Characterization of the portal signal during 24-h glucose delivery in unrestrained, conscious rats

To characterize the "portal signal" during physiological glucose delivery, liver glycogen was measured in unrestrained rats during portal (Po) and peripheral (Pe) constant-rate infusion, with minimal differences in hepatic glucose load (HGL) and portal insulin between the delivery routes. Hepatic blood flows were measured by Doppler flowmetry during open surgery. Changes in hepatic glucose, portal insulin, glucagon, lactate, and free fatty acid concentrations were generally similar in either delivery except for glucagon at 4 h. Hepatic glycogen, however, increased continuously in Po and was higher than Pe at 8 and 24 h, although it decreased to the level of Pe upon the removal of Po at 8 h. There was a near-linear relationship between hepatic glycogen and HGL in either delivery, with the slope being twice as high in Po and the intercepts converging to basal HGL. The hepatic response to Po did not alter upon 80% replacement by Pe. These results suggest that negative arterial-portal glucose gradients increase the rate of hepatic glycogen synthesis against the incremental HGL in an all-or-nothing mode.     

Nonhepatic response to portal glucose delivery in conscious dogs

The glycemic and hormonal responses and net hepatic and nonhepatic glucose uptakes were quantified in conscious 42-h-fasted dogs during a 180-min infusion of glucose at 10 mg. kg(-1). min(-1) via a peripheral (Pe10, n = 5) or the portal (Po10, n = 6) vein. Arterial plasma insulin concentrations were not different during the glucose infusion in Pe10 and Po10 (37 +/- 6 and 43 +/- 12 microU/ml, respectively), and glucagon concentrations declined similarly throughout the two studies. Arterial blood glucose concentrations during glucose infusion were not different between groups (125 +/- 13 and 120 +/- 6 mg/dl in Pe10 and Po10, respectively). Portal glucose delivery made the hepatic glucose load significantly greater (36 +/- 3 vs. 46 +/- 5 mg. kg(-1). min(-1) in Pe10 vs. Po10, respectively, P < 0.05). Net hepatic glucose uptake (NHGU; 1.1 +/- 0. 4 vs. 3.1 +/- 0.4 mg. kg(-1). min(-1)) and fractional extraction (0. 03 +/- 0.01 vs. 0.07 +/- 0.01) were smaller (P < 0.05) in Pe10 than in Po10. Nonhepatic (primarily muscle) glucose uptake was correspondingly increased in Pe10 compared with Po10 (8.9 +/- 0.4 vs. 6.9 +/- 0.4 mg. kg(-1). min(-1), P < 0.05). Approximately one-half of the difference in NHGU between groups could be accounted for by the difference in hepatic glucose load, with the remainder attributable to the effect of the portal signal itself. Even in the absence of somatostatin and fixed hormone concentrations, the portal signal acts to alter partitioning of a glucose load among the tissues, stimulating NHGU and reducing peripheral glucose uptake.     

Portal glucose infusion increases hepatic glycogen deposition in conscious unrestrained rats.

It has been demonstrated in the conscious dog that portal glucose infusion creates a signal that increases net hepatic glucose uptake and hepatic glycogen deposition. Experiments leading to an understanding of the mechanism by which this change occurs will be facilitated if this finding can be reproduced in the rat. Rats weighing 275-300 g were implanted with four indwelling catheters (one in the portal vein, one in the left carotid artery, and two in the right jugular vein) that were externalized between the scapulae. The rats were studied in a conscious, unrestrained condition 7 days after surgery, following a 24-h fast. Each experiment consisted of a 30- to 60-min equilibration, a 30-min baseline, and a 120-min test period. In the test period, a pancreatic clamp was performed by using somatostatin, insulin, and glucagon. Glucose was given simultaneously either through the jugular vein to clamp the arterial blood level at 220 mg/dl (Pe low group) or at 250 mg/dl (Pe high group), or via the hepatic portal vein (Po group; 6 mg. kg(-1). min(-1)) and the jugular vein to clamp the arterial blood glucose level to 220 mg/dl. In the test period, the arterial plasma glucagon and insulin levels were not significantly different in the three groups (36 +/- 2, 33 +/- 2, and 30 +/- 2 pg/ml and 1.34 +/- 0.08, 1. 37 +/- 0.18, and 1.66 +/- 0.11 ng/ml in Po, Pe low, and Pe high groups, respectively). The arterial blood glucose levels during the test period were 224 +/- 4 mg/dl for Po, 220 +/- 3 for Pe low, and 255 +/- 2 for Pe high group. The liver glycogen content (micromol glucose/g liver) in the two Pe groups was not statistically different (51 +/- 7 and 65 +/- 8, respectively), whereas the glycogen level in the Po group was significantly greater (93 +/- 9, P < 0.05). Because portal glucose delivery also augments hepatic glycogen deposition in the rat, as it does in the dogs, mechanistic studies relating to its function can now be undertaken in this species.     

Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal

Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. We hypothesize that the sympathetic nervous system normally restrains NHGU, and portal glucose delivery relieves the inhibition. Two groups of 42-h-fasted conscious dogs were studied using arteriovenous difference techniques. Denervated dogs (DEN; n=10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n=10) underwent a sham procedure. After a 140-min basal period, somatostatin was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the hepatic glucose load (HGL) for 90 min (P1). In P2, glucose was infused intraportally (3-4 mg.kg(-1).min(-1)), and the peripheral glucose infusion was reduced to maintain the HGL for 90 min. This was followed by 90 min (P3) in which portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. P1 and P3 were averaged as the peripheral glucose infusion period (PE). The average HGLs (mg.kg(-1).min(-1)) in CON and DEN were 55+/-3 and 54+/-4 in the peripheral periods and 55+/-3 and 55+/-4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg.kg(-1).min(-1)) in CON averaged 1.7+/-0.3 during PE and increased to 2.9+/-0.3 during P2. NHGU (mg.kg(-1).min(-1)) was greater in DEN than CON (P<0.05) during PE (2.9+/-0.4) and failed to increase significantly (3.2+/-0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.     

Importance of the hepatic arterial glucose level in generation of the portal signal in conscious dogs

The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs (n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 micromol x kg(-1) x min(-1)). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 +/- 2.2 and 12.8 +/- 2.1 vs. 11.5 +/- 1.6 and 23.8 +/- 3.3* vs. 9.0 +/- 2.4 and 13.8 +/- 4.2 micromol x kg(-1) x min(-1) in the two periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 +/- 1.2 and 39.5 +/- 4.3 vs. 26.3 +/- 3.7 and 24.5 +/- 3.7* vs. 36.1 +/- 3.8 and 53.3 +/- 8.5 micromol x kg(-1) x min(-1) in the first and second periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.     

Impact of continuous and pulsatile insulin delivery on net hepatic glucose uptake

The pancreas releases insulin in a pulsatile manner; however, studies assessing the liver's response to insulin have used constant infusion rates. Our aims were to determine whether the secretion pattern of insulin [continuous (CON) vs. pulsatile] in the presence of hyperglycemia 1) influences net hepatic glucose uptake (NHGU) and 2) entrains NHGU. Chronically catheterized conscious dogs fasted for 42 h received infusions including peripheral somatostatin, portal insulin (0.25 mU x kg(-1) x min(-1)), peripheral glucagon (0.9 ng x kg(-1) x min(-1)), and peripheral glucose at a rate double the glucose load to the liver. After the basal period, insulin was infused for 210 min at either four times the basal rate (1 mU x kg(-1) x min(-1)) or an identical amount in pulses of 1 and 4 min duration, followed by intervals of 11 and 8 min (CON, 1/11, and 4/8, respectively) in which insulin was not infused. A variable peripheral glucose infusion containing [3H]glucose clamped glucose levels at twice the basal level ( approximately 200 mg/dl) throughout each study. Hepatic metabolism was assessed by combining tracer and arteriovenous difference techniques. Arterial plasma insulin (microU/ml) either increased from basal levels of 6 +/- 1 to a constant level of 22 +/- 4 in CON or oscillated from 5 +/- 1 to 416 +/- 79 and from 6 +/- 1 to 123 +/- 43 in 1/11 and 4/8, respectively. NHGU (-0.8 +/- 0.3, 0.4 +/- 0.2, and -0.9 +/- 0.4 mg x kg(-1) x min(-1)) and net hepatic fractional extraction of glucose (0.04 +/- 0.01, 0.04 +/- 0.01, and 0.05 +/- 0.01 mg x kg(-1) x min(-1)) were similar during the experimental period. Spectral analysis was performed to assess whether a correlation existed between the insulin secretion pattern and NHGU. NHGU was not augmented by pulsatile insulin delivery, and there is no evidence of entrainment in hepatic glucose metabolism. Thus the loss of insulin pulsatility per se likely has little or no impact on the effectiveness of insulin in regulating liver glucose uptake.     

