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Increased plasma pancreatic glucagon concentrations have been reported during various states of decreased glucose tolerance. In vitro studies have demonstrated that human somatomammotropin stimulates glucagon release. The present investigation aimed at evaluating the role of plasma flucagon in the insulin resistance associated with normal pregnancy. Postprandial samples of plasma were obtained from 156 pregnant women between the 5th and the 40th week of pregnancy and were assayed for blood glucose, plasma insulin, glucagon and free fatty acids. Plasma insulin showed a gradual increase during pregnancy, and reached its maximal values during the last trimester. A moderate but significant increase in plasma glucagon was present between the 16th and the 28th week of gestation, whereas during the first and the last trimester of pregnancy its concentration was similar to that in non pregnant women. Intravenous glucose tolerance was performed during the last trimester and in a group of non pregnant control women. The slight decrease in glucose tolerance and the marked hyperinsulinemia associated with late pregnancy were accompanied by a more rapid and more pronounced decrease in plasma glucagon. A rapid and sustained decrease in glucagon was also observed when plasma FFA were raised by the intravenous administration of a triglyceride emulsion and heparin. These data suggest that glucagon is not involved in the insulin resistance associated with normal human pregnancy.

The influence of plasma free fatty acid (FFA) concentration on the secretion of human placental lactogen (hPL) was investigated in 16 normal young women during the last month of gestation, in order to determine whether hPL secretion is influenced in the same way as human growth hormone (hGH) during plasma FFA elevation. Maternal blood glucose (BG), plasma triglycerides (TG), FFA, immunoreactive insulin (IRI) and hPL levels were measured during and after a lipid emulsion infusion for 75 min (10 cases). The intravenous injection of 5,000 U of heparin at the 15th min of the lipid infusion was followed by a decrease in plasma triglyceride levels and by an accompanying rise in plasma FFA (rom 468 plus or minus 52 to 2,478 plus or minus 310 mueq/liter). In control experiments lipid infusion alone (3 cases) resulted in a moderate increase in FFA (718 plus or minus 157 to 1,046 plus or minus 255 mueq/liter), and separate iv heparin administration (3 cases) elevated the FFA levels from 728 plus or minus 50 to 1,649 plus or minus 153 mueq/liter). No significant change in either IRI or hPL levels was discernible in any of the tests performed. A tendency of blood glucose to increase was observed after heparin administration. It was concluded that a marked and sustained plasma FFA elevation, achieved through intravenous lipid and heparin infusion cannot alter hPL circulating levels in term human pregnancy.

The effect of raising arterial plasma glucagon concentrations on kidney glucagon uptake was investigated using an isolated dog kidney perfused with whole blood. In addition, the effect of insulin on the magnitude of glucagon uptake by the kidney was studied at various glucagon concentrations. Renal vein plasma glucagon (V) has been found to be proportional to renal artery plasma glucagon (A). V and A were highly significantly correlated. In the absence of exogenous insulin infusion, V equalled 0.733 +/- 0.034 A, while in the presence of insulin V equalled 0.747 +/- 0.015 A. When kidney glucagon uptake was measured directly it increased as a function of arterial plasma glucagon. The calculated regression lines were similar in the presence and in the absence of insulin. The mean clearance rate of glucagon by the kidney was similar at low, medium or high concentrations of glucagon and was not affected by the presence of insulin at a mean concentration of 335.7 +/- 15.7 muU/ml. At this concentration of insulin, kidney insulin uptake was not affected by glucagon at concentrations ranging from 32 to 1600 pg/ml. Comparison of kidney glucagon uptake at similar arterial plasma glucagon concentrations, but with different renal plasma flows, indicated that kidney glucagon uptake is more dependant on arterial plasma glucagon concentration than on the quantity of glucagon entering the kidney per minute. It is concluded that: 1) kidney glucagon uptake increases as a function of arterial plasma glucagon concentration; 2) the clearance rate of glucagon is similar at low, medium or high arterial concentrations of glucagon; 3) at concentration of 300-350 muU/ml, insulin does not affect kidney glucagon uptake, and 4) at concentrations of glucagon up to 1600 pg/ml, renal insulin uptake is not affected by glucagon. These studies indicate that insulin and glucagon are handled independantly by the kidney of the dog.

The isolated perfused rat pancreas was utilized to investigate the effect of oleic acid on insulin secretion. In the absence of glucose, a continuous infusion of oleic acid (1500 micromol/l) induced a biphasic insulin release. This effect was reduced at low extracellular calcium concentration. In the presence of oleic acid 1500 micromol/l, the insulin response to 10 mmol/l arginine occurred earlier, the total amount of insulin released in response to the amino acid being unchanged. Such an effect was not obtained when oleic acid in the medium was 750 micromol/l, but it was observed in the presence of oleic acid 1500 micromol/l when the concentration of albumin in the perfusate was increased from 2 g/100 ml to 4 g/100 ml. The insulin response to a continuous infusion of glucose (4.4 mmol/l and 16.7 mmol/l) was potentiated by the presence of oleic acid 1500 micromol/l in the perfusate. No modification of the biphasic pattern of insulin response to glucose 16.7 mmol/l was observed. These results demonstrate that high concentrations of oleic acid stimulate insulin release from the isolated perfused rat pancreas and modulate the insulin response to arginine or glucose.

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.

