Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism (original) (raw)
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Effects of insulin on glucagon-stimulated glucose production in the conscious dog
Metabolism, 1990
The relative importance of insulin and gkrcagon 8s primary regUL8tOrS of gkrcose metabolism in vivo was assessed in 18-hour fasted conscious dogs. Glucose turnover wirs determined using [3-3H]glucose and gluconeogenesis was 8sSeSSed using tracer (['4C]81enine) end A-V difference techniques during 8 4D-minute control period and a 3-hour period during which various hormonal perturbations were brought about. During the infusion of somatostatin and basal intraportal replacement amounts of insulin and gkJC8gOn for the entire study, the plasma glucose concentration (109 + 5 mg/dL), glucose production (3.24 f 0.30 mg/kg/min), and glucose utilization (3.17 + 0.32 mg/kg/min) remained unchanged. When the glucagon infusion rate WBS increased fourfold at the end of the control period, the plasm8 glucose level increased from 107 f 4 to 225 + 23 mg/dL by 1 hour and remained elevated. Glucose production increased from 3.14 f 0.29 to 7.66 f 0.51 mg/kg/min by 15 minutes and decreased to 4.23 f 0.36 mg/kg/min by 3 hours. Glucose utilization rose from 8 basal value of 3.20 f 0.26 to 5.46 ir 0.27 mg/kg/min by 3 hours. When 8 fourfold increase in the insulin infusion rate WBS brought about 8t the end of the control period, glucose production decreased from 2.83 f 0.20 to 1 .I 6 + 0.57 mg/kg/min by 1 hour, after which it increased slightly (1.62 f 0.81 mg/kg/min). Glucose utilization inCre8sed from 2.92 + 0.30 to 8.12 + 1.12 mg/kg/min by 3 hours. Euglycemia was m8int8ined by glucose infusion. Concomitant fourfold increases in the insulin and glucagon infusion rates caused glucose production to fall from 3.03 f 0.23 to 0.76 + 0.39 mg/kg/min by 1 hour and to remain similarly suppressed for 3 hours. Glucose utilizetion rose from 2.95 f 0.20 to 8.44 + 0.87 mg/kg/min and suglycemia w8s again maintained by glucose infusion. Gluconeogenic conversion increased (67 * 12%) in the studies in which insulin and glucagon were kept at basal values. but the level, fractional extraction, end hepatic uptake of alanine did not change significantly. The selective increase in glucagon Caused gluconeogenic conversion (169% ? 42%). hepatic fractional alanine extraction (0.32 + 0.05 to 0.66 + 0.10). and hepatic alanine uptake (2.96 + 0.45 to 4.54 + 0.43 fimollkglmin) to increase, while the alanine level decreased (387 2 40 to 272 ? 46 pmol/L). The selective increase in insulin was associated with 8n increase in gluconeogenic conversion (46% + 25%) similar to that apparent in the control group, no change in the fractional extraction or uptake of alanine by the liver, and a small fall in alanine level (337 + 33 to 249 * 55 pmol/L). Concomitant increases in both insulin and glucagon left gluconeogenic conversion unchanged (26% + 21%). but increased the fractional extraction of alanine by the liver (0.39 f 0.05 to 0.64 + 0.03). Hepatic alanine uptake did not change, but a decrease in the alanine level (353 + 46 to 174 + 16 pmol/L) was observed. These studies indicate that in the overnight fasted conscious dog, insulin is a potent inhibitor of the stimulatory effects of glucagon on hepatic glycogenolysis and gluconeogenesis. However, insulin is unable to limit alanine uptake by suppression of hepatic fractional extraction, instead it prevents increased alanine uptake by limiting the net release of alanine from extrahepatic tissues. @ 1990 by W. B. Saunders Company. MATERIALS AND METHODS Animals and Surgical Procedures Experiments were performed on 24 chronically catheterized overnight fasted conscious mongrel dogs of either sex, which were surgically prepared 17 days before study and maintained as previously described." The arterial, portal, and hepatic vein catheters
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 ...
