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The study investigated the respective influences of nicotinic acid and somatostatin on plasma concentrations of blood glucose, free fatty acids, glucagon, growth hormone and cortisol in insulin-dependent diabetic subjects. After administration of nicotinic acid alone, marked depression of plasma FFA was accompanied by significant increases of plasma glucagon, growth hormone and cortisol. The glucagon and growth hormone responses to nicotinic acid were significantly reduced when plasma FFA were raised by intravenous administration of heparin and triglycerides. Somatostatin alone induced a significant decrease in blood glucose, plasma glucagon and growth hormone concentrations. Plasma FFA remained unchanged. Somatostatin did not modify the nicotinic acid-induced fall in plasma FFA, but completely blocked the corresponding increments in glucagon and growth hormone. The cortisol rise was not altered by somatostatin. Rebound of glucagon and growth hormone levels were seen upon discontinuation of the somatostatin administration. These results demonstrate that the plasma FFA concentration plays a role in the regulation of glucagon and growth hormone secretion in insulin-dependent diabetics. Furthermore, they indicate that somatostatin, previously shown to be capable of negating the stimulatory effect of various factors on glucagon and growth hormone secretion, also affects the response of these hormones to FFA depression.

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.

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.

We investigated the hormonal and metabolic response to a 100-g sucrose load given 15 min after adaptation to moderate-intensity (50% Vmaxo2) long-duration (4-h) exercise in healthy volunteers. The effect of a 100-mg dose of the α-glucosidase inhibitor Acarbose ingested with the sucrose load was also investigated. “Naturally labeled [13C] sucrose” was used to follow the conversion to expired-air CO2 of the sugar ingested by isotope-ratio mass spectrometry. Circulating hormone and metabolite data were obtained in nine subjects, and indirect calorimetry and stable isotope methodology were applied to six of them. Under placebo, 93 ± 4 g sucrose were entirely oxidized during the 4 h of exercise, total carbohydrate utilization was 235 ± 14 g, endogenous carbohydrate utilization was 142 ± 13 g, and total lipid oxidation was 121 ± 7 g. A single oral dose of 100 mg Acarbose ingested with the sucrose load did not significantly modify total carbohydrate (239 ± 2 g/4 h) or lipid (122 ± 6 g/4 h) oxidation. In contrast, sucrose oxidation was reduced to 53 ± 6 g/4 h and endogenous carbohydrate utilization increased to 186 ± 7 g/4 h. Reduction of the rises in blood glucose and fructose and of the increases in plasma insulin and C peptide under Acarbose confirmed these effects, whereas lower circulating levels of alanine suggested a higher rate of gluconeogenesis. These data show that a 100-g glucose load ingested soon after initiation of exercise is a perfect available metabolic substrate. Furthermore, the simultaneous ingestion of 100 mg Acarbose significantly reduces the availability of sucrose during exercise, a finding that has to be considered if this or other compounds with similar properties are envisaged for the treatment of diabetic patients.

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.

By use of naturally enriched [13C]glucose as metabolic tracer, the utilization of exogenous glucose ingested during muscular exercise was investigated. Four subjects walked on an uphill treadmill for 2 h, and three other for 4 h. The energy expenditure, close to 50% of the individual maximum Vo2,, varied from 1.9 to 2.1 liters of O2/min, while the heart rate ranged between 142 and 165 beats/mm. The subjects who were on a mixed diet and had fasted overnight, were given 100 g of naturally labeled [13C]glucose. Following this intake? the expired CO2 became rapidly enriched in carbon-13. The increase was observed as early as 15 min after the oral intake, and reached a maximum within 1–2 h, when utilization of exogenous glucose varied between 500 and 650 mg/min, representing as much as 55% of the carbohydrate metabolism and 24% of the total energy expenditure. glucose metabolism; man; mass spectrometry; stable isotopes

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.