In order to determine whether changes in free fatty acid (FFA) levels affect hPL secretion in late human pregnancy in the same way as they affect human growth hormone (hGH) secretion, two types of experiments were performed: 1) I g of nicotinic acid (NA) was infused for 60 min inII patients and 1.5 g of NA was infused for 90 min in 8 additional patients; 2) triglycerides and heparin were administered iv for 120 min in 5 control cases and, in 11 other patients 0.3 U insulin/kg BW was injected at the 45th min of the triglycerideheparin infusion. Maternal blood glucose (BG), plasma triglycerides (TG), FFA, immunoreactive insulin (IRI) and hPL levels were sequentially determined in the course of these experiments. In both series of patients, the NA infusion resulted in substantial depression of FFA levels to around 50% of mean basal levels. The hPL levels displayed only negligible fluctuations, although FFA depression persisted for more than 2 hours. During the lipid-heparin infusion, an increase in plasma TG...

Twenty-five obese and 23 reference women were compared with respect to their peripheral insulin concentrations in response to the sight and smell of food. An additional 21 obese women were examined for different control purposes. The women were examined after fasting for approximately 16 hr. Venous blood samples for determination of glucose and insulin were drawn 20, 10, and 1 min prior to the demonstration of food for 5 min. After the food had been presented to the subject, samples were drawn at 1, 2, 3, 4, 5, 6, 10, 15, and 20 min. The response was calculated in two different ways: method I—the difference between meal basal insulin values and mean insulin values during and/or after stimulation, and method II—the “insulin area” over the mean basal concentration was calculated for 0–20 min after start of food presentation. Both methods resulted in significantly higher insulin responses in obese as compared to reference subjects. However, when performing duplicate experiments in the same subjects only method II resulted in reproducible results and even with this method the error was as high as 60%–90%. The high error of the method was partly expected since the insulin elevation is most likely not only a function of controlled external cues but also dependent on unknown sensorimotor and cognitive-affective alterations. No insulin response was observed when obese women were exposed to an external cue that was not food related. Atropine completely blocked the insulin elevation in response to food related external stimuli indicating that this insulin response is mediated via vagus.

The isolated perfused rat pancreas was used to investigate the effect of extracellular bicarbonate concentration (25 and 40 mmol/l) on the arginine-induced insulin and glucagon release with or without 5.5 mmol/l glucose in the perfusate. In the absence of glucose, the insulin response to arginine was increased at 40 mmol/l bicarbonate, while no potentiation by glucose of the arginine-induced insulin release, at this bicarbonate concentration, was observed. At 40 mmol/l bicarbonate, glucose inhibition of basal glucagon release was abolished. In contrast, the glucagon response to arginine was not affected by the bicarbonate concentration in the perfusion medium. These results confirm that the bicarbonate concentration in the medium markedly influences the insulin release from the isolated perfused rat pancreas, while the glucagon response to arginine seems to be less sensitive to changes in extracellular bicarbonate concentration.

We have measured fasting C-peptide reactivity (CPR) as well as CPR responses to a test meal in 83 diabetic patients and 41 non diabetic controls. In comparison to controls, basal CPR was decreased in lean insulin-treated diabetics with stable or brittle diabetes and in obese patients with brittle diabetes. Lean and obese maturity-onset diabetics had increased CPR levels and so had obese insulin-treated patients. Nevertheless, the CPR response to the test meal was clearly inadequate in all diabetics. In control patients, there was a positive correlation between fasting blood glucose and CPR levels. On the contrary, lean diabetics demonstrated a negative correlation between these parameters. Hemoglobin A1 levels were negatively correlated to fasting CPR levels in lean diabetics, indicating the importance of residual B-cell function for diabetes control. These correlations were obscured in obese diabetics. In our patients, circulating insulin antibodies had apparently no deleterious effect on metabolic control.

Twelve uremic patients (U) on regular hemodialysis were submitted to a standardized test meal. In comparison with normal controls (C), U patients demonstrated a slight increase of HbA1 level and a definite elevation of fasting plasma C-peptide immunoreactivity. They showed glucose intolerance at 60 and 120 min. This was associated with an inappropriate insulin response as evidenced by a significantly lower insulin/glucose index at 60 min. U patients were tested again during a hemodialysis session in order to reduce the 60-min glucose intolerance. Six patients (U1) were selected because they exhibited mean fasting and 60-min glucose values similar to those of the controls. In these conditions, the insulin response at 60 min was significantly decreased in comparison to basal conditions and this could not be accounted for by a concomitant decrease of plasma alpha-aminonitrogen values. It is concluded that, in uremic patients, glucose intolerance is associated with an inappropriately low B-cell response.

The influence of ketone body infusion on the serum GH and glucagon response to FFA depression and insulin hypoglycemia was investigated in 10 healthy men. Intravenous infusion of nicotinic acid induced suppression of both FFA and ketone bodies. This was accompanied by a delayed GH increase to 21.1 +/- 6.9 ng/ml (at 300 min). During an additional beta-hydroxybutyrate (OHB) infusion, FFA remained depressed, but ketone bodies were elevated, and the GH response was abolished (maximum 5.6 +/- 1.6 ng/ml). During infusion of OHB alone, FFA were suppressed. GH increased significantly, although less markedly than during suppression of both FFA and ketone bodies (to 9.3 +/- 3.1 ng/ml at 270 min). No GH rise occurred when both FFA and ketone bodies were kept elevated by the addition of a lipid infusion. The GH rise in response to insulin hypoglycemia was not changed by an OHB infusion (43.2 +/- 4.6 vs. 48.0 +/- 7.3 ng/ml). However, OHB increased the net GH output by significantly delaying the return to basal concentrations in the presence of a reduced FFA rebound. An effect of OHB infusion on the plasma glucagon concentration during all experiments was small, and its physiological significance is doubtful. These results confirm that FFA depression induces delayed GH secretion. They suggest that this is not wholly dependent on concomitant depression of ketone bodies. On the other hand, when ketone bodies are elevated, the GH response to FFA depression is diminished or absent. The net GH response to changes in lipid substrates probably depends on the concentration of both FFA and ketone bodies.

