Comparison of Peripheral and Portal Venous Insulin Administration on Postprandial Metabolic Responses in Alloxan-Diabetic Dogs: Effects of Identical Preprogrammed Complex Insulin Infusion Waveforms (original) (raw)
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Effect of infusion of insulin into portal vein on hepatic extraction of insulin in anesthetized dogs
American Journal of Physiology-Legacy Content, 1975
Hepatic extraction of insulin was examined in anesthetized dogs before and after constant infusion of insulin (20 and 50 mU/min) with use of samples from the portal vein, mesenteric vein, left common hepatic vein, and the femoral artery. In 19 dogs, measurement of portal vein insulin concentration indicated an overall recovery of 110% of the insulin infused. The range varied from 9 to 303%, indicating the potential for serious error in sampling the portal vein. Equilibrium arterial insulin concentrations were achieved 20 min after starting the infusion. Prior to insulin infusion, hepatic extraction of insulin averaged 4.56 plus or minus 0.43 mUmin, representing an extraction coefficient of 0.42 of the insulin presented to the liver. The proportion of insulin extracted by the liver did not change significantly during insulin infusion despite a 10-fold increase in portal vein insulin concentrations. During the infusion of insulin, a significant proportion of the extraheptic clearance ...
Diabetes, 1996
We investigated the mechanisms by which peripheral or portal insulin can independently alter liver glucose production. Isotopic ([3-3 H]glucose) and arteriovenous difference methods were used in conscious overnight-fasted dogs. A pancreatic clamp (somatostatin plus basal insulin and basal glucagon infusions) was used to control the endocrine pancreas. After a 40-min basal period, a 180-min experimental period followed in which selective increases in peripheral (PERI group, n = 5) or portal-vein (PORT group, n = 5) insulin were induced. In control dogs (CONT group, n = 10), insulin was not increased. Glucagon levels were fixed in all studies, and basal euglycemia was maintained by peripheral glucose infusion in the two experimental groups. In the PERI group, arterial insulin rose from 36 ± 12 to 120 ± 12 pmol/1, while portal insulin was unaltered. In the PORT group, portal insulin rose from 108 ± 42 to 192 ± 42 pmol/1, while arterial insulin was unaltered. Neither arterial nor portal insulin changed from basal in the CONT group. With a selective rise in peripheral insulin, the net hepatic glucose output (NHGO; basal, 11.8 ± 0.7 umol • kg" 1 • min" 1 ') did not change initially (11.8 ± 2.1 umol • kg" 1 • min" 1 , 30 min after the insulin increase), but eventually fell (P < 0.05) to 6.1 ± 0.9 umol • kg" 1 • min" 1 (last 30 min). With a selective rise in portal insulin, NHGO dropped quickly (P < 0.05) from 10.0 ± 0.9 to 5.6 ± 0.6 umol • kg" 1 • min" 1 (30 min after the insulin increase) and eventually reached 3.1 ± 1.1 umol • kg" 1 • min" 1 (last 30 min). When insulin levels were not increased (CONT group), NHGO dropped progressively from 10.1 ± 0.6 to 8.3 ± 0.6 umol • kg 1-min 1 (last 30 min). Conclusions drawn from the net hepatic glucose balance data were confirmed by the tracer data. Net hepatic gluconeogenic substrate uptake (three carbon precursors) fell 2.0 umol • kg" 1 • min" 1 in the PERI group, but rose 1.2 umol • kg" 1 • min" 1 in the PORT group and 1.2 umol • kg" 1 • min" 1 in the CONT group. A selective 84 pmol/1 rise in arterial insulin was thus associated with a fall in NHGO of ~50%, which took 1 h to manifest. Conversely, a selective 84 pmol/1 rise in portal insulin was associated with a 50% fall in
Diabetes, 2005
The results of the present study, using the conscious beagle dog, demonstrate that inhaled insulin (INH; Exubera) provides better glycemic control during an intraportal glucose load than identical insulin levels induced by insulin (Humulin) infusion into the inferior vena cava (IVC). In the INH group (n = 13), portal glucose infusion caused arterial plasma glucose to rise transiently (152 ± 9 mg/dl), before it returned to baseline (65 min) for the next 2 h. Net hepatic glucose uptake was minimal, whereas nonhepatic uptake rose to 12.5 ± 0.5 mg · kg−1 · min−1 (65 min). In the IVC group (n = 9), arterial glucose rose rapidly (172 ± 6 mg/dl) and transiently fell to 135 ± 13 mg/dl (65 min) before returning to 165 ± 15 mg/dl (125 min). Plasma glucose excursions and hepatic glucose uptake were much greater in the IVC group, whereas nonhepatic uptake was markedly less (8.6 ± 0.9 mg · kg−1 · min−1; 65 min). Insulin kinetics and areas under the curve were identical in both groups. These data...
