Insulin's direct effects on the liver dominate the control of hepatic glucose production (original) (raw)
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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, 2013
The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3β gene transcription. Thus, central and peripheral ...
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 ...
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...
Diabetes, 2001
Based on our earlier work, a 2.5-fold increase in insulin secretion should completely inhibit hepatic glucose production through the hormone's direct effect on hepatic glycogen metabolism. The aim of the present study was to test the accuracy of this prediction and to confirm that gluconeogenic flux, as measured by three independent techniques, was unaffected by the increase in insulin. A 40-min basal period was followed by a 180-min experimental period in which an increase in insulin was induced, with euglycemia maintained by peripheral glucose infusion. Arterial and hepatic sinusoidal insulin levels increased from 10 ؎ 2 to 19 ؎ 3 and 20 ؎ 4 to 45 ؎ 5 U/ml, respectively. Net hepatic glucose output decreased rapidly from 1.90 ؎ 0.13 to 0.23 ؎ 0.16 mg ⅐ kg ؊1 ⅐ min ؊1 . Three methods of measuring gluconeogenesis and glycogenolysis were used: 1) the hepatic arteriovenous difference technique (n ؍ 8), 2) the [ 14 C] phosphoenolpyruvate technique (n ؍ 4), and 3) the 2 H 2 O technique (n ؍ 4). The net hepatic glycogenolytic rate decreased from 1.72 ؎ 0.20 to ؊0.28 ؎ 0.15 mg ⅐ kg ؊1 ⅐ min ؊1 (P < 0.05), whereas none of the above methods showed a significant change in hepatic gluconeogenic flux (rate of conversion of phosphoenolpyruvate to glucose-6-phosphate). These results indicate that liver glycogenolysis is acutely sensitive to small changes in plasma insulin, whereas gluconeogenic flux is not. Diabetes 50:1872-1882, 2001 RESEARCH DESIGN AND METHODS Animal care and surgical procedures. Experiments were conducted on eight conscious mongrel dogs (23-29 kg) of either sex that had been fed a once-daily meat and chow diet (34% protein, 46% carbohydrate, 14.5% fat, and From the
Direct and Indirect Effects of Insulin on Glucose Uptake and Storage by the Liver
Diabetes, 2002
Studies were conducted in conscious 42-h–fasted dogs to determine how much of insulin’s effect on hepatic glucose uptake arises from its direct hepatic action versus its indirect (extrahepatic) action. Each experiment consisted of equilibration, basal, and experimental periods. During the latter, somatostatin, basal intraportal glucagon, portal glucose (21.3 μmol · kg−1 · min−1), and peripheral glucose (to double the hepatic glucose load) were infused. During the experimental period, insulin was infused intraportally at a basal rate (BI, n = 6), at a fourfold basal rate (PoI, n = 6), or via a peripheral vein to create a selective increase in the arterial insulin level similar to that in PoI (PeI, n = 6). Arterial and hepatic sinusoidal insulin levels (in picomoles per liter) during the experimental period were 31 ± 5 and 113 ± 15 in BI, 97 ± 11 and 394 ± 66 in PoI, and 111 ± 13 and 96 ± 9 in PeI, respectively. Net hepatic glucose uptake (NHGU) averaged 7.0 ± 1.1 μmol · kg−1 · min−1,...
Diabetes, 2021
Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein-to-arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels fivefold in healthy dogs. In one group (n = 7), the physiologic response was allowed to fully occur, while in another (n = 7), insulin’s indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothala...
Diabetes, 1997
We investigated the mechanism by which a selective increase in arterial insulin can suppress hepatic glucose production in vivo. Isotopic (3-3 H-glucose) and arteriovenous difference methods were used in overnight-fasted, conscious dogs. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon infusions) was used to control the endocrine pancreas. Equilibration (100 min) and basal (40 min) periods were followed by a 180-min test period. In control dogs (/i = 5), basal insulin delivery was continued throughout the study. In the other two groups, peripheral insulin was selectively increased at the beginning of the test period by stopping the portal insulin infusion and infusing insulin peripherally at twice the basal portal rate. One group (INS + FAT; n = 6) received an infusion of 20% intralipid + heparin (0.5 U • kg" 1 • min" 1) to clamp the nonesterified fatty acid (NEFA) levels during hyperinsulinemia; the other group (INS; n = 7) received only saline during the experimental period. In the INS group, a selective increase in peripheral insulin of 84 pmol/L was achieved (36 ± 6 to 120 ± 24 pmol/1, last 30 min) while portal insulin was unaltered (84 ± 18 pmol/1). In the INS + FAT group, a similar increase in peripheral insulin was achieved (36 ± 6 to 114 ± 6 pmol/1, last 30 min); again, portal insulin was unaltered (96 ± 12 pmol/1). In the control group, basal insulin did not change. Glucagon and glucose remained near basal values in all protocols. In the INS group, NEFA levels dropped from 700 ± 90 (basal) to 230 ± 65 umol/1 (last 30 min; P > 0.05), but in the INS + FAT group changed minimally (723 ± 115 [basal] to 782 ± 125 umol/1 [last 30 min]). In the INS group, net hepatic glucose output dropped by 6.7 umol • kg" 1 • min" 1 (P < 0.05), whereas in the INS + FAT group it dropped by 3.9 umol • kg' 1 • min" 1 (P < 0.05). When insulin levels were not increased (i.e., in the control group), net hepatic glucose output dropped 1.7 umol • kg • min" 1 (P < 0.05). In all groups, the net hepatic glucose output data were confirmed by the tracer-determined glucose production data. In the INS group, net hepatic gluconeogenic substrate uptake (ala-From the Departments of Molecular Physiology and Biophysics (D.