The levels of circulating IgG-insulin antibodies were determined in two groups of diabetic patients before and at 3-month intervals after starting insulin treatment either with monocomponent porcine insulin (n = 17) or with human semisynthetic insulin (SH) (n = 16). Patients were followed during 15.1 +/- 1.0 and 19.9 +/- 1.1 months, respectively (m +/- SEM). In addition, the quality of metabolic control and residual B-cell function were evaluated in the group under treatment with SHI. The percentage of patients who remained antibody-free after 12-21 months of treatment was 67.75% in the human insulin-treated group and only 25-43% in the one receiving porcine insulin (p less than 0.01). Moreover, insulin antibody titers, when present, were usually lower in subjects treated with human insulin. In SHI-treated patients: metabolic control was excellent during the first months of treatment as evidenced by values of mean daily blood glucose (7.3 +/- 0.6 mmol/l), M-index according to Schlichtkrull (7.4 +/- 2.4) and Hb1c (6.8 +/- 0.6%); residual B-cell function, evaluated at 3-month intervals by a circadian profile of plasma C-peptide did not decrease throughout the study; and a significant deterioration of blood glucose control occurred after 18 months of treatment, which might have been due to a less intensive supervision of the patients by the physicians and/or less careful attention by the patients themselves. This observation confirms the need for a continuous education of the patients regardless of the type of insulin used.

Peripheral blood glucose, plasma insulin and C-peptide levels were investigated after giving a standardized breakfast (500 kcal, 60 g carbohydrates) to 10 nonobese Type 2 diabetic patients previously treated by diet alone. Each patient received at random, at 1 week intervals, either 5 mg glipizide (meal + glipizide) or a placebo (meal alone) 30 min before breakfast. Basal values of blood glucose, plasma insulin and C-peptide were similar on both occasions. After meal + glipizide, the blood glucose increase was sharply limited whereas the rise in plasma insulin was steeper and reached twice as high a level. In contrast, the rise in plasma C-peptide was similar in both conditions. Consequently, the areas under the curves (0-300 min) showed a marked reduction in blood glucose after meal + glipizide (2289 +/- 149 versus 3101 +/- 169 mmol X min/1; 2p less than 0.001), associated with a significant increase in plasma insulin (14219 +/- 3261 versus 7591 +/- 1173 microU X min/ml; 2p less than 0.025) but no significant change in plasma C-peptide (342 +/- 45 versus 326 +/- 34 pmol X min/ml; N.S.). The insulin/C-peptide molar ratio was thus significantly increased after meal + glipizide (0.41 +/- 0.06 versus 0.23 +/- 0.04 at the 60th min; 2p less than 0.02). The dissociation between the responses of insulin and C-peptide suggests that a single dose of 5 mg glipizide in Type 2 diabetic subjects may enhance availability of peripheral insulin by extrapancreatic mechanism(s). This phenomenon may result in a higher circulating level of the hormone and therefore represent a further mode of action of sulphonylureas.(ABSTRACT TRUNCATED AT 250 WORDS)

The 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.

Seven normal volunteers were studied on two different occasions during which 4-h pulsatile (PULS: 0.8 mU · kg−1 · min−1, 7.5 min of 15) and continuous (CONT: 0.4 mU · kg−1 · min1) intravenous (i.v.) infusions of human insulin (Actrapid HM, Novo) were randomly compared. A euglycemic glucose clamp was performed and a 3-3H-glucose infusion was used for determination of endogenous glucose production (EGP) and metabolic clearance rate (MCR) of glucose. Plasma glucose was similar in both conditions; plasma insulin was stable at about 29 mU/L (CONT) and fluctuated between 10 and 45 mU/L (mean: 28, PULS). Exogenous glucose infused was 1.137 ± 0.058 and 1.088 ± 0.099 g · kg−1 · 4h−1 in CONT and PULS, respectively (NS). EGP was totally suppressed in both conditions. Glucose MCR increased similarly to a maximum of 6.71 ± 0.19 (CONT) and 6.79 ± 0.59 (PULS) ml · kg−1 · min−1 during the fourth hour. C-peptide plasma levels remained stable, whereas plasma glucagon, free fatty acids, and 3-hydroxybutyrate were similarly suppressed in both tests. Thus, under these conditions, pulsatile and continuous insulin infusions have similar metabolic effects. These data contrast with those of Matthews et al. (1983) who reported that, at lower plasma concentrations (5–19 mU/L), pulsatile insulin had greater hypoglycemic effect than did continuous delivery. It is concluded that pulsatile insulin shows no greater activity under normoglycemic, moderately hyperinsulinemic conditions in man.

Ten patients who had been totally duodeno-pancreatectomized and totally (N = 1) or partially gastrectomized (N = 9) for chronic pancreatitis (N = 9) or pancreatic carcinoma (N = 1) were investigated. None had a measurable basal level of either plasma C-peptide or a C-peptide response to i.v. glucagon. Immunoreactive glucagon (IRG) was present in all patients, and the mean level (69 ± 8 pg/ml) was not significantly different from the mean observed in normal subjects (81 ±16 pg/ml). Plasma IRG was unequivocally stimulated by arginine in 2 of the 10 subjects. The effect of somatostatin on plasma glucose and IRG during an oral glucose tolerance test was studied in 5 of the 10 patients. The effects of somatostatin on spontaneous hyperglycemia, plasma growth hormone, and IRG after withdrawal of insulin treatment was studied in 4 patients. Somatostatin blunted both the hyperglycemic and paradoxical IRG responses to the glucose challenge, and reduced the spontaneous rise of blood glucose that occurred after insulin withdrawal. This latter effect was not related to clear-cut changes in plasma growth hormone or in IRG. These data confirm the existence of circulating IRG in pancreatectomized patients and demonstrate the presence of circulating IRG in a completely gastrectomized and pancreatectomized patient. The somatostatin-induced improvement in glucose tolerance in the oral glucose tolerance test seems to be related to a reduction of the paradoxical IRG response. In contrast, the inhibition by somatostatin of the rise in blood glucose which occurs after insulin withdrawal does not seem to be mediated through IRG or growth hormone.

