Diabetologia

Wahren, J.; Felig, P.; Hagenfeldt, L.

doi: 10.1007/BF01219419pmid: 640298

125 14 14 4 4 J. Wahren P. Felig L. Hagenfeldt Department of Clinical Physiology, Karolinska Institute Huddinge University Hospital Huddinge Sweden Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA Department of Clinical Chemistry Karolinska Hospital Stockholm Sweden Summary During the initial phase of physical exercise muscle glycogen is the primary source of fuel for contracting muscle in normal man. When exercise continues beyond the first 5–10 min blood glucose and free fatty acids (FFA) become increasingly important substrates. Glucose utilization may account for 25–35% of the total substrate supply during mild to moderately heavy exercise. The augmented glucose utilization by working muscle is balanced by a rise in hepatic glucose production. The latter is achieved primarily by hepatic glycogenolysis during brief work, but during prolonged exercise gluconeogenesis may account for as much as 40–50% of the hepatic glucose output. Muscle uptake of FFA is determined primarily by its availability to the working muscle, and it may account for 30–60% of the total fuel supply. Ketone bodies are not utilized by working muscle in normal man. In patients with diabetes mellitus the metabolic effects of physical exercise are to a large extent determined by the time interval between insulin administration and the onset of exercise. Thus, in insulin treated patients with mild hyperglycaemia and no or minimal ketonaemia the utilization of glycogen, blood glucose and FFA by working muscle is similar to that of healthy subjects, and exercise is accompanied by a fall in blood glucose levels. In contrast, patients with more marked hyperglycaemia and hyperketonaemia may respond to exercise with a further rise in both blood glucose and ketone body levels, reflecting augmented rates of hepatic gluconeogenesis as well as ketogenesis. The repletion of muscle and liver glycogen, which takes place for 24–48 h after exercise, requires — besides carbohydrate feeding — a minimum concentration of insulin. Glycogen resynthesis probably accounts for a major part of the empirically well established beneficial effect of physical exercise in diabetic patients. The above considerations underscore the importance of adequate insulin administration in connection with exercise in diabetic patients.

Mirouze, J.; Selam, J.; Pham, T.; Mendoza, E.; Orsetti, A.

doi: 10.1007/BF01219420pmid: 640299

125 14 14 4 4 J. Mirouze J. L. Selam T. C. Pham E. Mendoza A. Orsetti Clinique des Maladies Métaboliques et Endocriniennes Hôpital Saint-Eloi Montpellier France Summary Remission of diabetes was attempted in 12 recent acute onset ketosis-prone juvenile diabetes after short term (5±1 days) but excellent blood glucose control by the external artificial beta-cell. The comparison group comprised patients undergoing traditional treatment (n=28). Nine (75%) persistent (over 3–14 months of duration) although partial (oral drugs required) remissions were obtained in the former group as compared to 3 (11%) in the latter group (p<0.05). Cases which showed remissions after insulin infusion had a plasma insulin response to IV glucagon still present before insulin infusion, and a daily urinary C-peptide excretion significantly enhanced after (p<0.01). Urinary C-peptide /blood glucose remained improved during the remission period. Thus, early effective treatment by means of the artificial pancreas may break the vicious circle hyperglycaemia-insulin depletion-hyperglycaemia and lead to frequent and sustained remissions of juvenile diabetes.

Fahrenkrug, J.; Muckadell, O.; Kühl, C.

doi: 10.1007/BF01219421pmid: 565310

125 14 14 4 4 J. Fahrenkrug O. B. Schaffalitzky de Muckadell C. Kühl Departments of Clinical Chemistry and Internal Medicine (T) Bispebjerg Hospital Copenhagen Denmark Summary Plasma immunoreactive secretin and insulin concentrations were measured in fasting normal humans after intraduodenal infusions of hydrochloric acid, isotonic or hypertonic glucose. The effect of intraduodenal acidification or intravenous bolus injections of secretin on plasma insulin concentrations during infusions of glucose was also examined. The intraduodenal glucose load did not cause an increase in plasma secretin concentrations. Secretin concentrations rose after acid both in the fasting state and during infusions of glucose. A concomitant rise in insulin levels was however only observed during infusions of glucose. Intravenous injection of secretin in a dose which mimicked the response to intraduodenal acidification was without effect on the glucose-stimulated insulin release, while a 30 times higher dose caused a highly significant augmentation of the insulin release. The insulin response pattern to this high dose of secretin differed completely from that observed after intraduodenal infusion of acid. It is concluded and confirmed that the stimulating effect of secretin on insulin secretion is pharmacological and that secretin plays no significant role in the entero-insular axis.

