Pietro Galassetti

A negative arterial-portal venous glucose gradient decreases skeletal muscle glucose uptake

The effect of a negative arterial-portal venous (a-pv) glucose gradient on skeletal muscle and whole body nonhepatic glucose uptake was studied in 12 42-h-fasted conscious dogs. Each study consisted of a 110-min equilibration period, a 30-min baseline period, and two 120-min hyperglycemic (2-fold basal) periods (either peripheral or intraportal glucose infusion). Somatostatin was infused along with insulin (3 x basal) and glucagon (basal). Catheters were inserted 17 days before studies in the external iliac artery and hepatic, portal and common iliac veins. Blood flow was measured in liver and hindlimb using Doppler flow probes. The arterial blood glucose, arterial plasma insulin, arterial plasma glucagon, and hindlimb glucose loads were similar during peripheral and intraportal glucose infusions. The a-pv glucose gradient (in mg/dl) was 5 +/- 1 during peripheral and -18 +/- 3 during intraportal glucose infusion. The net hindlimb glucose uptakes (in mg/min) were 5.0 +/- 1.2, 20.4 +/- 4.5, and 14.8 +/- 3.2 during baseline, peripheral, and intraportal glucose infusion periods, respectively (P < 0.01, peripheral vs. intraportal); the hindlimb glucose fractional extractions (in %) were 2.8 +/- 0.4, 4.7 +/- 0.8, and 3.9 +/- 0.5 during baseline, peripheral, and intraportal glucose infusions, respectively (P < 0. 05, peripheral vs. intraportal). The net whole body nonhepatic glucose uptakes (in mg . kg-1 . min-1) were 1.6 +/- 0.1, 7.9 +/- 1.3, and 5.4 +/- 1.1 during baseline, peripheral, and intraportal glucose infusion, respectively (P < 0.05, peripheral vs. intraportal). In the liver, net glucose uptake was 70% greater during intraportal than during peripheral glucose infusion (5.8 +/- 0.7 vs. 3.4 +/- 0.4 mg . kg-1 . min-1). In conclusion, despite comparable glucose loads and insulin levels, hindlimb and whole body net nonhepatic glucose uptake decreased significantly during portal venous glucose infusion, suggesting that a negative a-pv glucose gradient leads to an inhibitory signal in nonhepatic tissues, among which skeletal muscle appears to be the most important.The effect of a negative arterial-portal venous (a-pv) glucose gradient on skeletal muscle and whole body nonhepatic glucose uptake was studied in 12 42-h-fasted conscious dogs. Each study consisted of a 110-min equilibration period, a 30-min baseline period, and two 120-min hyperglycemic (2-fold basal) periods (either peripheral or intraportal glucose infusion). Somatostatin was infused along with insulin (3 × basal) and glucagon (basal). Catheters were inserted 17 days before studies in the external iliac artery and hepatic, portal and common iliac veins. Blood flow was measured in liver and hindlimb using Doppler flow probes. The arterial blood glucose, arterial plasma insulin, arterial plasma glucagon, and hindlimb glucose loads were similar during peripheral and intraportal glucose infusions. The a-pv glucose gradient (in mg/dl) was 5 ± 1 during peripheral and -18 ± 3 during intraportal glucose infusion. The net hindlimb glucose uptakes (in mg/min) were 5.0 ± 1.2, 20.4 ± 4.5, and 14.8 ± 3.2 during baseline, peripheral, and intraportal glucose infusion periods, respectively ( P < 0.01, peripheral vs. intraportal); the hindlimb glucose fractional extractions (in %) were 2.8 ± 0.4, 4.7 ± 0.8, and 3.9 ± 0.5 during baseline, peripheral, and intraportal glucose infusions, respectively ( P < 0.05, peripheral vs. intraportal). The net whole body nonhepatic glucose uptakes (in mg ⋅ kg-1 ⋅ min-1) were 1.6 ± 0.1, 7.9 ± 1.3, and 5.4 ± 1.1 during baseline, peripheral, and intraportal glucose infusion, respectively ( P < 0.05, peripheral vs. intraportal). In the liver, net glucose uptake was 70% greater during intraportal than during peripheral glucose infusion (5.8 ± 0.7 vs. 3.4 ± 0.4 mg ⋅ kg-1 ⋅ min-1). In conclusion, despite comparable glucose loads and insulin levels, hindlimb and whole body net nonhepatic glucose uptake decreased significantly during portal venous glucose infusion, suggesting that a negative a-pv glucose gradient leads to an inhibitory signal in nonhepatic tissues, among which skeletal muscle appears to be the most important.

