Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study.

BACKGROUND: Hypertensive patients frequently show resistance to insulin-stimulated glucose uptake and hyperinsulinemia. Diuretics and beta-adrenoceptor blocking agents have been found to decrease insulin sensitivity, whereas alpha 1-blockers and angiotensin converting enzyme inhibitors seem to improve it. OBJECTIVE: To compare the effects of a 3 months' antihypertensive treatment with carvedilol, a non-selective beta-adrenoceptor blocker with alpha 1-blocking properties, with the beta 1-selective receptor blocker metoprolol on insulin sensitivity in non-diabetic hypertensive patients. DESIGN: A multicenter double-blind randomized study. SUBJECTS AND METHODS: Seventy-two non-diabetic hypertensive patients were randomly assigned to treatment with either carvedilol or metoprolol. An isoglycemic, hyperinsulinemic glucose clamp was conducted before and after 12 weeks of treatment; the metabolic clearance rate for glucose was taken as an indicator of insulin sensitivity. RESULTS: The two groups did not differ in age, sex, body mass index, blood pressure or lipids, and treatment effectively lowered blood pressure. In both groups, insulin sensitivity was impaired at baseline. After metoprolol treatment, insulin sensitivity further decreased significantly by about 14%, whereas it increased after carvedilol. There was also a decrease in high-density lipoprotein and an increase in triglycerides levels in patients in the metoprolol-treated group, whereas these parameters remained unchanged in patients in the carvedilol-treated group. CONCLUSION: This study confirms previous findings of a reduction in insulin sensitivity after chronic metoprolol treatment. Carvedilol treatment, however, resulted in a small amelioration of insulin resistance and a better lipid profile [corrected]. We thus demonstrate that a beta-blocker with alpha 1-blocking properties has favorable effects on glucose metabolism, suggesting a potentially important role of peripheral blood flow in regulating glucose uptake. These findings imply that beta-blocker treatment, when combined with alpha 1-blocking activity has advantageous effects on insulin sensitivity and lipids and could therefore be suitable for patients with the metabolic syndrome.

[Newly manifested type IIb diabetes presents with significant hyperinsulinemia]. / Bei neu manifestiertem Typ-IIb-Diabetes besteht eine erhebliche Hyperinsulinämie.

BACKGROUND: Data concerning the insulin status in the early phase of NIDDM are controversial. PATIENTS AND METHOD: Since this has therapeutical implications, ten patients were identified with new-onset type 2 diabetes, defined by fasting blood glucose concentrations below 120 mg/dl, no previous history of diabetes and venous blood glucose concentrations at 120 min of an oral glucose tolerance test above 200 mg/dl (x 262 +/- 15 mg/dl) ("diabetic glucose tolerance"). Ten subjects with normal glucose tolerance and no familial history of NIDDM, who were matched for gender, age (n: 56 +/- 2 years, D: 61 +/- 5) and BMI (n: 28 +/- 1, D: 28 +/- 1), served as control group. Serum insulin was measured using a double-antibody sandwich-test (no cross-reaction with proinsulin and C-peptide) at 0, 30 and 120 min of an oGTT. RESULT: In the diabetic group, basal insulin levels were found to be elevated 1.7-fold (n: 7.9 +/- 1.4 uU/ml, D: 13.3 +/- 1.4, p = 0.03), 30 min values were the same in both groups and the 120 min value was 4.6-fold higher in the diabetic group (n: 33.9 +/- 8.7, D: 156.2 +/- 27.4, p = 0.0008). CONCLUSION: Thus, in new-onset diabetes, in the early phase of an oGTT (30 min) both insulin secretion and action are reduced, in the second phase (120 min) severe insulin resistance predominates at maximally stimulated secretion. These findings underline the therapeutical strategy in these patients, to reduce postprandial blood glucose increments and improve insulin resistance by diet and, if necessary, pharmacologically.

Potential role of bradykinin in forearm muscle metabolism in humans.