Fredholm, B.; Lunell, N.; Persson, B.; Wager, J.

doi: 10.1007/BF01219422pmid: 205475

125 14 14 4 4 B. B. Fredholm N. O. Lunell B. Persson J. Wager Department of Pharmacology Karolinska Institute Stockholm Sweden Department of Obstetrics at Huddinge University Hospital Stockholm Sweden Department of Paediatrics at St. Görans Hospital, Karolinska Institute Stockholm Sweden Summary Salbutamol was administered intravenously in doses increasing from 3.75 to 22.5 μg/min to 5 non-diabetic and 7 diabetic women in the last trimester of pregnancy. In diabetic as well as nondiabetic women the diastolic blood pressure fell progressively with increasing doses, and the systolic BP and heart rate increased at doses above 7.5 μg/min. The effect on fetal heart rate was less pronounced than the effect on maternal heart rate. Cyclic AMP levels in plasma were similar in non-diabetic and diabetic women before salbutamol. Twenty min following 3.75 μg/min a significant increase was seen in both groups. The peak increase (3–5 fold) was higher in the diabetic than in the non-diabetic women. Plasma insulin and C-peptide levels rose in a dose-dependent manner in the non-diabetic and four of the diabetic women. However, in three of the diabetic women the insulin level was unaffected by salbutamol and C-peptide was almost undetectable. Plasma concentrations of glucose, glycerol, NEFA and 3-HB were higher in the diabetics than in the non-diabetics before salbutamol and the elevations induced by salbutamol were also significantly larger in the diabetic women. The present data show that salbutamol in doses employed clinically may cause pronounced metabolic effects, especially in diabetic women, and it is suggested that when intravenous infusion of salbutamol is given to pregnant diabetic women not only cardiovascular but also some metabolic variable such as glucose should be carefully monitored.

Dietze, G.; Wicklmayr, M.; Mehnert, H.; Czempiel, H.; Henftling, H.

doi: 10.1007/BF01219423pmid: 640300

125 14 14 4 4 G. Dietze M. Wicklmayr H. Mehnert H. Czempiel H. G. Henftling 3rd Medical Department (Metabolism and Endocrinology) and Department of Nuclear Medicine Schwabing-City Hospital Munich Germany Summary The effect of a five day pretreatment with phenformin (3 x 50 mg daily) on hepatic metabolism was studied in six healthy volunteers. Arterial and hepatic venous concentrations of substrates and hepatic blood flow were estimated during a basal period and during a low-dose lactate infusion (0,03 mmol · kg −1 · min −1 ). The results have been compared with those obtained from untreated normal subjects in a previous study (16). During the baseline period arterial concentration of alanine and the hepatic venous concentration ratios of alanine: pyruvate and β -hydroxybutyrate: acetoacetate were significantly increased with phenformin treatment, while the balances of carbon dioxide and glucose and the fractional extraction of alanine were decreased compared to the values obtained in untreated subjects. During lactate infusion mean arterial lactate concentration was significantly increased and hepatic lactate extraction was decreased compared to untreated persons under the same conditions. In the phenformin-treated group lactate infusion resulted in hepatic output of pyruvate and the hepatic glucose balance remained unchanged compared to baseline. Since the rate of hepatic blood flow was not increased during lactate infusion a significantly smaller glucose output and lactate uptake was obtained with phenformin. These findings support the present view that the hypoglycaemic effect of biguanides is due, at least in part, to inhibition of hepatic gluconeogenesis.

Bernstein, R.; Davis, B.; Olefsky, J.; Reaven, G.

doi: 10.1007/BF01219424pmid: 205476

125 14 14 4 4 R. M. Bernstein B. M. Davis J. M. Olefsky G. M. Reaven Department of Medicine Stanford University School of Medicine and Veterans Administration Hospital Palo Alto California USA Summary Plasma insulin response to oral glucose, insulin resistance, and insulin suppression of hepatic glucose production were studied in 11 normal subjects and 11 hypertriglyceridaemic patients. Patients with hypertriglyceridaemia had a significantly higher insulin response to oral glucose. Insulin resistance was also significantly greater in hypertriglyceridaemic subjects as determined by measuring the steady-state plasma glucose response during a continuous infusion of epinephrine, propranolol, glucose, and exogenous insulin. Insulin suppression of hepatic glucose production was calculated from the results of two studies in which glucose turnover rate was measured by a continuous infusion of 3 H-2-glucose. The first study was performed under conditions of basal insulin secretion, and the second carried out at steady state exogenous insulin levels of approximately 100 μU/ml. The results indicated that basal hepatic glucose production was the same in both groups, and was suppressed to an equal degree by physiological levels of insulin. These data demonstrate that hepatic glucose production can be suppressed to an equal degree in normal and hypertriglyceridaemic subjects at comparable circulating insulin levels, at the same time that resistance to insulin-stimulated glucose uptake is observed in the hypertriglyceridaemic individuals.