Prior exercise increases net hepatic glucose uptake during a glucose load

The aim of these studies was to determine whether prior exercise enhances net hepatic glucose uptake (NHGU) during a glucose load. Sampling catheters (carotid artery, portal, hepatic, and iliac veins), infusion catheters (portal vein and vena cava), and Doppler flow probes (portal vein, hepatic and iliac arteries) were implanted. Exercise (150 min; n = 6) or rest (n = 6) was followed by a 30-min control period and a 100-min experimental period (3.5 mg. kg-1. min-1 of glucose in portal vein and as needed in vena cava to clamp arterial blood glucose at approximately 130 mg/dl). Somatostatin was infused, and insulin and glucagon were replaced intraportally at fourfold basal and basal rates, respectively. During experimental period the arterial-portal venous (a-pv) glucose gradient (mg/dl) was -18 +/- 1 in sedentary and -19 +/- 1 in exercised dogs. Arterial insulin and glucagon were similar in the two groups. Net hepatic glucose balance (mg. kg-1. min-1) shifted from 1.9 +/- 0.2 in control period to -1.8 +/- 0.2 (negative rates represent net uptake) during experimental period in sedentary dogs (Delta3.7 +/- 0.5); with prior exercise it shifted from 4.1 +/- 0.3 (P < 0.01 vs. sedentary) in control period to -3.2 +/- 0.4 (P < 0.05 vs. sedentary) during experimental period (Delta7.3 +/- 0.7, P < 0.01 vs. sedentary). Net hindlimb glucose uptake (mg/min) was 4 +/- 1 in sedentary animals in control period and 13 +/- 2 during experimental period; in exercised animals it was 7 +/- 1 in control period (P < 0. 01 vs. sedentary) and 32 +/- 4 (P < 0.01 vs. sedentary) during experimental period. As the total glucose infusion rate (mg. kg-1. min-1) was 7 +/- 1 in sedentary and 11 +/- 1 in exercised dogs, approximately 30% of the added glucose infusion due to prior exercise could be accounted for by the greater NHGU. In conclusion, when determinants of hepatic glucose uptake (insulin, glucagon, a-pv glucose gradient, glycemia) are controlled, prior exercise increases NHGU during a glucose load due to an effect that is intrinsic to the liver. Increased glucose disposal in the postexercise state is therefore due to an improved ability of both liver and muscle to take up glucose.The aim of these studies was to determine whether prior exercise enhances net hepatic glucose uptake (NHGU) during a glucose load. Sampling catheters (carotid artery, portal, hepatic, and iliac veins), infusion catheters (portal vein and vena cava), and Doppler flow probes (portal vein, hepatic and iliac arteries) were implanted. Exercise (150 min; n = 6) or rest ( n = 6) was followed by a 30-min control period and a 100-min experimental period (3.5 mg ⋅ kg-1 ⋅ min-1of glucose in portal vein and as needed in vena cava to clamp arterial blood glucose at ∼130 mg/dl). Somatostatin was infused, and insulin and glucagon were replaced intraportally at fourfold basal and basal rates, respectively. During experimental period the arterial-portal venous (a-pv) glucose gradient (mg/dl) was -18 ± 1 in sedentary and -19 ± 1 in exercised dogs. Arterial insulin and glucagon were similar in the two groups. Net hepatic glucose balance (mg ⋅ kg-1 ⋅ min-1) shifted from 1.9 ± 0.2 in control period to -1.8 ± 0.2 (negative rates represent net uptake) during experimental period in sedentary dogs (Δ3.7 ± 0.5); with prior exercise it shifted from 4.1 ± 0.3 ( P < 0.01 vs. sedentary) in control period to -3.2 ± 0.4 ( P < 0.05 vs. sedentary) during experimental period (Δ7.3 ± 0.7, P < 0.01 vs. sedentary). Net hindlimb glucose uptake (mg/min) was 4 ± 1 in sedentary animals in control period and 13 ± 2 during experimental period; in exercised animals it was 7 ± 1 in control period ( P < 0.01 vs. sedentary) and 32 ± 4 ( P < 0.01 vs. sedentary) during experimental period. As the total glucose infusion rate (mg ⋅ kg-1 ⋅ min-1) was 7 ± 1 in sedentary and 11 ± 1 in exercised dogs, ∼30% of the added glucose infusion due to prior exercise could be accounted for by the greater NHGU. In conclusion, when determinants of hepatic glucose uptake (insulin, glucagon, a-pv glucose gradient, glycemia) are controlled, prior exercise increases NHGU during a glucose load due to an effect that is intrinsic to the liver. Increased glucose disposal in the postexercise state is therefore due to an improved ability of both liver and muscle to take up glucose.