The American journal of physiology, 1997
We have previously shown that a selective increase of 84 pmol/l in either arterial or portal vein insulin (independent of a change in insulin in the other vessel) can suppress tracer-determined glucose production (TDGP) and net hepatic glucose output (NHGO) by approximately 50%. In the present study we investigated the interaction between equal increments in arterial and portal vein insulin in the suppression of TDGP and NHGO. Isotopic ([3-3H]glucose) and arteriovenous difference methods were used in conscious overnight fasted dogs. A pancreatic clamp was used to control the endocrine pancreas. A 40-min basal period was followed by a 180-min test period, during which arterial and portal vein insulin levels were simulataneously and equally increased 102 pmol/l. Hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. TDGP was suppressed approximately 60% by the last 30 min of the experimental period. In contrast, NHGO was su...
Insulin is required for the liver to respond to intraportal glucose delivery in the conscious dog
Diabetes, 1992
To determine whether insulin is essential for the augmented hepatic glucose uptake observed in the presence of intraportal glucose delivery, SRIF was used to induce acute insulin deficiency in 5 conscious dogs, and glucose was infused into the portal vein or a peripheral vein in two sequential, randomized periods. Insulin and C-peptide levels were below the limits of detection after SRIF infusion, and the load of glucose presented to the liver was approximately doubled and equivalent during the portal and peripheral periods. Net hepatic glucose output was 2.9 ± 0.9 and 2.1 ± 1. 1 jimol • kg" 1 • min~1 during portal and peripheral glucose delivery, respectively. In an additional set of protocols, pancreatectomized dogs were used to investigate the effects of prolonged insulin deficiency (n = 5) and acute insulin replacement (n = 4) on the hepatic response to intraportal glucose delivery. In the prolonged insulin deficiency protocol, SRIF was used to lower glucagon and thereby reduce circulating glucose levels, and glucose was infused into the portal or peripheral circulations in two sequential, randomized periods. As with acute insulin deficiency, net hepatic glucose output was still evident and similar (3.6 ± 1. 1 and 4.2 ± 1. 3 junol • k g 1 • min" 1) during portal and peripheral glucose delivery, respectively. When the pancreatectomized dogs were restudied using a similar protocol, but one in which insulin was replaced (4X-basal), and the glucose load to the liver was matched to that which occurred in the prolonged insulin deficiency protocol, net hepatic glucose uptake was 23.6 ± 6.1 jimol • kg" 1 • mirr 1 during portal glucose delivery but only 10.3 ± 3.5
Journal of Pharmacology and Experimental Therapeutics, 2006
This study compared the effects of endogenous (portal) insulin secretion versus peripheral insulin administration with subcutaneous or inhaled human insulin [INH; Exubera, insulin human (rDNA origin) inhalation powder] on glucose disposal in fasted dogs. In the control group, glucose was infused into the portal vein (Endo; n ϭ 6). In two other groups, glucose was infused portally, whereas insulin was administered peripherally by inhalation (n ϭ 13) or s.c. injection (n ϭ 6) with somatostatin and basal glucagon. In the Endo group, over the first 3 h, the arterial insulin concentration was twice that of the peripheral groups, whereas hepatic sinusoidal insulin levels were half as much.
Inhalation of Insulin in Dogs: Assessment of Insulin Levels and Comparison to Subcutaneous Injection
Diabetes, 2004
Pulmonary insulin delivery is being developed as a more acceptable alternative to conventional subcutaneous administration. In 15 healthy Beagle dogs (average weight 9.3 kg), we compared insulin distribution in arterial, deep venous, and hepatic portal circulation. Dogs received 0.36 units/kg s.c. regular human insulin (n ؍ 6) or 1 mg (2.8 units/kg) or 2 mg (5.6 units/kg) dry-powder human inhaled insulin (n ؍ 3 and 6, respectively). Postinhalation of inhaled insulin (1 or 2 mg), arterial insulin levels quickly rose to a maximum of 55 ؎ 6 or 92 ؎ 9 U/ml, respectively, declining to typical fasting levels by 3 h. Portal levels were lower than arterial levels at both doses, while deep venous levels were intermediate to arterial and portal levels. In contrast, subcutaneous insulin was associated with a delayed and lower peak arterial concentration (55 ؎ 8 U/ml at 64 min), requiring 6 h to return to baseline. Peak portal levels for subcutaneous insulin were comparable to those for 1 mg and significantly less than those for 2 mg inhaled insulin, although portal area under the curve (AUC) was comparable for the subcutaneous and 2-mg groups. The highest insulin levels with subcutaneous administration were seen in the deep venous circulation. Interestingly, the amount of glucose required for maintaining euglycemia was highest with 2 mg inhaled insulin. We conclude that plasma insulin AUC for the arterial insulin level (muscle) and hepatic sinusoidal insulin level (liver) is comparable for 2 mg inhaled insulin and 0.36 units/kg subcutaneous insulin. In addition, arterial peak concentration following insulin inhalation is two times greater than subcutaneous injection; however, the insulin is present in the circulation for half the time. Diabetes 53:877-881, 2004 RESEARCH DESIGN AND METHODS Fifteen healthy (seven male, eight female; overnight fasted) Beagle dogs (2-3 years old) were studied. The dogs' weights ranged from 8 to 10 kg and they were randomized to three exposure groups. Six dogs were assigned to subcutaneous administration of 0.36 units/kg regular human insulin, three dogs to inhalation of 1 mg dry-powder insulin, and six dogs to inhalation of 2 mg dry-powder insulin. All animals were killed at study end. The protocol was
The American journal of physiology, 1999
In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol. kg-1. min-1 of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 +/- 20 (basal) to 165 +/- 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 +/- 8 (basal) to 289 +/- 19 pmol/l (last 30 min). However, the overall arterial (50 +/- 8 pmol/l) and ...
