Portal venous hyperinsulinemia does not stimulate gut glucose absorption in the conscious dog.

The purpose of the present study was to assess whether physiological portal vein hyperinsulinemia stimulates gut glucose absorption in vivo. Chronically catheterized (femoral artery, portal vein, inferior vena cava, and proximal and distal duodenum) and instrumented (Doppler flow probe on portal vein) insulin (INS, 2 mU.kg(-1).min(-1), n = 6) or saline (SAL, n = 5) infused dogs were studied during basal (30 minutes) and experimental (90 minutes) periods. Arterial and portal vein plasma insulin were 3.3- and 3.2-fold higher, respectively, throughout the study in INS compared to SAL. An intraduodenal glucose infusion of 8 mg.kg(-1).min(-1) was initiated at t = 0 minutes. At t = 20 and 80 minutes, a bolus of 3-O-[3H]methylglucose (MG) and L-[14C]glucose (L-GLC) was injected intraduodenally. Phloridzin, an inhibitor of the Na+ -dependent glucose transporter (SGLT1), was infused from t = 60 to 90 minutes in the presence of a peripheral isoglycemic clamp. Net gut glucose output (NGGO) was 5.2 +/- 0.6 and 4.6 +/- 0.8 mg.kg(-1).min(-1) in INS and SAL, respectively, from t = 20 to 60 minutes. Transporter-mediated absorption was 87% +/- 2% of NGGO in both INS and SAL. Passive gut glucose absorption was 13% +/- 2% of NGGO in both INS and SAL. Phloridzin-induced inhibition of transporter-mediated absorption completely abolished passive absorption of L-GLC in both groups. This study shows that under physiological conditions, a portal vein insulin infusion that results in circulating hyperinsulinemia does not increase either transporter-mediated or passive absorption of an intraduodenal glucose load.

Prior exercise enhances passive absorption of intraduodenal glucose.

The purpose of this study was to assess whether a prior bout of exercise enhances passive gut glucose absorption. Mongrel dogs had sampling catheters, infusion catheters, and a portal vein flow probe implanted 17 days before an experiment. Protocols consisted of either 150 min of exercise (n = 8) or rest (n = 7) followed by basal (-30 to 0 min) and a primed (150 mg/kg) intraduodenal glucose infusion [8.0 mg x kg-1x min-1, time (t) = 0-90 min] periods. 3-O-[3H]methylglucose (absorbed actively, facilitatively, and passively) and l-[14C]glucose (absorbed passively) were injected into the duodenum at t = 20 and 80 min. Phloridzin, an inhibitor of the active sodium glucose cotransporter-1 (SGLT-1), was infused (0.1 mg x kg-1 x min-1) into the duodenum from t = 60-90 min with a peripheral venous isoglycemic clamp. Duodenal, arterial, and portal vein samples were taken every 10 min during the glucose infusion, as well as every minute after each tracer bolus injection. Net gut glucose output in exercised dogs increased compared with that in the sedentary group (5.34 +/- 0.47 and 4.02 +/- 0.53 mg x kg-1x min-1). Passive gut glucose absorption increased approximately 100% after exercise (0.93 +/- 0.06 and 0.45 +/- 0.07 mg x kg-1 x min-1). Transport-mediated glucose absorption increased by approximately 20%, but the change was not significant. The infusion of phloridzin eliminated the appearance of both glucose tracers in sedentary and exercised dogs, suggesting that passive transport required SGLT-1-mediated glucose uptake. This study shows 1). that prior exercise enhances passive absorption of intraduodenal glucose into the portal vein and 2). that basal and the added passive gut glucose absorption after exercise is dependent on initial transport of glucose via SGLT-1.

Transporter-mediated absorption is the primary route of entry and is required for passive absorption of intestinal glucose into the blood of conscious dogs.

To determine the contributions of transporter-mediated and passive absorption during an intraduodenal glucose infusion in a large animal model, six mongrel dogs had sampling catheters (portal vein, femoral artery, duodenum), infusion catheters (vena cava, duodenum) and a portal vein flow probe implanted 17 d before an experiment. Protocols consisted of a basal (-30 to 0 min) and an experimental (0-90 min) period. An intraduodenal glucose infusion of 44 micromol/(kg. min) was initiated at t = 0 min. At t = 20 and 80 min, 3-O-[3H]methylglucose and L-[14C]glucose (L-Glc) were injected intraduodenally. Phloridzin, an inhibitor of the Na+/K+ ATP-dependent transporter (SGLT1), was infused from t = 60 to 90 min in the presence of a peripheral isoglycemic clamp. Net gut glucose output was 21.1 +/- 3.0 micromol/(kg. min) from t = 0 to 60 min. Transporter-mediated glucose absorption was calculated using three approaches, which involved either direct measurements or indirect estimates of duodenal glucose analog radioactivities, to account for the assumptions and difficulties inherent to duodenal sampling. Values were essentially the same regardless of calculations used because transporter-mediated absorption was 89 +/- 1%, 90 +/- 2% and 91 +/- 2% of net gut glucose output. Phloridzin-induced inhibition of transporter-mediated absorption completely abolished passive absorption of L-Glc. We conclude that in dogs, transporter-mediated glucose absorption constitutes the vast majority of glucose absorbed from the gut and is required for passive glucose absorption. The method described here is applicable to investigation of the mechanisms of gut glucose absorption under a variety of nutritional, physiologic and pathophysiologic conditions.

