A. S. Luyckx

Glucose Naturally Labeled with Carbon-13: Use for Metabolic Studies in Man

The ratio of carbon-13 to carbon-12 is much higher in most commerical preparations of glucose used for oral glucose tolerance tests than it is in carbon dioxide in expired air. This recent discovery provided a novel and potentially significant means of studying glucose metabolism. The changes in the ratio of carbon-13 to carbon-12 in carbon dioxide expired after oral glucose administration were determined by mass spectrometry. In six healthy male volunteers, the administration of glucose resulted in a marked, reproducible rise in the isotopic ratio in expired carbon dioxide; the ratio reached its maximum at 4 hours and then declined progressively.

Mechanisms Involved in the Exercise-induced Increase in Glucagon Secretion in Rats

Previous studies in our laboratory indicate that a marked rise in plasma pancreatic glucagon occurs in rats subjected to non-exhausting exercise (forced swim or FOSWI). Male albino rats fas led overnight Were subjected to FOSWI for thirty to sixty minutes in tepid water. Blood for glucose, free fatty acids, insulin and glucagon determinations was obtained by cardiac puncture immediately after exercise or after a rest period in control animals. The FOSWI-induced rise in plasma glucagon was of pancreatic origin since it was significant with an antiserum highly specific for pancreatic glucagon and an antiserum weakly cross-reacting with gut GLI but absent with a nonspecific antiserum. Theglucagon rise was even more important in hypophysectomized rats. Intraperitoneal glucose injection (0.2 gnu per kilogram) decreased plasma glucagon in resting animals but did not abolish FOSWI-induced glucagon secretion. Adrenalectomy slightly reduced the glucagon response to FOSWI, whereas propranolol pretreatment (5 mg per kilogram intraperitoneally) completely blocked the glucagon rise. Phentolamme (25 mg. per kilogram) increased blood glucose, plasma IRI and glucagon in resting animals. FOSWI did not further increase the already elevated glucagon levels in the phentolamine-treated rats. The exercise-induced glucagon rise persisted in rats pretreated with phentolamine (5 mg. per kilogram) and practolol (12.5 mg. per kilogram). It is concluded that catecholamines and, in particular, sympathetic innervation of the islets play a major role in the exercise-induced glucagon secretion ana tfiat the adrenergic receptors involved are likely of the β2 type.

Glucagon and Diabetes: A Reappraisal

ConclusionsThe metabolic properties of glucagon, demonstrated bothin vitro andin vivo, qualify it as a potential diabetogenic hormone. Plasma glucagon levels are usually elevated in diabetes, the highest levels being found in the absence of insulin. Numerous lines of evidence indicate that excess glucagon levels contribute to the metabolic abnormalities of diabetes. Nevertheless, diabetes can occur in the absence of glucagon (pancreatectomy in man). The absence of high intra-islet levels of insulin may explain the persistence of abnormally high plasma concentrations of glucagon in the diabetic receiving conventional insulin therapy. In maturity-onset type diabetes, the intimate mechanisms leading to abnormal circulating glucagon levels are completely unknown. A search for selective glucagon inhibitors represents an attractive new way in diabetes management.

Quantitative Evaluation of the Oxidation of an Exogenous Glucose Load Using Naturally Labeled 13C-Glucose

Maize glucose was used as a natural tracer for studies of metabolism. It is richer in 13C than common vegetables and foods derived from these, and the C02 formed from it is consequently richer in 13C than the CO2 expired by man fed on a diet of common vegetables. The quantitative results, obtained by measurement of delta 13C of the expired CO2 and of VCO2 during the oxidation of an exogenous glucose load (about 100 g) in eight normal subjects over 7 hr, have shown a consumption of 28.64 +/- 1.44 g of glucose (mean +/- SEM), which represents about 30% of the load given. A comparison is made with the results obtained from other methods and the originality and usefulness of this new quantitative procedure is outlined.