Using the euglycemic-hyperinsulinemic glucose clamp and the human forearm technique, we have demonstrated that the improved glucose disposal rate observed after the administration of an angiotensin-converting enzyme (ACE) inhibitor such as captopril may be primarily due to increased muscle glucose uptake (MGU). These results are not surprising because ACE, which is identical to the bradykinin (BK)-degrading kininase II, is abundantly present in muscle tissue, and its inhibition has been observed to elicit the observed metabolic actions via elevated tissue concentrations of BK and through a BK B2 receptor site in muscle and/or endothelial tissue. These findings are supported by several previous studies. Exogenous BK applied into the brachial artery of the human forearm not only augmented muscle blood flow (MBF) but also enhanced the rate of MGU. In another investigation, during rhythmic voluntary contraction, both MBF and MGU increased in response to the higher energy expenditure, and the release of BK rose in the blood vessel, draining the working muscle tissue. Inhibition of the activity of the BK-generating protease in muscle tissue (kallikrein) with aprotinin significantly diminished these functional responses during contraction. Applying the same kallikrein inhibitor during the infusion of insulin into the brachial artery significantly reduced the effect of insulin on glucose uptake into forearm muscle. This is of interest, because in recent studies insulin has been suggested to elicit its actions on MBF and MGU via the accelerated release of endothelium-derived nitric oxide, the generation of which is also stimulated by BK in a concentration-dependent manner. This new evidence obtained from in vitro and in vivo studies sheds new light on the discussion of whether BK may play a role in energy metabolism of skeletal muscle tissue.

Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin.

The effect of bradykinin on glucose transporter translocation in isolated rat heart was compared with the effect of insulin. Hearts from male obese (fa/fa) Zucker rats were perfused under normoxic conditions and constant pressure in a classic Langendorff preparation with 12 mmol/l glucose as substrate, and a set of functional parameters was measured simultaneously. Bradykinin was administered at a concentration (10(-11) mmol/l) that did not increase coronary flow. Insulin was used at a concentration (8 x 10(-8) mmol/l) known to maximally stimulate glucose transport in this model. After 15 min of perfusion with insulin or bradykinin, subcellular membrane fractions of the heart were prepared, and distribution of glucose transporter protein (GLUT1 and GLUT4) in fractions enriched with surface membranes (transverse tubules [TTs] and sarcolemmal membranes [PMs]) and with low-density microsomal membranes (LDMs) were determined by immunoblotting with the respective antibodies. Both glucose transporter isoforms were translocated after stimulation with insulin (increased transporter protein content in the PM+TT-enriched fraction with a concomitant decrease in the LDM-enriched fraction) and, to a smaller extent, also with bradykinin. These data suggest that in hearts of insulin-resistant obese (fa/fa) Zucker rats, bradykinin interacts with or facilitates the translocation process of both GLUT1 and GLUT4.

Hypertension in the non-insulin-dependent diabetes mellitus syndrome: a critical review of therapeutic intervention.

BACKGROUND: Since it is not yet clear whether and to what degree treatment of mild hypertension will decrease cardiovascular morbidity and mortality in non-insulin-dependent diabetes (NIDDM), decisions concerning the treatment of hypertension diabetics are at present based on data from the non-diabetic population. RECENT RESEARCH ON CAUSES OF DIABETES: A large body of recent work on the sequence of events leading from the prediabetic to the hyperglycemic stages of the NIDDM syndrome has suggested that elevated blood pressure and other cardiovascular risk factors may precede NIDDM by many years and that after the onset of NIDDM intervention might be too late to be beneficial. PROSPECTIVE INTERVENTION STUDY IN PROGRESS: It is not possible to draw firm conclusions that can be applied to the treatment of hypertensive diabetics before the results of the United Kingdom Prospective Diabetes Study/Hypertension in Diabetes Study are published later this decade. Unfortunately, this study does not consider different stages within the NIDDM syndrome. Moreover, World Health Organization criteria are not used for the diagnosis of either NIDDM or hypertension, so that the study subjects are insufficiently characterized. Finally, confounding variables such as racial, ethnic and sex differences and the individual stage of the NIDDM syndrome (and consequent variation in antidiabetic treatment) have been either not considered or not completely ruled out. These shortcomings seriously threaten the significance of this otherwise important study. CONCLUSIONS: As long as there are no diabetes-specific data from adequately sized intervention studies, recommendations for antihypertensive treatment in NIDDM will be based on strategies accepted for the non-diabetic population. These recommendations involve symptom-based diagnostic and therapeutic concepts of both NIDDM and hypertension and ignore recent pathogenetic concepts which could lead to an interdisciplinary and integrated approach to cardiovascular risk management, and possibly to the prevention of end-stage NIDDM syndrome with its advanced macrovascular complications.