Sixteen hospitalized insulin requiring diabetics treated with a single daily subcutaneous injection were randomly allocated either to a mixture of porcine Actrapid + Lente MC or a mixture of Regular + NPH-Biosynthetic human insulin (Study 1). In Study 2, 10 patients receiving two daily insulin injections were treated at random with either porcine Actrapid + Monotard, or Actrapid + Monotard-Semisynthetic human insulin or Regular + NPH--Biosynthetic human insulin. Once an optimal insulin regimen was obtained, circadian blood glucose and plasma free insulin profiles (7-9 time points) were determined with the two (Study 1) or three (Study 2) insulin preparations, keeping the doses of insulin constant. In Study 1 no significant difference in blood glucose (BG) or plasma free insulin (FIRI) profiles was observed. The mean daily blood glucose, the mean amplitude of glycaemic excursions (MAGE), the index of blood glucose control (M-value of Schlichtkrull), as well as the postbreakfast increases in blood glucose and mean free IRI, were similar with both types of insulin. In Study 2, BG and FIRI profiles were also similar, except for a significantly lower (p less than 0.02) BG at 8.30 p.m. with both human insulins. No significant differences were found in free IRI at that time. Mean BG, M index, MAGE and mean FIRI were similar but the postbreakfast increase was significantly smaller with SHI. In conclusion, the pharmacokinetics of animal monocomponent, semisynthetic and biosynthetic human insulin appear similar, but evening BG control was better with both types of human insulins given twice daily.

It has previously been shown that nicotinic acid (NA)-induced depression of free fatty acids (FFA) stimulates the secretion of GH and glucagon. To evaluate this hormonal response further, we studied the influence of different doses of glucose administered by continuous iv infusion on the GH and glucagon increase during NA-induced FFA depression. In ten male non-obese volunteers, FFA depression by the infusion of NA (2.3 g over a period of 210 min) resulted in a late rise (from 150 min on) of GH (From 1.1 to 25.9 ng/ml) and an early increase (from 30 min on) of glucagon (from 71.7 to 138.2 pg/ml). When glucose was infused (approximately 60, 120 and 180 g, respectively, over a period of 270 min) during NA-induced FFA depression, the GH rise was reduced and delayed in relation to the amount of glucose infused, but could not be completely abolished (maximal GH concentration during the three NA-plus-glucose infusions: 16.5, 8.0 and 6.1 ng/ml, respectively). The glucagon rise was entirely reversed by the high glucose dose. Insulin did not rise during NA infusion alone. Its secretion in response to glucose infusion was not significantly influenced by FFA depression. Thus, during NA-induced FFA depression the secretion of two lipolytic hormones--GH and glucagon--is stimulated while the secretion of the lipogenetic hormone insulin remains low. Glucose has an inhibitory effect on the GH and glucagon response which, however, is different for each of the hormones.

Various pharmacological compounds, reserpine, propranolol, hydroquinidine, procaine, verapamil, atropine and nicotinic acid were tested for their ability to modify the glucagon plasma concentration in normal rats both in the basal state and after stimulation by exercise or insulin administration. These drugs were selected on the basis of their known effect on the autonomous nervous system, on transmembrane sodium or calcium fluxes or on the level of plasma free fatty acids. Basal plasma glucagon level was significantly increased 24 hr after administration of reserpine and conversely it was decreased 60 min after administration of hydroquinidine, procaine and atropine. The exercise-induced rise in plasma glucagon which was previously shown to be inhibited by propranolol was not affected by the tested substances with the exception of nicotinic acid. Indeed, blockade of the rise in plasma free fatty acids normally associated with exercise, result in a significantly greater increase in glucagon plasma concentration in animals treated by nicotinic acid. Insulin-induced hypoglycemia provoked a 6-fold increase in plasma glucagon concentration, this rise was not altered by reserpine, hydroquinidine, procaine nor verapamil. It was increased by propranolol which slightly potentiated the hypoglycemie effect of insulin as well as by nicotinic acid which accentuated the depression in plasma free fatty acid induced by insulin. The most striking change was that atropine reduced by about 50 per cent the rise in plasma glucagon secondary to insulin administration. In view of these results, it would be of interest to study the behaviour of plasma glucagon concentration in patients chronically treated with atropine, hydroquinicline or procaine analogs in their respective and already established therapeutic uses.

Summary In order to define metabolic factors which control human placental lactogen (HPL) secretion two types of experiment have been conducted: (a) hypoglycaemia was induced by intravenously-injected insulin in 21 normal women in late pregnancy; and (b) a sustained hyperglycaemia was obtained by glucose infusion in six normal women in late pregnancy. Serum HPL was determined using an immunosorbent antibody radioimmunoassay procedure. Blood glucose was estimated in both experiments and plasma immunoreactive insulin in the second. The results show an inverse relationship between blood glucose and serum HPL concentrations. Hyperglycaemia caused the HPL level to fall and conversely insulin-induced hypoglycaemia caused it to rise. Moreover, declining blood glucose levels after the cessation of a glucose infusion were accompanied by an increase in HPL comparable to that seen during frank hypoglycaemia.