Improvement of metabolic control in insulin dependent diabetics treated with the α-glucosidase inhibitor Acarbose for two months

SummaryAcarbose, an α-glucosidase inhibitor, delays starch digestion and inhibits intestinal sucrase and maltase activity. Twenty-eight insulin dependent diabetics were given Acarbose (3×100 mg daily) over a two month period, preceded and followed by a two month placebo period. Acarbose reduced post-break-fast and post-dinner blood glucose values by 25% (p <0.001) and 24% (p<0.05) respectively. It also significantly reduced mean daily blood glucose by 18% (p < 0.05) and mean amplitude of glycaemic excursions from 8.0±0.6 to 5.5±0.4 mmol/l (p<0.0005). Weight did not change significantly. Daily caloric and carbohydrate intake remained constant throughout the study while insulin requirements decreased slightly but significantly. Out of the 28 patients, 18 had absent while ten had slight residual B cell function as assessed by plasma C-peptide measurements. Treatment with Acarbose did not significantly affect residual B cell function. The beneficial effect of Acarbose on blood glucose control was seen in patients both with and without residual B cell secretion. The major side-effect was flatulence which was never severe enough to interrupt treatment, but led to a 50% reduction of the dose in one patient. It is concluded that Acarbose represents a useful additional means of improving metabolic control in insulin dependent diabetics.

Effect of glucose ingestion on energy substrate utilization during prolonged muscular exercise

SummaryThe distribution of substrates utilized during prolonged exercise was investigated in normal human volunteers with and without ingestion of 100 g exogenous glucose. The energy provided by protein oxidation was derived from urinary nitrogen excretion and the total energy provided by carbohydrates and lipids was calculated from respiratory quotient (RQ) determinations. The contribution of exogenous glucose to the energy supply was determined by an original procedure using “naturally labeled 13C-glucose” as metabolic tracer. Protein oxidation provided between 1 and 2% of the total energy requirement; this amount was not affected by glucose ingestion. In the absence of exogenous glucose ingestion, carbohydrate were progressively replaced by lipids as source of energy. Exogenous glucose contributed markedly to total carbohydrate oxidation and decreased the percentage of energy derived from lipids. In addition, ingestion of exogenous glucose resulted in a significant economy of endogenous carbohydrates and permitted to prolong the duration of exercise.

A 6-hour nocturnal interruption of a continuous subcutaneous insulin infusion: 1. Metabolic and hormonal consequences and scheme for a prompt return to adequate control

SummaryInterruption of a continuous subcutaneous insulin infusion, most often due to technical problems occurring during the night, is a not uncommon event whose metabolic consequences have received relatively little attention until now. We have therefore investigated the changes in blood glucose, plasma non-esterified fatty acids, 3-hydroxybutyrate, glucagon and free insulin in eight C-peptide negative Type 1 diabetic patients whose pumps were deliberately stopped between 23.00 h and 05.00 h. A control test with the pump functioning normally was carried out in each patient and the studies were randomized. Considering the values at 23.00 h as reference, interruption of the insulin infusion resulted in (1) a rapid decrease in plasma free insulin significant after 1 h and reaching a nadir of 6±2 mU/l after 6 h; (2) a rise in blood glucose which was significant at hour 3 and reached 17.4±1.9 mmol/l at hour 6; (3) a moderate increase in plasma non-esterified fatty acids which remained in the range of 700–800 μmol/l; (4) an early and linear rise in plasma 3-hydroxybutyrate, significant after 1 h and averaging 1290±140 μmol/l after 6 h; (5) a late increase (hour 5) in plasma glucagon. The second aim of our study was to provide for the patient a precise scheme of insulin supplements administered via the pump and based on blood glucose monitoring (Dextrostix — Glucometer) and semi-quantitative evaluation of ketonuria (Acetest). Resetting the pump at its basal rate at 05.00h and giving insulin supplements (2–8 U) at 06.45 h (with the usual breakfast dose) and again at 10.00 h have proved efficacious in restoring satisfactory metabolic control by noon the day after starting the experiment. These results form practical recommendations to patients undergoing this type of accident.