Effect of fast duration on disposition of an intraduodenal glucose load in the conscious dog

UNLABELLED The effects of prior fast duration (18 h, n = 8; 42 h, n = 8) on the glycemic and tissue-specific responses to an intraduodenal glucose load were studied in chronically catheterized conscious dogs. [3-3H]glucose was infused throughout the study. After basal measurements, glucose spiked with [U-14C]glucose was infused for 150 min intraduodenally. Arterial insulin and glucagon were similar in the two groups. Arterial glucose (mg/dl) rose approximately 70% more during glucose infusion after 42 h than after an 18-h fast. The net hepatic glucose balance (mg. kg-1. min-1) was similar in the two groups (basal: 1.8 +/- 0.2 and 2.0 +/- 0.3; glucose infusion: -2.2 +/- 0.5 and -2.2 +/- 0.7). The intrahepatic fate of glucose was 79% glycogen, 13% oxidized, and 8% lactate release after a 42-h fast; it was 23% glycogen, 21% oxidized, and 56% lactate release after an 18-h fast. Net hindlimb glucose uptake was similar between groups. The appearance of intraduodenal glucose during glucose infusion (mg/kg) was 900 +/- 50 and 1,120 +/- 40 after 18- and 42-h fasts (P < 0.01). CONCLUSION glucose administration after prolonged fasting induces higher circulating glucose than a shorter fast (increased appearance of intraduodenal glucose); liver and hindlimb glucose uptakes and the hormonal response, however, are unchanged; finally, an intrahepatic redistribution of carbons favors glycogen deposition.The effects of prior fast duration (18 h, n = 8; 42 h, n = 8) on the glycemic and tissue-specific responses to an intraduodenal glucose load were studied in chronically catheterized conscious dogs. [3-3H]glucose was infused throughout the study. After basal measurements, glucose spiked with [U-14C]glucose was infused for 150 min intraduodenally. Arterial insulin and glucagon were similar in the two groups. Arterial glucose (mg/dl) rose ∼70% more during glucose infusion after 42 h than after an 18-h fast. The net hepatic glucose balance (mg ⋅ kg-1 ⋅ min-1) was similar in the two groups (basal: 1.8 ± 0.2 and 2.0 ± 0.3; glucose infusion: -2.2 ± 0.5 and -2.2 ± 0.7). The intrahepatic fate of glucose was 79% glycogen, 13% oxidized, and 8% lactate release after a 42-h fast; it was 23% glycogen, 21% oxidized, and 56% lactate release after an 18-h fast. Net hindlimb glucose uptake was similar between groups. The appearance of intraduodenal glucose during glucose infusion (mg/kg) was 900 ± 50 and 1,120 ± 40 after 18- and 42-h fasts ( P < 0.01). CONCLUSION glucose administration after prolonged fasting induces higher circulating glucose than a shorter fast (increased appearance of intraduodenal glucose); liver and hindlimb glucose uptakes and the hormonal response, however, are unchanged; finally, an intrahepatic redistribution of carbons favors glycogen deposition.

