Antiketogenic action of fructose in man.

The effect of fructose infusion (10 gm. every five minutes as a bolus followed by 0.5 gm. per kilogram X hours) on arterial concentrations and hepatic balances of ketones was studied in four juvenile diabetics 24 hours after the withdrawal of insulin. Arterial and hepatic venous concentrations of beta-hydroxybutyrate, acetoacetate, free fatty acids, fructose, and oxygen were measured. Hepatic blood flow was also determined. At constant rates of splanchnic fructose extraction, an 82 per cent diminution of the arterial hepatic venous concentration difference of the ketones was observed but the arteriovenous difference of free fatty acis rose moderately. Since hepatic blood flow was only slightly increased (17 per cent) there was no doubt that total hepatic ketone body formation was reduced. The magnitude of this antiketogenic action became apparent from the continuous fall of the arterial ketone concentrations. Since splanchnic oxygen uptake rose 40 per cent, it is suggested that the antiketogenic effect of fructose was due not only to enhanced re-esterification but also to accelerated oxidation of free fatty acids.

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.

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.

Low-dose glucose infusion in patients who have undergone surgery. Possible cause of a muscular energy deficit.

To evaluate the effect of the glucose-induced insulin release on peripheral substrate metabolism, we studied muscle metabolism in seven patients after elective surgery and in four healthy volunteers combining the forearm and the euglycemic glucose clamp technique (insulin infusion, 0.2 mU/kg per minute). Arterial and deep venous concentrations of substrates and hormones were determined in the basal period and during steady state of the infusion period. After 90 minutes of insulin infusion, the whole-body glucose infusion rate was significantly lower in patients who had elective surgery, although plasma insulin concentrations were comparable. In both groups this was related to a reduced supply of free fatty acids and ketones in muscle. In controls the resulting lack of substrates in muscle appeared to be compensated by an enhanced uptake of glucose, not seen in the patients who had elective surgery. Surprisingly, as indicated by the significantly reduced lactate production (-0.15 +/- 0.05 vs -0.62 +/- 0.32 mumol/100 g per minute basal), in this group the glucose taken up was oxidized aerobically to a greater extent. However, the total resulting energy gain was small. Thus, a peripheral energy deficit might arise favoring increased oxidation of amino acids. To avoid this undesired side effect, only those substrates should be administered that minimize pancreatic insulin release.

Substrate balances across the forearm during the early postoperative period.

The substrate metabolism of skeletal muscle has been studied by the forearm technique in 23 patients after abdominal operation. The data were compared to those of 55 healthy volunteers after an overnight fast. While the uptake of glucose into forearm muscle tissue was increased in relation to its elevated arterial concentration, its rate of oxidation was clearly reduced and the muscle extraction of ketone bodies was increased. Simultaneously, the production of lactate was doubled and the output of glycerol and alanine significantly enhanced. From these data one may conclude that 3 hours after abdominal surgery the energy requirements of skeletal muscle tissue are adequately met by the substrates provided that glucose sparing occurs in association with a rising arterial concentration of KB, and that the release of alanine is accelerated in spite of abundant caloric supply.

Substrate balances across skeletal muscle tissue in severe sepsis.

Substrate metabolism of skeletal muscle was studied by the forearm technique in eight patients with severe sepsis. The data were compared to those of 13 patients after elective surgery. In the septic group forearm blood flow was increased, but muscular utilisation of oxygen was diminished. Arterial concentrations of free fatty acids and ketone bodies were low. Thus, both only played a minor role in the supply of skeletal muscle with substrates. From the decreased production of lactate and alanine and the comparable utilisation of glucose we conclude that in the septic patients energy expenditure of skeletal muscle was mainly met by oxidation of glucose. In contrast to reduced lipolysis of adipose tissue intramuscular lipolysis may still be working since muscular production of lactate and glycerol was correlated. These findings suggest a changing pattern of arterial supply of substrates and utilisation of substrates by skeletal muscle during deterioration of clinical condition in the course of sepsis.

Inhibition of muscular glucose uptake by lipid infusion in man.

During a high-dose intravenous infusion of a mixed MCT/LCT-lipid emulsion and a conventional LCT-emulsion respectively, muscle substrate metabolism was investigated using the human forearm technique. With both lipid emulsions, a decrease in fractional muscular glucose extraction was seen, leading to significantly reduced muscular glucose uptake rates. An inverse linear relation between arterial tree fatty acids supply and fractional glucose extraction was seen suggesting that a mechanism according to Randle's glucose fatty acid concept is operating in skeletal muscle in man.

Comparison of metabolic clearance rates of MCT/LCT and LCT emulsions in diabetics.

In seven moderately overweight noninsulin-dependent diabetics with slightly elevated triglyceride levels, disappearance rates of infused medium chain triglyceride/long chain triglyceride (MCT/LCT) and long chain triglyceride (LCT) emulsions were compared. Five metabolically healthy volunteers served as controls. During a 3-hr lipid infusion, serum triglycerides reached a steady state with both emulsions in the healthy controls, whereas, in diabetic patients, steady state triglyceride levels were seen only with MCT/LCT. After the end of the lipid infusion, the longest half-life value in the decline of triglyceride levels was found with LCT in diabetics, whereas significantly shorter and quite similar half-life values were found with LCT in healthy controls and with MCT/LCT in diabetics. As expected, the shortest half-life for serum triglycerides was found in healthy controls after MCT/LCT-infusion. Virtually the same differences in serum concentrations and in half-life times were seen with free fatty acids. According to these data, if needed, parenteral nutrition with lipids in states of disturbed glucose and lipid metabolism may preferentially be done with MCT/LCT emulsions.

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.

The kallikrein-kinin-prostaglandin system: involvement in the control of capillary blood flow and substrate metabolism in skeletal muscle tissue.

In spite of numerous work done in this field it is not clarified so far how the acceleration of the capillary blood flow, of glucose uptake, and of muscle growth occurring during work and after ischemia is controlled in muscle tissue. Since the signal for the induction of these responses stems from inside the cell, tissue factors have been postulated which should be responsible for the enlargement of the capillary net and the improvement of the tissue's insulin sensitivity. The accumulation of new evidences during the last few years points to an involvement of the kallikrein-kinin-prostaglandin system.

Effects of kallikrein (K), bradykinin (B) and insulin (I), on substrate metabolism in the isolated perfused rat heart.

In the isolated rat heart preparation, perfused at physiological glucose levels, effects of kallikrein (K), bradykinin (B) and insulin (I) on carbohydrate metabolism have been compared. A flow- and I-independent K-effect, obviously working via proteolytic kinin formation, was shown. While I elevated glucose-uptake into the heart preferably via accelerated transport across the membrane and increased rates of glycogen synthesis, B and K significantly activated PFK and reduced myocardial glucose uptake. The latter effect is probably due to an accelerated glycolytic flux leading to decreased G6P-levels and thereby stimulating glycogenolysis. Since aprotinin was able to abolish the K-effect, the latter may possibly be mediated via kinin release.

[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.

[Modification of postoperative glucose-tolerance disorders using bradykinin]. / Beeinflussung der postoperativ gestörten Glucosetoleranz durch Bradykinin.

Glucose tolerance after abdominal operation was studied with and without infusion of bradykinin. With bradykinin a normalization of the postoperative decreased assimilation of glucose was found.

[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.

[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.

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.