1) In normal subjects, oral administration of regular coffee and of caffeine increases NEFA plasma concentration without modifying blood glucose, plasma insulin, cortisol and growth hormone concentration; 2) this NEFA mobilizing effect of caffeine and regular coffee is not observed in obese people; 3) in normal subjects, caffeine administration improves oral glucose tolerance and potentiates the insulinogenic effect of orally administered glucose.

Glucagon in concentrations similar to those found in human plasma markedly stimulates lipolysis in rat adipose tissuein vitro. The effects of these “physiological” concentrations of glucagon are reduced or abolished by insulin at concentrations of 25 and 100μU/ml. Considering the marked insulinogenic effect of glucagon these observations may provide an explanation for the delayed increase of blood FFA observed after glucagon injectionin vivo.

Hamsters bearing a transplantable pancreatic tumor developed marked hypoglycemia upon fasting. Glucose assimilation constant and fasting plasma insulin levels were statistically higher in these animals than in the controls. The insulin content of the tumor (expressed in “humaninsulin equivalent” was 0.072 ± 0.014 U./gm. wet weight. Insulin could be extracted with acid-alcohol and inactivated with anti-insulin serum or cysteine. The possible significance of these findings is discussed.

We have investigated the influence of a single oral administration of indomethacin on blood glucose, plasma free fatty acids (FFA), alpha-amino-nitrogen, insulin and glucagon concentrations in young healthy subjects. Two groups of 6 subjects were studied, the first received a standardized 500 kcal mixed meal without any previous drug administration (controls) whereas the second group received 50 mg indomethacin 2 h before ingesting an identical meal. Plasma indomethacin concentration reached its maximum (2.36 +/- 0.36 micro g/ml) 15 min after administration and declined to 0.45 +/- 0.04 micro g/ml after 2 h. Indomethacin ingestion was followed by a significant increase in blood glucose and plasma FFA reaching their maximum value at 45 min and returning to basal levels at 120 min. No simultaneous changes in plasma alpha-amino-nitrogen, insulin or glucagon levels were detected during this period. The meal was followed by a rise in blood glucose and plasma insulin as well as by a decrease in plasma FFA concentration. No significant differences were detected between the controls and the subjects receiving indomethacin. In controls, the meal was followed by a rise in plasma alpha-amino-nitrogen and a modest although significant increase in glucagon levels. In indomethacin-treated subjects, the increment of alpha-amino-nitrogen was less marked and the increase in plasma glucagon was not observed. Thus, indomethacin by itself can exert several metabolic effects; however, it does not deteriorate the blood glucose or insulin profile after a regular meal. The present work is the first to demonstrate that an inhibitor of prostaglandin synthesis inhibits the plasma glucagon rise occurring after a physiological stimulus such as a normal meal. On the basis of previous in vitro experiments, we suggest that this effect results from an inhibition of glucagon secretion by the PG synthesis inhibitor.

The diuretic effects of torasemide and of furosemide were compared in a double blind cross-over study in 13 patients with stable chronic heart failure. Single doses of 10 mg and 20 mg of torasemide and of 40 mg of furosemide were given orally, in a randomized order on 3 consecutive days. In addition, a placebo was administered on the day preceding the 3 active drug treatment days to obtain control data. Each experimental day was divided into three urine collection periods - 0 to 4 h, 4 to 12 h and 12 to 24 h. Urine output, ion excretion and clearance were measured during each of the 3 periods as well as for the 24-h period. Torasemide 20 mg was distinctly more active in each of the 3 collection periods and in the 24-h period than furosemide 40 mg, whereas no significant difference was found between furosemide 40 mg and torasemide 10 mg for most of the experimental data. From 0 to 4 h, both torasemide and furosemide significantly increased the urinary flow rate and the urinary excretion of sodium, chloride and calcium, while they decreased the urinary osmolality when compared to placebo. All the effects persisted in the 4 to 12 h period after torasemide 20 mg in contrast to furosemide, whose effects were limited to the 0 to 4 h period. In the third period (12-24 h), the urine volume fell below the placebo value after furosemide but not torasemide, and only torasemide 20 mg was followed by a persistent decrease in the urine osmolality.(ABSTRACT TRUNCATED AT 250 WORDS)

Acarbose, an alpha-glucosidase inhibitor, delays starch digestion and inhibits intestinal sucrase and maltase activity. Twenty-eight insulin dependent diabetics were given Acarbose (3 x 100 mg daily) over a two month period, preceded and followed by a two month placebo period. Acarbose reduced post-breakfast and post-dinner blood glucose values by 25% (p less than 0.001) and 24% (p less than 0.05) respectively. It also significantly reduced mean daily blood glucose by 18% (p less than 0.05) and mean amplitude of glycaemic excursions from 8.0 +/- 0.6 to 5.5 +/- 0.4 mmol/l (p less than 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.