Adequate utilization of glucose given orally during prolonged muscular exercise remains a matter of controversy. The aim of the present study was to investigate whether the time when glucose is ingested during exercise affects exogenous glucose disposal. Nine healthy male volunteers were submitted to a 4-h period of treadmill exercise at about 45% of their maximum O2 consumption. A 100-g load of naturally labeled [13C]glucose was given orally after 120 min (5 subj, group A) or 15 min (4 subj, group B) of exercise. In the 2 h after glucose ingestion, total carbohydrate oxidation (indirect calorimetry) was similar in both groups (A: 147 +/- 12 g/2 h; B: 135 +/- 12 g/2 h) as was lipid oxidation (A: 51 +/- 4 g/2 h; B: 57 +/- 11 g/2 h). Exogenous glucose oxidation was 54 +/- 2 g/h in group A vs. 55 +/- 6 g/2 h in group B. The blood glucose response to oral glucose was similar in the two conditions, whereas the C-peptide response, already modest, was further blunted when glucose was ingested after 2 h of exercise compared with the response observed after 15 min. In conclusion, glucose ingestion during prolonged exercise of moderate intensity is effectively oxidized, 55% of the load given being recovered as expired CO2 within 2 h; utilization of glucose given orally is similar when ingestion takes place 15 or 120 min after initiation of exercise.

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...

The aim of the present study was to investigate the extent to which an oral load of glucose ingested 3 h before a 4-h exercise bout of moderate intensity represents an energy source readily available during that exercise. Therefore, five healthy male volunteers drank 100 g of naturally labeled [13C]glucose dissolved in 400 ml of water, rested for 3 h, and then exercised on a treadmill for the next 4 h at about 45% of their individual maximum O2 consumption. Total glucose oxidation was derived from nonprotein respiratory quotient and exogenous glucose oxidation evaluated by the 13C methodology as previously described. Total carbohydrate oxidation averaged 285 +/- 17 g during the 7 h of the test, the global amount of carbohydrate oxidized during the exercising period was 253.1 +/- 16.9 g/4 h. Exogenous glucose oxidation averaged 11.3 +/- 0.7 g during the 3-h period of rest and increased markedly after the beginning of exercise, reaching 18.9 +/- 2.2 g/30 min during the first 30 min of exercise; the total amount of exogenous glucose oxidized during the 4 h of exercise was 67.5 +/- 9.4 g. Throughout the whole period of exercise, blood glucose concentrations remained between 3.5 and 4.0 mmol/l. Exercise induced a major fall in plasma insulin levels that reached undetectable values after 3 and 4 h, whereas plasma glucagon levels tended to rise, but their level never significantly exceeded the basal values; plasma free fatty acids and glycerol increased markedly during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

The 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.

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.

Two chemically unrelated inhibitors of lipolysis were used in order to differentiate between the effect of FFA depression and a possible FFA-unrelated drug effect, respectively, on the plasma concentrations of GH, cortisol, and glucagon. Saline infusion served as a control experiment. In eight healthy male volunteers, a similar FFA depression by either iv infusion of nicotinic acid (3-pyridine-carboxylic acid, NA) or oral intake of an adenosine derivative, N(6)-allyl-N(6)-cyclohexyl-adenosine (AD-D), was followed by a significant GH increase (to 22.1 +/- 6.2 and 9.6 +/- 2.9 ng/ml at 240 and 270 min, respectively). Due to the large scatter of the GH concentrations during NA infusion, these responses were not significantly different. No GH increase occurred when the FFA depression was prevented by addition of a lipid infusion. In contrast, plasma cortisol and glucagon both increased significantly (by 107.4 micrograms/liter at 270 min and by 48.4 pg/ml at 60 min, respectively) during NA- but not during AD-D-induced FFA depression. Addition of the lipid infusion abolished the cortisol increase during NA infusion but had no influence on basal cortisol concentrations during AD-D intake. It lowered glucagon to values slightly below basal concentrations when added to the NA infusion and more markedly during AD-D administration. The results provide evidence that 1) depression of plasma FFA per se stimulates the secretion of GH, and 2) the increase of cortisol and glucagon during NA infusion is probably unrelated to the FFA depression. Hence, the stimulatory effect of FFA lack on glucagon secretion needs to be reconsidered.

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.