Pancreatic glucagon secretion during a short period of hemorrhage in anesthetized dogs

Glucagon has been implicated in the hormonal metabolic response to hemorrhage. However, evidence for this has been obtained largely from observations of circulating plasma glucagon concentration. A clear increase in the pancreatic glucagon secretion remains to be demonstrated. Plasma concentrations of pancreatic immunoreactive glucagon (IRG) and insulin (IRI) were determined in portal venous and aortic blood, and plasma glucose in aortic blood. Dogs were bled (approximately 15 mL/kg) until aortic systolic blood pressure dropped to approximately 50% (70.5 +/- 8.1 mmHg, n = 7) (1 mmHg = 133.32 Pa) of its control value (135 +/- 7.1 mmHg, n = 7), and the hemorrhagic hypotension was maintained for 10 min. The net portal venous IRG delivery rate rose significantly and continued to increase during the hemorrhagic hypotension despite a significant fall in the portal venous blood flow. Aortic IRG increased significantly along with the increase in portal venous IRG delivery rate (r = 0.838, n = 42, p less than 0.01). The portal venous delivery rate of IRI decreased significantly in response to hemorrhage. The aortic IRG/IRI concentration ratio increased significantly during the hemorrhage-induced hypotension. Aortic glucose concentration increased significantly 5 min after hemorrhage and continued to rise until the end of the hemorrhagic hypotension. The present study demonstrates that the secretion of pancreatic glucagon actually increases during the early phase of hemorrhage. The results also indicate that the increase in aortic IRG during the hemorrhagic hypotension is due to the increased pancreatic glucagon secretion. It is suggested that the pancreatic glucagon may be involved in the early hyperglycemic response to hemorrhage.     

Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region

Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on glucose disposal in vivo was assessed in conscious dogs by use of tracer and arteriovenous difference techniques. After a basal period, each experiment consisted of three periods (P1, P2, P3) during which somatostatin, glucagon, insulin, and glucose were infused. The control group (C) received saline in P1, P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol.kg(-1).min(-1)) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1 and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose and insulin concentrations increased to two- and fourfold basal, respectively, and glucagon remained basal. GLP-1 levels increased similarly in the PePe and PePo groups during P2 ( approximately 200 pM), whereas portal GLP-1 levels were significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased slightly but not significantly in all groups. During P3, NHGU increased in PePe and PePo groups to a greater extent than in C, but no significant effect of the route of infusion of GLP-1 was demonstrated (16.61 +/- 2.91 and 14.67 +/- 2.09 vs. 4.22 +/- 1.57 micromol.kg(-1).min(-1), respectively). In conclusion: GLP-1 increased glucose disposal in the liver independently of insulin secretion; its full action required long-term infusion. The route of infusion did not modify the hepatic response.     

Chronic hepatic artery ligation does not prevent liver from differentiating portal vs. peripheral glucose delivery

Infusion of glucose into the hepatic artery blocks the stimulatory effect of the "portal signal" on net hepatic glucose uptake (NHGU) during portal glucose delivery. We hypothesized that hepatic artery ligation (HAL) would result in enhanced NHGU during peripheral glucose infusion because the arterial glucose concentration would be perceived as lower than that in the portal vein. Fourteen dogs underwent HAL approximately 16 days before study. Conscious 42-h-fasted dogs received somatostatin, intraportal insulin, and glucagon infusions at fourfold basal and at basal rates, respectively, and peripheral glucose infusion to create hyperglycemia. After 90 min (period 1), seven dogs (HALpo) received intraportal glucose (3.8 mg. kg-1. min-1) and seven (HALpe) continued to receive only peripheral glucose for 90 min (period 2). These two groups were compared with nine non-HAL control dogs (control) treated as were HALpe. During period 2, the arterial plasma insulin concentrations (24 +/- 3, 20 +/- 1, and 24 +/- 2 microU/ml) and hepatic glucose loads (39.1 +/- 2.5, 43.8 +/- 2.9, and 37.7 +/- 3.7 mg. kg-1. min-1) were not different in HALpe, HALpo, and control, respectively. HALpo exhibited greater (P < 0.05) NHGU than HALpe and control (3.1 +/- 0.3, 2.0 +/- 0.4, and 2.0 +/- 0.1 mg. kg-1. min-1, respectively). Net hepatic carbon retention was approximately twofold greater (P < 0.05) in HALpo than in HALpe and control. NHGU and net hepatic glycogen synthesis during peripheral glucose infusion were not enhanced by HAL. Even though there exists an intrahepatic arterial reference site for the portal vein glucose concentration, the failure of HAL to result in enhanced NHGU during peripheral glucose infusion suggests the existence of one or more comparison sites outside the liver.     

