure are generally at higher risk of developing type 2 diabetes mellitus. Several factors may be involved, such as a lack of physical activity, hypermetabolic state, intracellular metabolic defects, poor muscle perfusion, and poor nutrition. Serum levels of inflammatory cytokines and leptin are elevated in patients with heart failure. Activation of the sympathetic system in CHF not only increases insulin resistance but also decreases the release of insulin from the pancreatic beta cells, increases hepatic glucose production by stimulating both gluconeogenesis and glycogenolysis, and increases glucagon production and lipolysis. People who develop type 2 diabetes mellitus usually pass through the phases of nuclear peroxisome proliferator-activated receptor modulation, insulin resistance, hyperinsulinemia, pancreatic beta-cell stress and damage leading to progressively decreasing insulin secretion, and impaired fasting and postprandial blood glucose levels. Once hyperglycemia ensues, the risk of metabolic and cardiovascular complications also increases. It is possible that the cornerstone of diabetes mellitus prevention in patients with CHF could be controlled by increased physical activity in a cardiac rehabilitation framework. Pharmacologic interventions by some medications (metformin, orlistat, ramipril and acarbose) can also effectively delay progression to type 2 diabetes mellitus in general high risk populations, but the magnitude of the benefit in patients with CHF is unknown. In patients with CHF and overt diabetes mellitus, ACE inhibitors may provide a special advantage and should be the first-line agent. Recent reports have suggested that angiotensin receptor antagonists (angiotensin receptor blockers), similar to ACE inhibitors, provide beneficial effects in patients with diabetes mellitus and should be the second-line agent if ACE inhibitors are contraindicated. Treatment with HMG-CoA reductase inhibitors should probably now be considered routinely for all diabetic patients with CHF, irrespective of their initial serum cholesterol levels, unless there is a contraindication.

Arterielle Hypertonie und metabolisches Syndrom

Das metabolische Syndrom oder Insulinresistenzsyndrom ist eine metabolische Storung, die durch eine eingeschrankte physiologische Reaktion auf Insulin charakterisiert ist. Die klinische Definition stutzt sich auf den Nachweis einer arteriellen Hypertonie, einer abdominellen Adipositas, erhohte Triglyzerid- sowie niedrige HDL-Cholesterin-Werte und eine diabetische Stoffwechsellage. Die Pravalenz des Insulinresistenzsyndroms nahm in den letzten Jahrzehnten dramatisch zu und ist auf die Anderung des Lebensstils in industrialisierten Landern sowie in Schwellen- und Entwicklungslandern zuruckzufuhren. Die klinische Bedeutung des metabolischen Syndroms liegt im hohen Risiko, fruhzeitig kardiovaskulare Erkrankungen zu bekommen bzw. an diesen zu versterben. Ziel arztlichen Handelns ist es deshalb, das Auftreten eines metabolischen Syndroms zu verhindern (Pravention) und begleitende Faktoren wie arterielle Hypertonie und Dyslipidamie zu therapieren. Die abdominelle Adipositas ist hierbei als Schlussel fur die Entstehung des metabolischen Syndroms zu sehen, weshalb eine konsequente Gewichtsreduktion die erste Prioritat einnehmen sollte. Die Gewichtsreduktion mit Ruckgang der Adipositas fuhrt nachfolgend auch zur Verbesserung von Hypertonie und Dyslipidamie. Die Bedeutung eines aeroben Ausdauertrainings wird kontrovers diskutiert, es wird jedoch als begleitende Masnahme zur Gewichtsreduktion empfohlen. Erhohte Blutdruckwerte sind zum einen Kardinalsymptom des metabolischen Syndroms, zum anderen fuhren sie zu einer uberproportionalen Steigerung des kardiovaskularen Risikos bei Patienten mit diabetischer Stoffwechsellage. Aus diesem Grund wird eine aggressive Blutdrucksenkung auf Werte unter 130/80 mmHg gefordert, wobei Diuretika, ACE-Hemmer und Angiotensin-II-Typ- 1-Rezeptor-Blocker als First-Line-Antihypertensiva verwendet werden sollten.