Plasma C-peptide concentrations have been determined in the basal state and in response to intravenous arginine in 10 insulin-dependent diabetics. Five patients had fasting C-peptide levels above 0.08 pmol/ml and responded to the arginine infusion with a rise in C-peptide levels of more than 0.2 pmol/ml (responsive diabetics). The remaining 5 patients had fasting C-peptide below 0.03 pmol/ml and showed no C-peptide response to arginine (nonresponsive diabetics). Fasting blood glucose and the rise in blood glucose in response to arginine were higher in non-responsive than in responsive diabetics. The magnitude of blood glucose rise in response to arginine was inversely correlated with increments in plasma C-peptide. I n addition, the fasting levels of FFA and 3-hydroxybutyrate were significantly lower in C-peptide responsive than in nonresponsive patients. These data give further support to the concept that measurements of fasting plasma C-peptide permit to distinguish secretors from nonsecretors, and demonstrate that residual beta-cell function is associated with a lesser degree of aminoacid-induced hyperglycemia.

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.

A single dose of glibenclamide 5 mg was administered to six Type 2 diabetics, randomly treated for 7 days either with acarbose (3 X 100 mg daily) or with placebo. The serum concentration of the drug was measured for 10 h. Peak concentrations, times-to-peak concentration, elimination half-lives and the extent of bioavailability of the drug were not significantly modified by acarbose. The combined administration of glibenclamide and acarbose resulted in a modest improvement in the blood glucose profile after breakfast and lunch, together with a significant diminution in plasma insulin. Thus, acarbose appears a useful additional treatment for Type 2 diabetics already receiving sulphonylurea derivatives.

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.

Bilateral kidney exclusion in the anesthetized dog is followed by a rapid and sustained increase in arterial plasma glucagon. This occurs even if endogenous glucagon secretion is inhibited by somatostatin or completely suppressed by abdominal evisceration and, in both cases, replaced by a constant infusion of exogenous glucagon. It is concluded that the rise in plasma glucagon occurring after bilateral kidney exclusion is not due to an increase in endogenous glucagon production but results from an abrupt cessation of kidney glucagon uptake.

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.

Adipsic hypernatremia, a rare disorder, usually secondary to a hypothalamic lesion, is caused by the combination of partial central diabetes insipidus with hypo- or adipsia. We studied a patient who presented with a global hypothalamic dysfunction including adipsic hypernatremia. An extensive work-up disclosed the presence of pseudotumor cerebri and an empty sella turcica. Although endocrine abnormalities including true diabetes insipidus have been reported in conjunction with pseudotumor cerebri or an empty sella, no patient described presented such a global hypothalamic dysfunction or adipsic hypernatremia. The increased intracranial pressure is postulated to be the responsible mechanism for both the empty sella and the hypothalamic dysfunction.

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.

T HE PLASMA of totally depancreatized dogs contains normal, or even increased, quantities of a material immunometrically indistinguishable from pancreatic glucagon. ~-3 On the other hand, glucagon cannot be detected in the blood of dogs following complete abdominal evisceration? Since Sasaki et al. 5 demonstrated the presence in the dog stomach of a material biologically, physicochemically, and immunometrically identical to pancreatic glucagon, as well as the existence of "true" alpha cells in the gastric fundus, it appeared likely that the glucagon detected in the plasma of the pancreatectomized dog might, at least in part, originate from the gastric fundus. The aim of the present work was to study the glucagon response of isolated dog stomach to the intra-arterial administration of arginine. The release of gastrin was simultaneously investigated.

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.