Acta Endocrinologica, 1983
The metabolism of exogenously infused porcine insulin and glucagon was assessed concurrently in normal fasted dogs under anaesthesia. Hepatic and renal extraction of glucagon were 25.6 \ m=+-\ 2.3 and 43.7 \ m=+-\ 3.9%, respectively, and its metabolic clearance 16.5 \ m=+-\ 0.8 ml/ kg/min. Hepatic and renal extraction accounted for 28.5 \ m=+-\ 4.2 and 28.7 \ m=+-\ 3.7% of total glucagon clearance, respectively. Insulin MCR was 18.3 \m=+-\1.5 ml/kg/min and its hepatic and renal extraction were 49.6 \ m=+-\3.4 and 41.7 \ m=+-\4.4% accounting for 51.9 \ m=+-\4.4 and 27.3 \ m=+-\3.9% of total insulin clearance, respectively. Neither total glucagon metabolic clearance nor its hepatic or renal components saturated even in the face of circulating glucagon levels extending into the pharmacologic range up to 14 ng/ml. In contrast however, with increasing arterial
Diabetes, 1998
The contribution of portal insulin delivery to the disappearance of glucose administered intravenously was assessed in the present study. Paired insulin-modified intravenous glucose tolerance tests (IVGTTs) were performed in dogs in which insulin was administered into the portal vein or into a peripheral vein. Peripheral insulin levels were matched in the paired IVGTTs by adjusting the portal insulin dose in proportion to firstpass hepatic insulin extraction. Two sets of IVGTTs were performed. In the first set, hepatic insulin extraction was assumed to be 50% (insulin doses of 0.03 U/kg portal and 0.015 U/kg peripheral; n = 6); in the second set, the assumed extraction rate was reduced to 33% (0.0225 U/kg portal and 0.015 U/kg peripheral; n = 8). In the second set of experiments, a control "zero" dose (no insulin injection) was also performed. For these latter three IVGTTs, the exogenous glucose bolus was labeled with 3-[ 3 H]glucose (25 µCi) to separately assess i n s u l i n 's effects on the rate of glucose disappearance (R d ) and endogenous glucose production (EGP). For the paired IVGTT based on 33% extraction, the area under the insulin curves after the portal insulin injection was within 2% of that observed with peripheral insulin injection (1,820 ± 711 vs. 1,791 ± 661 µU/ml min; P = 0.79). For these conditions, neither the glucose profiles nor the minimal model estimate of insulin sensitivity (S I ) was significantly influenced by the higher portal insulin delivery (S I : 3.69 ± 0.56 vs. 3.35 ± 0.60 1 0 -4 m i n -1 per µU/ml; portal vs. peripheral; P > 0.05). Analysis of the 3-[ 3 H]glucose tracer dynamics failed to reveal any differences in the portal versus peripheral insulin effect on glucose disappearance or production. We conclude that portal insulin delivery per se does not significantly affect insulin's ability to normalize plasma glucose during acute glucose challenges. Diabetes 47:714-720, 1998 I nsulin is secreted directly into the portal vein, from which a large fraction (~50%) is extracted on first pass (1). The large extraction results in higher insulin concentrations in the portal vein than those observed in the systemic (peripheral) circulation. The physiological significance of the high portal insulin concentration and high hepatic insulin extraction has remained elusive for many years (2-5). It was originally thought that portal insulin delivery was responsible for rapid suppression of hepatic glucose output (HGO); however, several studies have now shown that during euglycemic-hyperinsulinemic clamps, the suppression of endogenous glucose production (EGP; the sum of HGO and glucose production by the kidneys [6]) is primarily determined by peripheral insulin's effect to suppress free fatty acid (FFA) levels (1,, and that higher portal insulin concentrations per se do not further suppress EGP (9,10). It has also been shown that during euglycemic glucose clamps, glucose uptake by the liver is not sensitive to insulin (11).