New aspects of insulin resistance in hypertension.

Primary hypertension is a frequent polygenic disease with strong genetic and environmental components. During the last decade, evidence has been increasing that insulin resistance as a marker of increased risk for Type 2 diabetes and cardiovascular atherosclerotic disease is present not only in individuals with obesity, Type 2 diabetes and impaired glucose tolerance, but also in the majority of the hypertensive population. Insulin resistance describes a tissue- and pathway-specific defect of glucose metabolism present in the so called 'metabolic syndrome'. Hyperinsulinaemia compensates for insulin resistance, leading to a cluster of undesirable processes predisposing to diabetes, atheroma and, directly or indirectly, hypertension. Candidate mechanisms whereby this metabolic syndrome might lead to hypertension include renal sodium retention, vascular hyperresponsiveness, arteriolar smooth muscle cell proliferation, altered cellular electrolyte transport and composition, stimulation of sympatho-adrenergic activity and growth promoting effects. Insulin per se does not appear to be the cause of elevated blood pressure as frequently seen in insulin-resistant states, but it may act with other factors to promote hypertension and atherosclerotic cardiovascular disease.

[How can primary prevention of coronary heart disease be improved in general practice?]. / Wie kann die Primärprävention der koronaren Herzerkrankung in der Praxis verbessert werden?

BACKGROUND: The basic issue of primary prevention strategies of coronary heart disease is an individually adapted cardiovascular risk factor management. However, transformation of these strategies by health care professionals is still insufficient, as was demonstrated by three studies performed in private practice. METHODS AND RESULTS: In oral glucose tolerance tests performed in 234 patients with essential hypertension who were under regular medical control, 25.6% turned out to have previously unknown diabetes and 41.4% had impaired glucose tolerance. In the remaining 33.3% with normal glucose tolerance, mean total serum cholesterol was 260 mg/dl. 82 patients with essential hypertension and known diabetes had a mean total serum cholesterol of 276 mg/dl. Neither cohort was under lipid lowering drugs. Out of 290 unselected patients treated for type II-diabetes in private practice, 62% were hypertensive. Of those, hypertension was not known untreated or not sufficiently treated in 78.2%. CONCLUSION: As a consequence, in patients at high cardiovascular risk, not only the "leading" disease (i.e. diabetes, hypertension, hyperlipidaemia), but also the concomitant constellation deserves attention and early intervention.

[The metabolic syndrome. Pathophysiologic causes, diagnosis, therapy]. / Das metabolische Syndrom. Pathophysiologische Ursachen, Diagnostik, Therapie.

The individual components of the metabolic syndrome such as central obesity, dyslipidemia with increased triglycerides and decreased HDL-cholesterol, hyperuricemia, hypertension and progressive glucose intolerance are markers for an increased risk of atheroma and type 2 (non-insulin-dependent) diabetes. All components, with the exception of hyperuricemia, are associated with skeletal muscle insulin resistance, leading to compensatory chronic hyperinsulinemia. Insulin resistance/hyperinsulinemia, in turn, is associated with a series of hypertensiogenic and atherogenic side effects, aggravating the individual components of the metabolic syndrome. From a more pathophysiologically orientated point of view, early identification of individuals obviously at risk for atheroma and type 2 diabetes, as well as early intervention aimed at the improvement of reduced insulin action may play a central role in an integrated life-style approach of primary prevention of atherosclerosis and type 2 diabetes.

Possible synergistic effect of ACE inhibition and calcium-channel blockade on insulin sensitivity in insulin-resistant type II diabetic hypertensive patients.