Prevention of overt hypoglycemia during exercise: stimulation of endogenous glucose production independent of hepatic catecholamine action and changes in pancreatic hormone concentration.

These studies were conducted to determine the magnitude and mechanism of compensation for impaired glucagon and insulin responses to exercise. For this purpose, dogs underwent surgery >16 days before experiments, at which time flow probes were implanted and silastic catheters were inserted. During experiments, glucagon and insulin were fixed at basal levels during rest and exercise using a pancreatic clamp with glucose clamped (PC/GC; n = 5), a pancreatic clamp with glucose unclamped (PC; n = 7), or a pancreatic clamp with glucose unclamped + intraportal propranolol and phentolamine hepatic alpha- and beta-adrenergic receptor blockade (PC/HAB; n = 6). Glucose production (R(a)) was measured isotopically. Plasma glucose was constant in PC/GC, but fell from basal to exercise in PC and PC/HAB. R(a) was unchanged with exercise in PC/GC, but was slightly increased during exercise in PC and PC/HAB. Despite minimal increases in epinephrine in PC/GC, epinephrine increased approximately sixfold in PC and PC/HAB during exercise. In summary, during moderate exercise, 1) the increase in R(a) is absent in PC/GC; 2) only a moderate fall in arterial glucose occurs in PC, due to a compensatory increase in R(a); and 3) the increase in R(a) is preserved in PC/HAB. In conclusion, stimulation of R(a) by a mechanism independent of pancreatic hormones and hepatic adrenergic stimulation is a primary defense against overt hypoglycemia.

Prior exercise and the response to insulin-induced hypoglycemia in the dog.

To test whether hepatic insulin action and the response to an insulin-induced decrement in blood glucose are enhanced in the immediate postexercise state as they are during exercise, dogs had sampling (artery, portal vein, and hepatic vein) catheters and flow probes (portal vein and hepatic artery) implanted 16 days before a study. After 150 min of moderate treadmill exercise or rest, dogs were studied during a 150-min hyperinsulinemic (1 mU.kg(-1).min(-1)) euglycemic (n = 5 exercised and n = 9 sedentary) or hypoglycemic (65 mg/dl; n = 8 exercised and n = 9 sedentary) clamp. Net hepatic glucose output (NHGO) and endogenous glucose appearance (R(a)) and utilization (R(d)) were assessed with arteriovenous and isotopic ([3-(3)H]glucose) methods. Results show that, immediately after prolonged, moderate exercise, in relation to sedentary controls: 1) the glucose infusion rate required to maintain euglycemia, but not hypoglycemia, was higher; 2) R(d) was greater under euglycemic, but not hypoglycemic conditions; 3) NHGO, but not R(a), was suppressed more by a hyperinsulinemic euglycemic clamp, suggesting that hepatic glucose uptake was increased; 4) a decrement in glucose completely reversed the enhanced suppression of NHGO by insulin that followed exercise; and 5) arterial glucagon and cortisol were transiently higher in the presence of a decrement in glucose. In summary, an increase in insulin action that was readily evident under euglycemic conditions after exercise was abolished by moderate hypoglycemia. The means by which the glucoregulatory system is able to overcome the increase in insulin action during moderate hypoglycemia is related not to an increase in R(a) but to a reduction in insulin-stimulated R(d). The primary site of this reduction is the liver.

Effects of nitric oxide inhalation on periodic breathing in awake patients with chronic heart disease.

BACKGROUND: Periodic breathing, an abnormal pattern of respiration consisting of alternating hyperpnea and hypopnea, has been recognized in patients with heart failure. Although fluctuations in pulmonary blood flow have been considered as a possible cause of this type of breathing, its patho-physiological mechanisms are not fully understood. In this study, we sought to determine whether inhaled nitric oxide (NO), a selective pulmonary vasodilator, attenuates periodic breathing. METHODS: Eight cardiac patients who exhibited clear oscillatory ventilation while awake (age: 62 +/- 16 years, left ventricular ejection fraction: 48 +/- 20%) were enrolled in the study. After breathing room air (RA) for 15 min, the subjects inhaled air containing 30 ppm of NO for 15 min. Respiratory gas variables including minute ventilation (VE) were measured on a breath-by-breath basis throughout the test. RESULTS: There were no differences in VE (10.7 +/- 1.5 vs. 11.0 +/- 1.7 l/min) or among any of the other hemodynamic or respiratory gas variables studied in the control and NO tests, with the exception of the end-tidal CO(2) partial pressure (5.0 +/- 0.4 vs. 4.8 +/- 0.5%; p = 0.018). The % magnitude of oscillation (i.e., the difference between the peak and nadir of oscillating VE, divided by the mean VE) was 40.0 +/- 22.4% in RA and not influenced by inhaled NO (43.9 +/- 20.8%, p = 0.57). CONCLUSION: Inhaled NO at a concentration of 30 ppm did not attenuate periodic breathing in awake patients with mild heart failure.