We investigated the respective roles of insulin deprivation and counter-regulatory hormones in the metabolic deterioration after a nocturnal interruption of continuous subcutaneous insulin infusion in Type 1 (insulin-dependent) diabetic patients without residual insulin secretion. Changes in blood glucose, plasma non-esterified fatty acids, 3-hydroxybutyrate, glucagon, growth hormone, cortisol and free insulin in seven patients whose pumps were deliberately stopped between 23.00 h and 05.00 h were compared in two randomized tests carried out either during an intravenous somatostatin infusion at a constant rate of 250 μg/h from 22.00 h until 07.00 h (somatostatin test) or during a saline infusion (control test). Arrest of the pumps resulted in a rapid (already significant after 1 h) and progressive (nadir after 5–6 h) decrease in plasma free insulin concentrations with no statistically significant differences between the two tests. Somatostatin remarkably depressed basal levels of growth hormone and the late significant increase in glucagon (+39±14 pg/ml at 05.00 h, 2p< 0.05) observed during the control test. In contrast, cortisol secretion was not inhibited. The sharp linear increase in blood glucose observed from 01.00 to 05.00 h (38±4 μmol·l-1· min-1) in the control test was fully suppressed with a paradoxical tendency to hypoglycaemia until 03.00 h and a less steep rise from 03.00 to 05.00 h (18±5 μmol·l-1·min-1, 2p

In order to evaluate the metabolic consequences of a 2-h nocturnal interruption of continuous subcutaneous insulin infusion (CSII), seven insulin-dependent diabetic patients without residual insulin secretion were investigated. The changes in blood glucose, plasmafree insulin, glucagon, free fatty acids, and 3-hydroxybutyrate (3 OH-B) concentrations have been compared during two randomized tests carried out either during the normal functioning of a Mill-Hill pump from 10 p.m. to 8 a.m. (1.00 ± 0.06 U insulin/h, keeping adequate metabolic control) or during the same conditions but with a deliberate arrest of the pump between 11 p.m. and 1 a.m. Considering the value recorded at 11 p.m. asreference, interruption of the insulin infusion resulted in: (1) a rapid (already significant after 1 h) and sustained (maximal fall: –12.5 ± 2.5 mU/L at 3 a.m.) decrease in plasma free insulin; (2) a delayed (significant after 4 h) and linear rise in blood glucose (maximal increase: + 4.0 ± 1.3 mmol/L at 5 a.m.); (3) an early (significant at midnight) and prolonged rise in plasma free fatty acids (+ 387 ± 148 μumol/L at 3 a.m.); (4) a delayed (significant after 3 h) and sustained increase in plasma 3 OH-B (+ 347 ± 88 μumol/L at 3 a.m.); and (5) no significant changes in plasma glucagon. Thus, a 2-h interruption of CSII in resting nocturnal conditions is sufficient to induce significant, delayed, and sustained metabolic alterations in C-peptide-negative patients despite good baseline blood glucose control. Resetting the pump at its basal rate is insufficient to quicklyrestore adequate circulating insulin levels and effectively counteract the metabolic disturbances. The efficacy of a bolus insulin injection in these conditions should be evaluated.

Insulin-stimulated glucose disposal was investigated using the euglycemic hyperinsulinemic glucose clamp technique in six women with anorexia nervosa (27.3 +/- 4.9 yr old; weight, 38.8 +/- 6.6 kg) and compared to results obtained in six normal women (22.6 +/- 1.2 yr old; weight, 58 +/- 2.5 kg) and seven obese women (26.8 +/- 7.7 yr old; weight, 92.5 +/- 13.8 kg). The glucose clamp was performed for 2 h using the Biostator and a continuous insulin infusion of 100 mU kg-1 h-1. Plasma levels of insulin were determined at 30-min intervals. Plasma levels of glucagon, FFA, glycerol, 3-hydroxy-butyrate, and alanine were measured basally. Blood glucose levels were similar in normal subjects and anorectic patients; they were slightly but significantly higher in the obese patients. The indices of insulin sensitivity measured were the MCR of glucose and the ratio of glucose infused to insulin infused (G/I). They were very similar in anorectic subjects [MCR, 13.5 +/- 2.4 (+/- SEM) ml kg-1 min-1; G/I, 5.2 +/- 0.9 mg/mU) and normal subjects (MCR, 13.5 +/- 1.7 ml kg-1 min-1; G/I, 5.2 +/- 0.4 mg/mU), but were significantly reduced in obese patients (MCR, 5.1 +/- 0.8 ml kg-1 min-1; G/I, 2.6 +/- 0.3 mg/mU; P less than 0.0025). Differences in plasma insulin among the three groups were not statistically significant. Plasma alanine levels were higher in anorectic than in normal or obese subjects, suggesting defective gluconeogenesis. Thus, insulin-stimulated glucose disposal is normal in patients with anorexia nervosa, a finding that contrasts with the previously reported increase in erythrocyte insulin receptors in this disease.

The present study aimed at investigating the effects of an epinephrine (EPI) intravenous infusion (10 micrograms/min for 30 min) in normal subjects and in obese patients before and after 13 days of protein-supplemented fasting (PSF, 70 g protein/day). Blood glucose, plasma free fatty acids (FFA), lactate, insulin (IRI) and glucagon were determined before, during (15, 30 min) and after (+30 and +60 min) the EPI infusion. 1. When compared to lean control subjects, obese patients exhibited a less marked rise in blood glucose and a more important increase in plasma FFA, EPI infusion decreased IRI plasma levels in normals but not in the obese. Plasma glucagon was lower in the obese under basal conditions and their A cell reactivity to EPI was clearly reduced. 2. Comparison of the results obtained in obese patients before and after PSF revealed that EPI-induced blood glucose rise was not altered despite lower basal values after PSF. Plasma lactate response was impaired, probably because of the depletion in muscle glycogen. Reduction in basal plasma IRI was associated with a significantly higher FFA mobilization. Abnormally low basal EPI-stimulated glucagon concentrations persisted after PSF despite concomitant reductions in blood glucose and plasma IRI.