So-called insulin resistance is a frequent phenomenon and a marker of increased risk for both type II diabetes mellitus and atherosclerosis. Today, insulin resistance is widely understood as a tissue- and pathway-specific defect of insulin-stimulated glucose uptake into skeletal muscle that is compensated for by hyperinsulinemia, leading to a cluster of undesirable hypertensiogenic, diabetogenic, and atherogenic processes. Additional defects of insulin-stimulated muscle blood flow and cellular kation balance are presently attracting increasing awareness. Clinical and experimental evidence suggests that angiotensin-converting enzyme (ACE) inhibition ameliorates both insulin-stimulated skeletal-muscle glucose uptake and blood flow in insulin-resistant states by a direct stimulation of cellular glucose uptake, which appears to be kinin-mediated. This improvement of insulin sensitivity could mean not only improvement of glucose metabolism, but also reduction of chronically elevated serum insulin and the ensuing atherogenic consequences (hyper- and dyslipidemia, sympathetic overactivity, growth of vascular smooth-muscle cells, hypertension, etc.). Ca(2+)-channel blockers that do not increase heart rate appear to exert direct antiatherogenic effects while being metabolically neutral. Thus, the combination of Ca(2+)-channel blockade by sustained release verapamil and ACE inhibition by trandolapril in insulin-resistant type II diabetic patients with essential hypertension appears to be promising in terms of possible synergistic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

What is the clinical significance of insulin resistance?

Insulin resistance is a frequent phenomenon and a marker of increased risk for non-insulin-dependent diabetes mellitus (NIDDM) and atherosclerosis. According to recent estimations, not only individuals with obesity, NIDDM, and impaired glucose tolerance (IGT) but also one fourth of the "healthy" glucose tolerant and the majority of the hypertensive population are insulin resistant. Insulin resistance describes a tissue- and pathway-specific defect of glucose metabolism that is compensated for by hyperinsulinemia, leading to a cluster of undesirable hypertensiogenic, diabetogenic, and atherogenic processes. The initial defect can be directly measured by glucose clamp and other sophisticated techniques; the clinical syndrome may be derived from a network of related variables known to be associated with reduced insulin action. Because neither clamps nor serum insulin screenings will be available on a widespread basis, early diagnosis based on clinical criteria is crucial. A new interpretation of the "thrifty" genotype hypothesis may explain why insulin resistance, which formerly apparently represented an advantage in the evolutionary selection process, is such a frequent phenomenon. Improvement of impaired insulin action as a therapeutic principle may play a future central role in an integrated lifestyle approach of primary prevention of noncommunicable diseases such as NIDDM, hypertension, and atherosclerosis.

Changes of hepatic morphology during parenteral nutrition with lipid emulsions containing LCT or MCT/LCT quantified by ultrasound.

Fatty infiltration of the liver with cholestasis is one of the complications of total parenteral nutrition (TPN). The cause has not yet been determined. It seems probable, however, that these alterations could be prevented when a mixture of medium- and long-chain triglycerides (MCT/LCT) is used as a fat component instead of the application of long-chain emulsions (LCT) alone. To determine whether this could also be demonstrated morphologically in man, 14 patients needing TPN (25 kcal/kg BW x day, carbohydrate 45%, fat 35%, protein 20%) were examined by ultrasound in order to compare liver size and gray-scale value before and after 7 days of TPN. Seven of the patients were randomly administered a MCT/LCT emulsion as their fat intake, the other seven were exclusively given LCT. There were no changes in liver size and gray-scale value in the MCT/LCT-group, whereas both parameters showed a significant rise in the patients with LCT (size: 10.4 +/- 1.4 to 11.5 +/- 1.4 cm; gray-scale value: 9.3 +/- 1.0 to 11.6 +/- 0.7). These data suggest that TPN, administered with a mixture of MCT/LCT emulsions as fat components, could reduce the risk of hepatic dysfunction such as cholestasis and fatty infiltration of the liver.

[Effect of prostaglandin E1 on amino acid metabolism of human skeletal muscle]. / Einfluss von Prostaglandin E1 auf den Aminosäurestoffwechsel des menschlichen Skelettmuskels.

The influence of an intraarterial infusion of PGE1 on the amino acid metabolism of human skeletal muscle was examined in healthy volunteers using the forearm technique. A continuous increase of perfusion from 2.9 +/- 0.1 ml/100 g x min to 5.4 +/- 1.5 after 60 min could be observed. Muscular amino acid balances were not changed after 30 min but significantly after 60 min of PGE1 infusion. Muscular release of most of the amino acids was reduced or shifted to an uptake. The accumulated balance of the amino acids showed a significant increase from -21.9 to +33.2 nmol/100 g x min after 60 min. Thus the infusion of PGE1 led to an inhibition of muscular proteolysis and/or to a stimulation of proteosynthesis. In view of the fact that kinines are released during exercise and are partially effective via prostaglandine liberation, the protein-anabolic effect of exercise might be explained by action of prostaglandins.