Aging is associated with elevated muscle triglyceride content and increased insulin-stimulated fatty acid uptake

The purpose of the present study was to examine the utilization of fatty acids (FA) and muscle substrates by skeletal muscle in young, middle-aged, and old adult rats under hyperglycemic and hyperinsulinemic conditions. Male Fischer 344 x Brown Norway rats aged 5, 15, or 24 mo underwent hindlimb perfusion with a medium of 20 mM glucose, 1 mM palmitate, 1,000 microU/ml insulin, [1-14C]palmitate, and [3-3H]glucose. Glucose uptake and palmitate delivery were similar among age groups. Palmitate uptake and oxidation as well as muscle protein concentration of fatty acid translocase (FAT/CD36) and plasma membrane fatty acid-binding protein (FABPPM) were significantly increased (P < or = 0.05) in 24- vs. 5- and 15-mo-old animals. Compared with 5- and 15-mo-old animals, pre- and postperfusion muscle triglyceride (TG) levels were significantly (P < 0.05) elevated 72-145% in red and 112-129% in white muscles of 24-mo-old animals. Palmitate uptake was associated with total preperfusion TG concentration (r2 = 0.27, P < 0.05) and total TG synthesis rate (r2 = 0.68, P < 0.05). These results indicate that, under insulin-stimulated conditions, FA uptake is significantly increased in old animals, which is associated with increased rates of TG synthesis and may contribute to the accumulation of TG in muscle of old animals.     

Effects of hyperglycemia on hepatic gluconeogenic flux during glycogen phosphorylase inhibition in the conscious dog

The aim of these studies was to investigate the effect of hyperglycemia with or without hyperinsulinemia on hepatic gluconeogenic flux, with the hypothesis that inhibition would be greatest with combined hyperglycemia/hyperinsulinemia. A glycogen phosphorylase inhibitor (BAY R3401) was used to inhibit glycogen breakdown in the conscious overnight-fasted dog, and the effects of a twofold rise in plasma glucose level (HI group) accompanied by 1) euinsulinemia (HG group) or 2) a fourfold rise in plasma insulin were assessed over a 5-h experimental period. Hormone levels were controlled using somatostatin with portal insulin and glucagon infusion. In the HG group, net hepatic glucose uptake and net hepatic lactate output substantially increased. There was little or no effect on the net hepatic uptake of gluconeogenic precursors other than lactate (amino acids and glycerol) or on the net hepatic uptake of free fatty acids compared with the control group. Consequently, whereas hyperglycemia had little effect on gluconeogenic flux to glucose 6-phosphate (G-6-P), net hepatic gluconeogenic flux was reduced because of increased hepatic glycolytic flux during hyperglycemia. Net hepatic glycogen synthesis was increased by hyperglycemia. The effect of hyperglycemia on gluconeogenic flux to G-6-P and net hepatic gluconeogenic flux was similar. We conclude that, in the absence of appreciable glycogen breakdown, the increase in glycolytic flux that accompanies hyperglycemia results in decreased net carbon flux to G-6-P but no effect on gluconeogenic flux to G-6-P.     

Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux

We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 microeq.kg(-1).min(-1) portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5- to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity.     

Intraportal administration of neuropeptide Y and hepatic glucose metabolism

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group (n = 7), NPY was infused intraportally at 0.2 and 5.1 pmol.kg(-1).min(-1) during P2 and P3, respectively. The control group (n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 +/- 1 and 10 +/- 2 micromol.kg(-1).min(-1) in control and NPY, respectively (P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 +/- 0.005 and 0.039 +/- 0.008 in control and NPY, respectively (P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 +/- 2 vs. 14 +/- 2 micromol.kg(-1).min(-1), P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs.     