The effects of HDV-insulin on carbohydrate metabolism in Type 1 diabetic patients

The aim of this study was to compare the metabolic effects of a single equimolar subcutaneous injection of hepatic directed vesicle-insulin (HDV-insulin) and regular insulin on glucose levels and intermediary metabolism during a 75-g oral glucose tolerance test (OGTT). Nine Type 1 diabetic patients underwent two experiments separated by 4 weeks. Each experimental protocol consisted of an identical evening meal followed by overnight euglycemic control achieved by a continuous low-dose insulin infusion. The next morning a subcutaneous injection (0.1 U/kg) of HDV-insulin or regular insulin was administered 30 min before a 75-g OGTT. The overnight basal insulin infusion was maintained unaltered throughout the 150-min OGTT. Plasma glucose, glucoregulatory hormones (insulin, glucagon, cortisol), and intermediary metabolites (lactate, alanine, glycerol, NEFA, beta-hydroxybutyrate) were measured to assess the metabolic effects of the two insulin preparations. Compared to regular insulin, an equivalent subcutaneous dose of HDV-insulin significantly lowered glucose levels during OGTT (mean reduction 2.2+/-0.4 mmol/l; P<.005). Plasma levels of insulin and glucagon were equivalent during both series of experiments. Blood lactate, glycerol and plasma NEFA levels were not different during OGTT indicating similar peripheral action of the insulins. beta-Hydroxybutyrate levels were significantly reduced (P<.05) following HDV-insulin supporting a preferential hepatic action of the preparation. We conclude that HDV-insulin can significantly lower plasma glucose excursions compared to an equivalent dose of regular insulin during an OGTT in Type 1 diabetic patients. The metabolic profile of equivalent peripheral insulin, glucagon and glycerol levels but reduced beta-hydroxybutyrate values support a hepatospecific effect of HDV-insulin.

Role of a negative arterial-portal venous glucose gradient in the postexercise state

Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs. EXPERIMENTAL PROTOCOL exercise (-180 to -30 min), transition (-30 to -20 min), basal period (-20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 ± 1 in Pe and -10 ± 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg ⋅ kg-1 ⋅ min-1, negative = uptake) was 4.2 ± 0.3 (basal period) and -1.2 ± 0.3 (glucose infusion); in Po it was 4.1 ± 0.5 and -3.2 ± 0.4, respectively ( P < 0.005 vs. Pe). Total glucose infusion (mg ⋅ kg-1 ⋅ min-1) was 11 ± 1 in Po and 8 ± 1 in Pe ( P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar. CONCLUSIONS the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.UNLABELLED Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs. EXPERIMENTAL PROTOCOL exercise (-180 to -30 min), transition (-30 to -20 min), basal period (-20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 +/- 1 in Pe and -10 +/- 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg x kg(-1) x min(-1), negative = uptake) was 4.2 +/- 0.3 (basal period) and -1.2 +/- 0.3 (glucose infusion); in Po it was 4.1 +/- 0.5 and -3.2 +/- 0.4, respectively (P < 0.005 vs. Pe). Total glucose infusion (mg x kg(-1) x min(-1)) was 11 +/- 1 in Po and 8 +/- 1 in Pe (P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar. CONCLUSIONS the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.

Leptin responses to antecedent exercise and hypoglycemia in healthy and type 1 diabetes mellitus men and women

These studies examined the effects of hypoglycemia or exercise on leptin levels in 47 (23 women, 24 men) healthy (age 26+/-2 years, body mass index 23+/-0.5 kg.m(-2)) and type 1 diabetes mellitus (T1DM) subjects (age 29+/-2 years, body mass index 27+/-2 kg.m(-2)). In Study 1, healthy and T1DM subjects were exposed to morning and afternoon 120-min hyperinsulinemic hypoglycemic ( approximately 50 mg/dl) or euglycemic ( approximately 90 mg/dl) clamps. In Study 2, healthy subjects were studied during morning and afternoon 90-min exercise bouts at 50% VO(2max). In Study 1, basal levels of leptin were significantly greater in T1DM vs. the healthy subjects (13.8+/-3 vs. 5.4+/-1 ng/dl; P<.05). However, during the last 30 min of morning hypoglycemia, plasma leptin levels significantly decreased from 5.4+/-1 to 4.0+/-1 ng/dl (P<.05) and remained low during afternoon hypoglycemia (4.3+/-1 ng/dl) in healthy but not T1DM subjects. In Study 2, plasma leptin levels did not significantly change during exercise the bout in healthy men, but significantly decreased 3 h after morning exercise, and continued to decrease during afternoon exercise in healthy women (P<.0001). Thus, plasma leptin levels decrease in response to hypoglycemia in healthy but not T1DM subjects. However, T1DM patients do have increased basal leptin levels compared to healthy man. Lastly, there is a marked sexual dimorphism in plasma leptin responses to repeated episodes of exercise.