Meuli, C.; Zapf, J.; Froesch, E.

doi: 10.1007/BF01219425pmid: 640301

125 14 14 4 4 C. Meuli J. Zapf E. R. Froesch Department of Medicine Metabolic Unit Kantonsspital Zürich Switzerland Summary Human serum in a concentration of 10% in the perfusion medium failed to increase glucose uptake by the isolated perfused rat heart, indicating that nonsuppressible insulin-like activity (NSILA) in whole serum was inactive in this system. When NSILA-carrier protein was added to partially purified NSILA-S, its biological activity on the rat heart disappeared. In contrast, the action of insulin was not affected by the presence of NSILA-carrier protein. Binding of 125 I-labelled NSILA-S to rat heart was inhibited by NSILA-carrier protein. 125 I-labelled insulin binding was not inhibited. These results support the hypothesis that NSILA-S bound to serum carrier protein is a large molecular compound which does not readily diffuse out of the capillary bed and therefore does not exert insulin-like effects in vivo.

Assan, R.; Heuclin, Chr; Girard, J.

doi: 10.1007/BF01219426pmid: 640302

125 14 14 4 4 R. Assan Chr Heuclin J. R. Girard Department of Diabetology Hôtel-Dieu Paris Physiology of Development Laboratory Collège de France Paris France Summary An experimental model of phenformininduced lactic acidosis was established in rats. Following a subtotal nephrectomy, renal failure developed (serum creatinine 4.5±0.1mg/100ml and 2.8±0.1 mg/100 ml on the 1st and 8th postoperative days respectively). Immediately after nephrectomy intra-peritoneal phenformin treatment, 16 mg/day, was commenced. Lactic acidosis developed progressively within 8 days, or earlier in the rats with the most severe renal insufficiency. The metabolic pattern was very similar to that observed in diabetic patients with a biguanide-induced lactic acidosis: on the 8th day, 2 h after the last phenformin injection, blood lactate was 10.8±1.0 mmol/1 (controls: 1.50±0.03); pyruvate was 0.56±0.06 mmol/1 (controls: 0.10±0.01) and blood pH: 7.00 ± 0.02 (vs 7.34±0.02); 3-hydroxybutyrate was 1.41±0.37 mmol/1 (vs 0.32 ±0.03); acetoacetate: 0.51±0.15 mmol/1 (vs 0.17 ±0.01), and free glycerol: 0.63 ±0.07 mmol/1 (vs 0.14 ±0.02). Increased concentrations of alanine (1.66±0.26 mmol/1, vs 0.48 ± 0.04 in controls) and low blood glucose levels (23± 8 mg/ 100 ml vs 70 ± 2, after a 12 hours fast) accompanied the lactic acidosis in spite of high glucagon levels (2030±170 pg/ml vs 108±10 in controls) and low insulin/glucagon molar ratio (0.19 vs 6.9 in controls). Normal rats, treated with phenformin at same doses, and nephrectomized rats injected with saline served as controls and remained free of lactic acidosis. Hydroxyphenformin (16 mg/day) injected in nephrectomized rats, was biologically inactive. Glucose production from 14 C-lactate was 425 ±85 μmol/100 g body wt/h, vs 1050 ± 90 in control animals. Blood lactate specific activity declined more slowly in the lactic acidotic rats than in controls, suggesting that a decrease in lactate utilization contributed to hyperlactataemia more than an increased lactate production.

Marquié, G.

doi: 10.1007/BF01219427pmid: 640303

125 14 14 4 4 G. Marquié Department of Nutrition, Institute of Biology University of Science and Technology Algiers Algeria Summary Administration of a hypoglycaemic sulphonamide, gliclazide, at 10 mg/kg/day p. o. to rabbits for 60 days did not affect the development of plasma lipid disturbances induced by a high cholesterol diet. The accumulation of cholesterol in the liver was significantly reduced by up to 34% when compared with animals on the high cholesterol diet. The high concentrations of glycerides and fatty acids in the aorta were significantly decreased towards normal values and histology showed that the gliclazide strongly inhibited the development of aortic and particularly coronary lesions induced by the atherogenic diet. A normal appearance of coronary arteries was noted in more than 50% of cases.

doi: 10.1007/BF01219428pmid: N/A