[Essential hypertension and diabetes mellitus]. / Essentielle Hypertonie und Diabetes mellitus.

While the incidence of essential hypertension is not increased in type 1 diabetics, it is about three times as high in type 2 diabetics. Since in 50% of the cases, hypertension is present before the metabolic disorder becomes manifest, an association between the etiologies of the two disturbances was suspected as long as 65 years ago. A new understanding of the significance of insulin resistance and hyperinsulinemia suggests that the two conditions are part of a single metabolic disorder. This is supported by the fact that normal-weight hypertensives can also manifest insulin resistance, and they more often develop a type 2 diabetes mellitus. These facts urge us to re-think our therapeutic approach to hypertension, and to employ, as far as possible, only those substances that have no negative influence on the incidence of the metabolic disorder. With the introduction of ACE-inhibitors capable of improving insulin sensitivity, we now have, for the first time, the possibility of improving the prognosis of the metabolic syndrome. Moreover, their molecular mechanism of action provides initial clues as to the possible etiology of the syndrome.

Clinical studies with CE-inhibitors in diabetes.

Early antihypertensive intervention in diabetes often means intervention in a cluster of cardiovascular risk factors including glucose intolerance per se, hyperlipidemia, obesity and hypertension, which are not just coexistent but may be causally linked together by the resistance of peripheral tissues to the action of insulin. Blood pressure lowering treatment should therefore be metabolically neutral in order to avoid aggravation of this risk factor syndrome. Clinical studies applying CE-inhibitors in type II diabetes are critically reviewed under this aspect. The majority of the available studies in type II diabetes report a reduction of insulin resistance and a marginal improvement of metabolic control. The order of magnitude in HbA1 reduction is nearly 10% of the glycosylated haemoglobin, reduction of fasting and postprandial blood glucose approximates 1 mmol/l. From a more extended view, considering essential hypertension as insulin resistant and thus possibly "prediabetic" state, this marginal metabolic effect gets further support from recent studies in essential hypertension consistently reporting an improvement of metabolic parameters of similar magnitude. This might become a central argument in the discussion about individualized and metabolically neutral antihypertensive treatment in essential hypertension.

[ACE-inhibitors and glucose metabolism]. / ACE-Hemmer und Glukosestoffwechsel.

ACE-inhibitors exhibit their blood pressure-lowering activity not only via a reduction of angiotensin II but also via on increase of kinin levels. The latter are known to improve insulin action and hence carbohydrate metabolism in normal volunteers and diabetics. Accordingly, ACE-inhibitors display the same effects. As clinical trials show they are especially useful for the treatment of hypertension in diabetes mellitus.

Metabolic effects of kinins: historical and recent developments.

In 1928, Frey and co-workers discovered kallikrein in human urine and described its prolonged hypotensive effect in the dog. Four years later, the same authors first reported a blood glucose-lowering effect of orally administered kallikrein in diabetic patients. However, the observed blood glucose-lowering effect of kallikrein appeared to fade with repeated administration, and therefore its possible metabolic role was not further investigated and fell into disregard. One decade ago, experimental data yielded indirect evidence that the regulation of local skeletal muscle blood flow and glucose uptake during work was mediated by proteolytically cleaved kinins. Further experiments demonstrated that in insulin-resistant states such as postoperative stress and type II diabetes, reduced muscular insulin sensitivity was increased and partly restored by continuous low-dose infusion of synthetic bradykinin. Recent work showing that tissue kallikrein is present in a number of different tissue sites, including skeletal muscle and our own observation of local kinin overflow after muscle work in healthy subjects, but not in type II diabetics, support the concept of a skeletal muscle kallikrein-kinin system (KKS) that is locally activated upon contraction. Moreover, in isolated perfused rat heart preparations, favorable effects of kinins on myocardial glucose uptake, oxidation, and glycolytic flux have been reported. Most interestingly, cardioprotective effects of kinins have been observed and attributed to improved energy and substrate metabolism in ischemic hearts. Taken together, these data gave rise to the concept that tissue KKS might be involved in the local modulation of skeletal muscle and myocardial tissue blood flow and substrate metabolism, and that activation of the KKS is defective in insulin-resistant states.