Alterations in basal glucose metabolism during late pregnancy in the conscious dog

We assessed basal glucose metabolism in 16 female nonpregnant (NP) and 16 late-pregnant (P) conscious, 18-h-fasted dogs that had catheters inserted into the hepatic and portal veins and femoral artery approximately 17 days before the experiment. Pregnancy resulted in lower arterial plasma insulin (11 +/- 1 and 4 +/- 1 microU/ml in NP and P, respectively, P < 0.05), but plasma glucose (5.9 +/- 0.1 and 5.6 +/- 0.1 mg/dl in NP and P, respectively) and glucagon (39 +/- 3 and 36 +/- 2 pg/ml in NP and P, respectively) were not different. Net hepatic glucose output was greater in pregnancy (42.1 +/- 3.1 and 56.7 +/- 4.0 micromol. 100 g liver(-1).min(-1) in NP and P, respectively, P < 0.05). Total net hepatic gluconeogenic substrate uptake (lactate, alanine, glycerol, and amino acids), a close estimate of the gluconeogenic rate, was not different between the groups (20.6 +/- 2.8 and 21.2 +/- 1.8 micromol. 100 g liver(-1). min(-1) in NP and P, respectively), indicating that the increment in net hepatic glucose output resulted from an increase in the contribution of glycogenolytically derived glucose. However, total glycogenolysis was not altered in pregnancy. Ketogenesis was enhanced nearly threefold by pregnancy (6.9 +/- 1.2 and 18.2 +/- 3.4 micromol. 100 g liver(-1).min(-1) in NP and P, respectively), despite equivalent net hepatic nonesterified fatty acid uptake. Thus late pregnancy in the dog is not accompanied by changes in the absolute rates of gluconeogenesis or glycogenolysis. Rather, repartitioning of the glucose released from glycogen is responsible for the increase in hepatic glucose production.     

A portal-arterial glucose concentration gradient as a signal for an insulin-dependent net glucose uptake in perfused rat liver

Since in the usual perfusion of isolated rat liver via the portal vein an insulin-dependent increase of hepatic glucose uptake could not be demonstrated, the possibility was considered that hepatic glucose uptake might not be a function of the absolute concentration of this substrate but of its concentration gradient between the portal vein and the hepatic artery. Therefore a new method was established for the simultaneous perfusion of isolated rat liver via both the hepatic artery (20-35% flow) and the portal vein (80-65% flow). When glucose was offered in a concentration gradient, 9.5 mM in the portal vein and 6 mM in the hepatic artery, insulin given via both vessels caused a shift from net glucose release to uptake. This insulin-dependent shift was not observed when glucose was offered without a gradient or with an inverse gradient, 6 mM in the portal vein and 9.5 mM in the hepatic artery. Using a portal-arterial glucose gradient as a signal the liver might be able to differentiate between endogenous and exogenous glucose.     

Elevated plasma proinsulin/insulin ratio is a marker of reduced insulin secretory capacity in healthy young men.

AIM: To examine whether reduced insulin secretory capacity or increased insulin secretory demand is associated with elevated ratio of plasma proinsulin to immunoreactive insulin (PI/IRI ratio) in non-diabetic subjects. SUBJECTS AND METHODS: We measured various indices of insulin secretory function and insulin sensitivity by frequently sampled intravenous glucose tolerance test (FSIGT) and hyerglycemic glucose clamp in 21 healthy young men. We then examined the relationships between these indices and PI, IRI, or PI/IRI ratio in the fasting state. RESULTS: Insulin sensitivity index (SI) measured by FSIGT correlated inversely with basal IRI (r=-0.53, P < 0.01) and PI levels (r=-0.57, P < 0.01), but there was no significant correlation between SI and PI/IRI ratio (r=0.26, NS). On the other hand, PI/IRI ratio correlated inversely with insulin secretory indices, such as acute insulin responses during FSIGT (r =-0.46, P < 0.01) and hyperglycemic glucose clamp (r=-0.54, P < 0.01) and submaximum insulin response during hyperglycemic glucose clamp (r=-0.59, P < 0.01). CONCLUSIONS: These results indicate that elevated PI/IRI ratio may serve as a marker of reduced insulin secretory function in non-diabetic subjects.     