Renal handling of endogenous glucagon in the dog: Comparison with insulin☆

Abstract The renal handling of endogenous pancreatic glucagon and insulin was studied using dog kidneys acutely transplanted to the neck vessels of a perfusing anesthetized dog. Mean glucagon uptake under basal conditions averaged 89 ± 14 pg/min/g of kidney, the corresponding value for insulin being 7.0 ± 1.2 μU/min/g of kidney. On a molar basis, kidney glucagon uptake under basal conditions was approximately one half that of insulin uptake. A massive intravenous glucose load resulted in both enhanced insulin uptake and reduced glucagon uptake. Urinary glucagon excretion accounted for only a small percentage of total renal uptake. These findings indicate that glucagon uptake by the kidney might be an important factor in determining the final concentration of circulating glucagon and give a possible explanation for the high plasma glucagon values reported in severe renal failure.

Effect of acute kidney exclusion by ligation of renal arteries on peripheral plasma glucagon levels and pancreatic glucagon production in the anesthetized dog

Bilateral kidney exclusion in the anesthetized dog resulted in an immediate and important increase in arterial plasma glucagon. Forty minutes after ligation of the renal arteries, plasma glucagon averaged 200% of the basal values and 90 min after ligation, mean plasma glucagon averaged 357% of the mean basal value. Comparable changes were observed when basal plasma glucagon was markedly suppressed by intravenous infusion of glucose. The rate of production of glucagon by the pancreas was not significantly increased by kidney exclusion. Since the uptake of glucagon by the kidney was previously shown to be quantitatively important, the present findings suggest that abrupt cessation of kidney glucagon uptake is the major factor responsible for the rise in peripheral plasma glucagon levels observed after ligation of renal arteries.

Glucose Utilization During Exercise in Normal and Diabetic Subjects: The Role of Insulin

Due to selective isotopic effects occurring during photosynthesis, certain natural sugars are enriched in 13C Using such “naturally labeled 13C-glucose,” we studied glucose oxidation during exercise in seven normal volunteers and in six insulin-dependent diabetics after an overnight fast. In the diabetics, blood glucose was monitored the night before the test and adjusted to about 100 mg/dl by intravenous insulin infusion. The insulin infusion was withheld 15 min before exercise in four diabetics and maintained at 0.9 U/h for 2 h; then it was maintained at 0.6 U/h for 2 h in five diabetics. Three patients underwent both tests. All subjects exercised on a treadmill for 4 h at about 45% of their max. After 15 min adaptation, all received 100 g 13C-labeled glucose orally. Total glucose oxidation was derived from non-protein RQ and exogenous glucose oxidation evaluated as previously described. The diabetics had no residual B-cell function as indicated by negligible plasma C-peptide values and a lack of Cpeptide response to the oral glucose challenge. Total glucose oxidation averaged 230 ± 14 g/4 h in the normal subjects. It was similar (238 ± 19 g/4 h) in the diabetics receiving an intravenous insulin infusion, but decreased to 176 ± 14 g/4 h when no insulin was infused. Exogenous glucose oxidation was 92 ± 3 g/4 h and 84 ± 8 g/4 h (not statistically different) in the controls and in the insulin-infused diabetics, respectively. It was 43 ± 11 g/4 h in the diabetics exercising without being infused with insulin. We conclude that (1) in well-insulinized diabetic patients, prolonged muscular exercise can be performed under metabolic conditions which are basically similar to those of normal subjects; (2) during prolonged exercise, well-insulinized diabetic patients are able to oxidize up to 85–90% of a 100-g exogenous glucose load given orally and oral glucose can thus be ingested during prolonged exercise in well-controlled juvenile insulintreated diabetics; (3) even in the absence of insulin administration during exercise, juvenile diabetics who start exercising when blood glucose is near normal are able to perform a 4-h exercise at 45–50% of their max. Under these conditions, however, they are unable to utilize more than 40–45% of a 100-g glucose load given orally. They rely more upon lipid stores than the normal subjects or the well-insulinized diabetics.