In the absence of counterregulatory hormones, the increase in hepatic glucose production during insulin-induced hypoglycemia in the dog is initiated in the liver rather than the brain (original) (raw)
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Diabetes, 1992
To determine the relationship between decreases in glucose and metabolic regulation in the absence of counterregulatory hormones, we infused overnight-fasted, conscious, adrenalectomized dogs (lacking cortisol and EPI) with somatostatin (to eliminate glucagon and growth hormone) and intraportal insulin (30 pmol kg" 1 min" 1), creating arterial insulin levels of-2000 pM. Glucose was infused during one 120-min period, two 90-min periods, and one 45-min period to establish levels of 5.9 ± 0.1, 3.4 ± 0.1, 2.5 ± 0.1, and 1.7 ± 0.1 mM, respectively. NE levels were 1.24 ± 0.23, 1.85 ± 0.27, 2.04 ± 0.26, and 2.50 ± 0.20 nM, respectively. During the euglycemic control period, the liver took up glucose (7.5 ± 1. 9 junol kg" 1 min" 1), but hypoglycemia triggered successively greater rates of net hepatic glucose output (3.0 ± 0.7, 4.6 ± 0.9, and 6.9 ± 1. 4 ixmol • kg" 1 • min" 1). Total gluconeogenic precursor uptake by the liver increased with hypoglycemia. Intrahepatic gluconeogenic efficiency rose progressively (by 106 ± 42,199 ± 56, and 268 ± 55%). Both glycerol and NEFA levels rose, indicating lipolysis was enhanced. Net hepatic NEFA uptake and ketone production increased proportionally, but the ketone level rose only with severe hypoglycemia. In conclusion, despite marked hyperinsulinemia and the absence of glucagon, EPI, and cortisol, we observed that lipolysis and glucose
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.
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, 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
Journal of Clinical Investigation, 1980
study the effects of hyperglycemia on the metabolism of alanine and lactate independent of changes in plasma insulin and glucagon, glucose was infused into five 36-h-fasted dogs along with somatostatin and constant replacement amounts ofboth insulin and glucagon. Hepatic uptakes of alanine and lactate were calculated using the arteriovenious difference technique. [14C]Alanine was infused to measure the conversion of alanine and lactate into glucose. Hyperglycemia (M115 mg/dl) of 2 h duration caused the plasma alanine level to increase by over 50%. This change was caused by an increase in the inflow of alanine into plasma since the net hepatic uptake of the amino acid did not change. Taken together, the above findings indicate that glucose per se can significantly impair the fractional extraction of alanine by the liver. Hepatic extraction oflactate was also affected by hyperglycemia and had fallen to zero within 90 min ofstarting the glucose infusion. This fall was associated with a doubling of arterial lactate level. Conversion of [14C]alanine and ['4C]lactate into [14C]glucose was suppressed by 60±11 % after 2 h of hyperglycemia, and because this fall could not be entirely accounted for by decreased lactate extraction an inhibitory effect of glucose on gluconeogenesis within the liver is suggested. These studies indicate that the plasma glucose level per se can be an important determinant of the level of alanine and lactate in plasma as well as the rate at which they are converted to glucose.
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
- and -Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog
Diabetes, 2001
The responses of the pancreatic ␣and -cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 ± 1.7 (basal) to 6.0 ± 1.7 and 5.8 ± 1.0 µmol · kg -1 · min -1 by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 ± 0.2 (basal) to 5.2 ± 0.3 and 4.4 ± 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portalarterial difference in plasma insulin decreased (P < 0.01) from 78 ± 18 and 90 ± 24 to 24 ± 6 and 12 ± 12 pmol/l over the first 30 min of the test period and decreased to 18 ± 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 ± 5 and 4 ± 2 to 51 ± 5 and 10 ± 5 ng/l by 30 min (P < 0.05) and to 79 ± 16 and 31 ± 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 ± 0.1 mmol/l, and the NHGO decreased from 10 ± 0.6 to -3.3 ± 0.6 µmol · kg -1 · min -1 (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 ± 0.2 to 6.2 ± 0.2 mmol/l by 30 min, and the NHGO decreased from 10 ± 1.7 to 0 µmol · kg -1 · min -1 by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 ± 18 and 78 ± 24 to 126 ± 30 and 192 ± 42 pmol/l by 30 min, after which they averaged 138 ± 24 and 282 ± 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 ± 7 and 4 ± 3 to 34 ± 7 and 3 ± 2 ng/l during the test period. These data show that the ␣and -cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level. Diabetes 50:367-375, 2001
Diabetes, 2002
The direct acute effects of insulin on the regulation of hepatic gluconeogenic flux to glucose-6-phosphate (G6P) in vivo may be masked by the hormone's effects on net hepatic glycogenolytic flux and the resulting changes in glycolysis. To investigate this possibility, we used a glycogen phosphorylase inhibitor (BAY R3401) to inhibit glycogen breakdown in the overnight-fasted dog, and the effects of complete insulin deficiency or a fourfold rise in the plasma insulin level were assessed during a 5-h experimental period. Hormone levels were controlled using somatostatin with portal insulin and glucagon infusion. After the control period, plasma insulin infusion 1) was discontinued, creating insulin deficiency; 2) increased fourfold; or 3) was continued at the basal rate. During insulin deficiency, glucose production and the plasma level and net hepatic uptake of nonesterified free fatty acids increased, whereas during hyperinsulinemia they decreased. Net hepatic lactate uptake increased sixfold during insulin deficiency and 2.5-fold during hyperinsulinemia. Net hepatic gluconeogenic flux increased more than fourfold during insulin deficiency but was not reduced by hyperinsulinemia. We conclude that in the absence of appreciable glycogen breakdown, an acute gluconeogenic effect of hypoinsulinemia becomes manifest, whereas inhibition of the process by a physiologic rise in insulin was not evident.
Journal of Clinical Investigation, 1976
determinations of glucose outflow and inflow, and rates of gluconeogenesis from alanine, before, during and after insulin-induced hypoglycemia were obtained in relation to alterations in circulating epinephrine, norepinephrine, glucagon, cortisol, and growth hormone in six normal subjects. Insulin decreased the mean (+SEM) plasma glucose from 89+3 to 39+2 mg/dl 25 min after injection, but this decline ceased despite serum insulin levels of 153±22 gtU/ml. Before insulin, glucose inflow and outflow were constant, averaging 125.3±7.1 mg/kg per h. 15 min after insulin, mean glucose outflow increased threefold, but then decreased at 25 min, reaching a rate 15% less than the preinsulin rate. Glucose inflow decreased 80% 15 min after insulin, but increased at 25 min, reaching a maximum of twice the basal rate. Gluconeogenesis from alanine decreased 68% 15 min after insulin, but returned to preinsulin rates at 25 min, and remained constant for the next 25 min, after which it increased linearly. A fourfold increase in mean plasma epinephrine was found 20 min after insulin, with maximal levels 50 times basal. Plasma norepinephrine concentrations first increased significantly at 25 min after insulin, whereas significantly increased levels of cortisol and glucagon occurred at 30 min, and growth hormone at 40 min after insulin. Thus, insulin-induced hypoglycemia in man results from both a decrease in glucose production and an increase in glucose utilization. Accelerated glycogenolysis