The respective roles of glucose and insulin in the regulation of glucagon release from the canine stomach were investigated using an isolated blood-perfused preparation. At normal blood glucose and plasma insulin levels, the stomach released small amounts of glucagon. Such basal gastric glucagon release was not modified by hyperglycemia. In contrast, gastric glucagon release was increased by hypoglycemia or 2-deoxy-D-glucose-induced cytoglycopenia. Antibody neutralization of basal circulating concentrations of insulin (10 +/- 1 microU/ml) doubled the stimulation induced by hypoglycemia alone. It is concluded that: 1) suppression of gastric glucagon release is observed with very low concentrations of insulin; 2) basal gastric glucagon release is not further suppressed by hyperglycemia; and 3) that hypoglycemia and cytoglycopenia stimulate gastric glucagon secretion.

The effect of a 14 day-administration of butylbiguanide was investigated in a group of 10 obese patients with mild-to-moderate glucose intolerance. Glucose tolerance was significantly improved, while fasting blood glucose and plasma levels of free fatty acids, insulin and glucagon remained unchanged. The estimation of the amount of the oral glucose load oxidized into CO2 was performed by means of a recently described procedure using “naturally labelled 13C-glucose” as tracer. The curves depicting the oxidation of the exogenous glucose load were similar in shape and magnitude before and after administration of the biguanide; in the latter case, however, slightly higher rates of oxidation of exogenous glucose were recorded during the 2nd, 3rd and 4th hours of the test. These data do not provide evidence that the biguanide-induced improvement in glucose tolerance in patients with mild-to-moderate glucose intolerance is associated with any inhibiting or delaying effect of this type of drug on intestinal absorption (and subsequent oxidation) of the exogenous glucose load. On the contrary, a slight, but statistically significant, increase in the oxidation of exogenous glucose has been observed after butylbiguanide.

The isolated perfused rat pancreas was used to investigate the effect of extracellular phosphate on the arginine-induced insulin release. In the absence of any metabolic substrate, the insulin response to arginine was monophasic. In the absence of phosphate in the medium, the insulin release was unaffected until the 15th minute of the stimulation period, but was significantly augmented from that time onward. In the presence of oleic acid in the perfusate, the insulin response to arginine was also monophasic but occurred earlier than in controls. In this condition, phosphate omission resulted in an increase of the insulin response to arginine from the 3rd minute of the stimulatory period onward. In the presence of glucose 5.5 mM in the medium the insulin response to arginine was biphasic and was not affected by extracellular phosphate omission.

To compare the metabolic effects of pulsatile vs. continuous iv insulin infusion, normal men had two glucose-controlled iv glucose infusions using the Biostator for 260 min, during which endogenous pancreatic hormone secretion was inhibited by a somatostatin infusion and glucagon was replaced by continuous glucagon infusion. The two tests were performed at 1-week intervals, during which human insulin was infused either continuously at a constant rate of 0.2 mU kg-1 min-1 or in a pulsatile manner at a rate of 1.3 mU kg-1 min-1 with a switching on/off length of 2/11 min. Blood glucose levels and glucose infusion rates (GIR) were continuously monitored, and glucose turnover was estimated using a [3H]glucose infusion. In both tests, plasma C-peptide dropped markedly, whereas plasma glucagon levels were about twice basal values. Plasma insulin averaged 7 mU liter-1 during continuous infusion and oscillated between 1.5 and 35 mU liter-1 during pulsatile delivery. During the first 30-60 min of both tests, the glucose appearance rate and endogenous glucose production (EGP) increased, resulting in moderate hyperglycemia, which completely suppressed GIR. During the last 65 min, EGP declined, while the glucose disappearance rate and the glucose MCR increased, so that GIR increased progressively to maintain the blood glucose clamped at about 5 mmol liter-1. During this period, no significant differences were found between the two modes of insulin administration for any of the parameters studied. Thus, continuous and pulsatile insulin iv infusion, resulting in physiological peripheral plasma insulin levels, altered the glucose turnover parameters equally, in particular inhibiting EGP, which was stimulated by glucagon during the first part of the study, and stimulating peripheral glucose uptake at the end of the study period.

The effects of glucose ingestion on the changes in blood glucose, FFA, insulin and glucagon levels induced by a prolonged exercise at about 50% of maximal oxygen uptake were investigated. Healthy volunteers were submitted to the following procedures: 1. a control test at rest consisting of the ingestion of 100 g glucose, 2. an exercise test without, or 3. with ingestion of 100 g of glucose. Exercise without glucose induced a progressive decrease in blood glucose and plasma insulin; plasma glucagon rose significantly from the 60th min onward (+45 pg/ml), the maximal increase being recorded during the 4th h of exercise (+135 pg/ml); plasma FFA rose significantly from the 60th min onward and reached their maximal values during the 4th h of exercise (2177 +/- 144 muEq/l, m +/- SE). Exercise with glucose ingestion blunted almost completely the normal insulin response to glucose. Under these conditions, exercise did not increase plasma glucagon before the 210th min; similarly, the exercise-induced increase in plasma FFA was markedly delayed and reduced by about 60%. It is suggested that glucose availability reduces exercise-induced glucagon secretion and, possibly consequently, FFA mobilization.