Journal of Clinical Investigation, 1982
glucose (25 g) fed to seven healthy, conscious dogs resulted in an increase in peripheral plasma glucose from 109±3 to 178±10 mg/dl. Concurrently serum insulin increased in the portal vein to levels approximately threefold greater than those in the periphery. Hepatic insulin delivery rose from 10.8±0.7 to 59.0±19.9 mU/min at 60 min, coincident with an increased hepatic insulin extraction from 3.3 to 41.4 mU/min (corresponding to an increase in hepatic extraction from 31±4 to 59±7%), both returning to basal at 3 h. In each animal there was a positive correlation between hepatic insulin delivery and extraction (r = 0.80, P < 0.001 for the seven experiments combined). These changes in hepatic insulin delivery and extraction after glucose feeding were correlated with changes in hepatic glucose metabolism associated with insulin action. As hepatic insulin extraction increased, hepatic glucose output declined, both parameters returning to basal levels by 3 h, indicating a negative correlation between hepatic insulin extraction and hepatic glucose output (r = 0.63, P < 0.001; n = 7). The factors that mediate this marked and rapidly occurring increase in hepatic insulin extraction after oral glucose are unknown, and may include hepatic insulin delivery, glucose levels in the blood supplying the liver, factors related to increased hepatic blood flow, and gut factors released by oral glucose intake. The association of changes in hepatic insulin extraction in vivo with an insulin effect on the liver as measured This study was presented in part at the National Meeting of the American Diabetes Association,
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
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
Diabetologia, 1987
In seven insulin-deficient (< 3 mU/1) pancreatectomised dogs, the direct and glucagon-related indirect effects of intraportal insulin infusion (350 ~U/kg-min; 12 + 1 mU/1) on glucose production were determined. Insulin was infused for 300 min during which time the plasma glucagon concentration was allowed to fall (314+94 to 180+63 ng/l) for 150 min before being replaced by an infusion intraportally at 2.6ng/kg-rnin (323+61ng/1) for the remaining 150min. Glucose production and gluconeogenesis were determined using arterio-venous difference and tracer techniques. Insulin infusion shut off net hepatic glucose output and caused the plasma glucose, blood glycerol and plasma non-esterified fatty acid levels to fall. It caused the hepatic fractional extraction of alanine (0.41 +0.10 to 0.21 +0.06) and lactate (0.32__+0.09 to 0.04___0.03) to fall which increased their concentrations. When glucagon was replaced, all of these changes were fully or partly reversed with the exception of the changes in glycerol and nonesterified fatty acids. Indeed, 70% of the fall in hepatic glucose production and virtually 100% of the changes in lactate and alanine metabolism produced by basal insulin infusion were mediated by a fall in glucagon. However, the fall in hepatic uptake of glycerol was unaffected by changes in glucagon and thus gluconeogenesis from this substrate was inhibited by insulin per se probably as a result of reduced lipolysis. The latter effect of insulin may explain the incomplete restoration of hepatic glucose production when hyperglucagonaemia was re-established during insulin infusion.
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 ...
Rates of glucagon activation and deactivation of hepatic glucose production in conscious dogs
Metabolism, 1998
To determine the time course of glucagon activation and deactivation of hepatic glucose production (HGP), studies were conducted in 18-hour fasted, conscious dogs. Somatostatin was infused with insulin replaced intraportaliy at 1.8 pmol • kg-1 • min-1 and glucagon replaced peripherally at 1.0 ng • kg-1 • min-L After a 2-hour control period, glucagon infusion was either (1) increased fourfold for 4 hours (GGN 4X), (2) increased fourfold for 30 minutes and returned to a basal rate for 3.5 hours (GGN 4X/1X), or (3) fixed at the basal rate for 4 hours (GGN 1X). In the latter two protocols, glucose was infused peripherally to match glucose concentrations observed during GGN 4X. Glucose turnover was determined by deconvolution with the impulse response of the glucose system described by a two-compartment, time-varying model identified from high-performance liquid chromatography (HPLC)-purified [3-3H]glucose tracer data. In GGN 4X, HGP was stimulated from 15.2-0.9 ~mol • kg-1. min-1 to 52.7-6.5 i~mol • kg-1 • min-1 after just 15 minutes, but it decreased over the subsequent 3 hours to a rate 25% above basal. In GGN 4X/1X, the increase in HGP during the first 30 minutes equaled that observed in GGN 4X, but when glucagon infusion was returned to basal, HGP decreased in 15 minutes to rates equal to those observed in GGN 1X. The times for half-maximal activation and deactivation of glucagon action were equal (4.5-+ 1.0 and 4.0 _+ 1.1 minutes, respectively). The very rapid and sensitive hepatic response to glucagon makes pancreatic glucagon release a key component of minute-to-minute glucose homeostasis.
Journal of Pharmacology and Experimental Therapeutics, 2009
Diabetic patients treated with inhaled insulin exhibit reduced fasting plasma glucose levels. In dogs, insulin action in muscle is enhanced for as long as 3 h after insulin inhalation. This study was designed to determine whether this effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients. Human insulin was administered via inhalation (Exubera; n = 9) or infusion (Humulin R; n = 9) in dogs using an infusion algorithm that yielded matched plasma insulin kinetics between the two groups. Somatostatin was infused to prevent insulin secretion, and glucagon was infused to replace basal plasma levels of the hormone. Glucose was infused into the portal vein at 4 mg/kg/min and into a peripheral vein to maintain the arterial plasma glucose level at 160 mg/dl. Arterial and hepatic sinusoidal insulin and glucose levels were virtually identical in the two groups. Notwithstanding, glucose utilization was greater when insulin was administered by inhalation. At its peak, the peripheral glucose infusion rate was 4 mg/kg/min greater in the inhalation group, and a 50% difference between groups persisted over 8 h. Inhalation of insulin caused a greater increase in nonhepatic glucose uptake in the first 3 h after inhalation; thereafter, net hepatic glucose uptake was greater. Inhalation of insulin was associated with greater than expected (based on insulin levels) glucose disposal. This may explain the reduced fasting glucose concentrations observed in humans after administration of certain inhaled insulin formulations compared with subcutaneous insulin.