To investigate further the hormonal and metabolic adaptations occurring when carbohydrates are ingested after prolonged exercise, we have compared the fate of a 100-g oral glucose load (using 'naturally labelled' 13C-glucose) in healthy volunteers after an overnight fast at rest either without previous exercise or after a 3-h exercise performed on a treadmill at about 50% of the individual VO2 max. In comparison to the control conditions, the oral glucose tolerance test (OGTT) performed in the post-exercise recovery period was characterized by a greater rise in peripheral blood glucose levels and delayed insulin response. Plasma glucagon values were significantly elevated at the time glucose was given (+48 +/- 13 pg ml-1) and at the end of the OGTT. Plasma-free fatty acid (FFA) levels were 1675 +/- 103 microEq 1-1 when glucose was given, and subsequently reduced to values similar to those observed in the control conditions. Indirect calorimetry indicated that OGTT in post-exercise recovery was associated with decreased carbohydrate and increased lipid oxidation when compared to control conditions. Exogenous glucose oxidation was also significantly reduced: 21.1 +/- 2.6 vs. 35.9 +/- 1.9 g per 7 h. We suggest that the higher plasma glucagon levels and the delayed insulin response played a role in the decreased hepatic glucose retention previously described by others in post-exercise recovery. Our data also suggest that the higher lipid oxidation rate observed at the time glucose was given in the post-exercise period could explain, according to the Randle 'glucose-fatty acid cycle', the decreased carbohydrate oxidation and the preferential muscle glycogen repletion already well documented. The reason why the lipid oxidation rate remains increased 3-7 h after glucose ingestion in spite of the fact that FAA levels at that time are similar to those observed in control conditions is still unknown; further kinetic studies are needed to clarify this point.

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)

To study the metabolic effects of pulsatile glucagon administration, six male volunteers were submitted to a 260-min glucose-controlled glucose intravenous infusion using the Biostator. The endogenous secretion of the pancreatic hormones was inhibited by somatostatin (100 micrograms X h-1), basal insulin secretion was replaced by a continuous insulin infusion (0.2 mU X kg-1 X min-1), and glucagon was infused intravenously in two conditions at random: either continuously (125 ng X min-1) or intermittently (812.5 ng X min-1, with a switching on/off length of 2/11 min). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classical methodology using a D-[3-3H]glucose infusion allowed us to study glucose turnover. While basal plasma glucagon levels were similar in both conditions (122 +/- 31 vs. 115 +/- 18 pg X ml-1), they plateaued at 189 +/- 38 pg X ml-1 during continuous infusion and varied between 95 and 501 pg X ml-1 during pulsatile infusion. When compared with continuous administration, pulsatile glucagon infusion initially induced a similar increase in endogenous (hepatic) glucose production and blood glucose, did not prevent the so-called “evanescent” effect of glucagon on blood glucose, and after 3 h tended to reduce rather than increase hepatic glucose production. In conclusion, in vivo pulsatile hyperglucagonemia in normal man fails to increase hepatic glucose production.

The isolated, perfused, canine stomach was used to investigate the effect of three neurotransmitters—nor-epinephrine, acetylcholine (or its analogue carbamyl-choline), and VIP (vasoactive intestinal peptide)—on gastric glucagon release. Norepinephrine at the two concentrations tested (3.10−6 and 7.10−7 M) did not influence gastric glucagon release. In contrast, acetylcholine or carbamylcholine (5.10−6 M) as well as VIP (46–60 ng/ml) unequivocally stimulated gastric glucagon release, an effect apparently independent of the changes in blood flow. These results are in sharp contrast with the previously reported lack of effect of an electric stimulation of the vagus nerves on the release of glucagon from the dog stomach. An absence of innervation of the canine gastric A-cell would probably best explain this situation.

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

A new method for continuous blood collection using the Biostator is described. Blood is withdrawn through the double lumen catheter by a tube installed in the optional channel of the infusion pump. The amount of blood withdrawn from the patient is slightly greater than that necessary for continuous glucose analysis; the excess blood can be collected into assay tubes. Blood collection is continuous and produces a sample of diluted heparinized blood. The volume of blood collected depends on the size of the tube used, i.e. for a tube with a lumen diameter of 0.020 inches, the mean (+/- SD) volume collected was 1.21 +/- 0.07 ml/10 min (n = 13). The mean time interval between sampling and arrival at the glucose sensor by the double lumen catheter was 119 versus 108 s with the conventional method. The proposed modification does not affect blood glucose measurements (correlation coefficient compared with the reference method r = 0.9572; n = 13). To compensate for blood dilution, a dilution-factor depending on tubing diameter has to be calculated in each experiment.