Fourteen insulin-treated diabetics were submitted to an arginine infusion test performed with either 11.7 or 5.85 mg kg-1 min-1 arginine monohydrochloride infused during 40 min with or without previous oral administration of a low (75 + 50 mg) or a high (75 mg + 3 mg/kg) dose of indomethacin. Blood glucose, plasma non-esterified fatty acids, insulin, C-peptide and glucagon were determined at regular intervals before, during and after the arginine infusion. These parameters were totally unaffected by the two doses of indomethacin both in the basal state and during the arginine infusions at the two loads tested. Eight subjects had a basal C-peptide level above 0.07 pmol/ml and a mean (+/- SEM) maximal rise of 0.21 +/- 0.04 pmol/ml during the arginine infusion, whereas the remaining six patients had virtually zero values throughout the tests. The arginine-induced plasma glucagon rise was similar for the two rates of arginine infusion; the sum of the increments in plasma glucagon averaged 877 +/- 120 and 647 +/- 92 pg/ml (p greater than 0.1) for the high and low rates of arginine infusion, respectively. The magnitude of the blood glucose rise appeared independent of the amount of arginine infused. Confirming previous reports, we found that the blood glucose rise after arginine was three to four times higher in subjects without C-peptide than in subjects with C-peptide. The mean glucagon response did not differ significantly between subjects with or without C-peptide. Thus, residual B cell function determines the magnitude of the blood glucose rise but not the glucagon response after intravenous arginine.

Interruption 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 nonesterified fatty acids which remained in the range of 700-800 mumol/l; (4) an early and linear rise in plasma 3-hydroxybutyrate, significant after 1 h and averaging 1290 +/- 140 mumol/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 05.00 h 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.

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.

Blood glucose and pyruvate, plasma insulin, and glucagon levels as well as erythrocyte insulin receptors were measured during an oral glucose tolerance test in 38 normal women before and after 6 months' use of one of three new oral contraceptives containing low doses of 19 nortestosterone-derived progestogens, levonorgestrel, and desogestrel. A slight deterioration of glucose tolerance was observed, with the area under the glucose curve increasing by only 7%, 9%, and 12% after Ovidol (Aaciphar SA, Brussels, Belgium), Marvelon (Organon, SA, Brussels, Belgium), and Trigynon (Schering SA, Brussels, Belgium) administration, respectively. We did not find any argument in favor of the development of a state of insulin resistance in women using these compounds, because erythrocyte receptor binding was not modified and plasma insulin responses to glucose were decreased. The glucose-induced suppression of plasma glucagon levels seemed less effective for treatment with the desogestrel-containing preparations than with the levonorgestrel-containing oral contraceptives.

The effect of a 6-wk training period on the oxidation of a 100-g glucose load given orally during exercise was investigated in six healthy male volunteers. The subjects were submitted before and 24 h after the training program to a 105-min exercise bout (performed at about 40% of the pretraining VO2max) followed by a 90-min resting period. Naturally labeled [13C]glucose was given 15 min after the beginning of exercise. Exogenous glucose oxidation was derived from 13CO2 measurements in expired air, and total glucose and lipid oxidation were evaluated by indirect calorimetry. Training (60-min bicycling 5 days a week at 30-40% VO2max) resulted in a 29% increase in VO2max. During the 15 min of exercise that preceded glucose ingestion, the rate of total carbohydrate oxidation was slightly decreased after training, whereas the rate of lipid oxidation was slightly increased. Training did not affect the response of blood glucose, plasma insulin, or plasma free fatty acids to the glucose ingested during exercise; in contrast, the circulating levels of epinephrine, glycerol, and lactate were significantly reduced after training. Substrate utilization measurements revealed similar oxidation rates of carbohydrates (106.9 +/- 2.7 before vs. 100.2 +/- 4.7 g/3 h after training) and of lipids. However, detailed analysis revealed a significant 17% increase in exogenous glucose oxidation, thus indicating a significant sparing of endogenous carbohydrates. In conclusion, physical training induces a modest but significant increase in the oxidation of an oral load of glucose given during subsequent exercise of moderate intensity, a phenomenon reinforcing the sparing of endogenous carbohydrate stores.

Publisher Summary This chapter describes the factors controlling glucagon secretion. Glucagon secretion has been investigated using isolated tissues, isolated perfused organs, in situ organs, or entire organisms isolated tissues include pancreas slices as such, or slices from a duct-ligated pancreas, and isolated islets of Langerhans prepared either by microdissection, or by collagenase digestion of pancreatic pieces. Isolated organs systems use isolated rat, dog pancreas, or stomach, preparations which are perfused by artificial media, or blood. Appropriate catheterizations permit simultaneous measurements of blood flow, and net pancreatic, or gastric glucagon production in large animals such as the dog or the pig. At the level of the whole organism, samples can be taken at the portal vein, or peripherally, and in this last instance, one should remember that liver glucagon uptake may represent 30%-85% of liver glucagon inflow. There is evidence that glucose entry into the A cell may require insulin and, it has been demonstrated that insulin simultaneously increases glucose utilization by the A cells, augments their ATP formation and permits glucose to inhibit glucagon secretion.

Overnight fasted anesthetized dogs were treated with prostaglandin PGE 1 infused at a rate of 0.5 or 1 μg/kg/min for 40 min and compared with saline-infused dogs. PGE 1 infusion caused a significant transient drop in arterial blood pressure (25–30 per cent) and in pancreaticoduodenal vein (PDV) blood flow (40–50 per cent). Total insulin output was unchanged during infusion. The cessation of PGE 1 infusion (1 μg/ kg/min) was accompanied by a slight tendency toward recovery of PDV blood flow and a highly significant (P 1 infusion; however a moderate hypoglycemia was recorded at the time of maximal insulin output. These results (1), confirm that insulin output is relatively independant of gross changes in pancreaticoduodenal blood flow; and (2), demonstrate that insulin release is significantly increased in response to PGE 1 infusion. The relationship between the PGE 1 -induced insulin increase and the adenylate cyclase system of the β-cell remains to be elucidated.