Unlike mice, dogs exhibit effective glucoregulation during low-dose portal and peripheral glucose infusion

Portal infusion of glucose in the mouse at a rate equivalent to basal endogenous glucose production causes hypoglycemia, whereas peripheral infusion at the same rate causes significant hyperglycemia. We used tracer and arteriovenous difference techniques in conscious 42-h-fasted dogs to determine their response to the same treatments. The studies consisted of three periods: equilibration (100 min), basal (40 min), and experimental (180 min), during which glucose was infused at 13.7 micromol.kg(-1).min(-1) into a peripheral vein (p.e., n = 5) or the hepatic portal (p.o., n = 5) vein. Arterial blood glucose increased approximately 0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. p.e. exhibited an increase in nonhepatic glucose uptake (non-HGU; Delta8.6 +/- 1.2 micromol.kg(-1).min(-1)) within 30 min, whereas p.o. showed a slight suppression (Delta-3.7 +/- 3.1 micromol.kg(-1).min(-1)). p.o. shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 +/- 2.8 micromol.kg-1.min-1) within 30 min, but p.e. still exhibited NHGO (6.0 +/- 1.9 micromol.kg(-1).min(-1)) at that time and did not initiate NHGU until after 90 min. Glucose rates of appearance and disappearance did not differ between groups. The response to the two infusion routes was markedly different. Peripheral infusion caused a rapid enhancement of non-HGU, whereas portal delivery quickly activated NHGU. As a result, both groups maintained near-euglycemia. The dog glucoregulates more rigorously than the mouse in response to both portal and peripheral glucose delivery.     

In vivo insulin responsiveness for glucose uptake and production at eu- and hyperglycemic levels in normal and diabetic rats.

Whole body glucose uptake (BGU) and hepatic glucose production (HGP) at maximal plasma insulin concentrations (+/- 5000 microU/ml) were determined by eu- (EC) (6 mM) and hyperglycemic (HC) (20 mM) clamps (120 min), combined with [3-3H]glucose infusion, in normal and streptozotocin-treated (65 mg/kg) 3-day diabetic, conscious rats. In normal rats, during EC, BGU was 12.4 +/- 0.4 mg/min and during HC, when urinary glucose loss was 0.54 +/- 0.09 mg/min, BGU was 25.5 +/- 1.6 mg/min. However, throughout the final 60 min of HC, glucose infusion rate (GIR) was not constant but a linear decline in time (r = -0.99) of 17%, P less than 0.0001, was observed indicating a hyperglycemia-induced desensitization process. In diabetic rats, during EC, BGU was 7.7 +/- 0.3 mg/min and during HC, BGU was 15.5 +/- 1.4 mg/min. Throughout the final 60 min of HC, GIR was constant, suggesting that the hyperglycemia-induced desensitization process was already completed. In normal and diabetic rats, HGP was similar: during EC 0.2 +/- 0.5 mg/min and 0.1 +/- 0.5 mg/min, and during HC 0.4 +/- 0.4 mg/min and 0.5 +/- 0.6 mg/min, respectively. In vitro adipocyte and muscle insulin receptor studies showed normal to increased receptor number and increased receptor autophosphorylation in diabetic compared to normal rats. In conclusion: (i) 3-day diabetic rats show, at maximal plasma insulin concentrations, insulin resistance to BGU, but not to HGP. The resistance to BGU is equally present (reduction of 38%) at eu- and hyperglycemic levels as compared to normal rats. (ii) 3-day diabetic rats reveal no defect in adipocyte and muscle insulin receptor function. These data indicate that the diabetes induced insulin resistance for BGU is at the post-receptor level and due to a decreased maximal capacity (Vmax) for glucose uptake, with no change in affinity, or Km.     

The release and metabolism of pancreatic hormones after major hepatectomy in the dog.

Major hepatectomy in the dog induced a 50% decrease in peripheral serum glucose, a 11-fold increase in portal plasma glucagon and a 36-fold increase in the portal glucagon/insulin ratio 3 hr after operation. Peripheral serum glucose levels were inversely correlated to the logarithmic value of portal plasma glucagon (r = -0.50, p less than 0.01) and that of the portal glucagon/insulin ratio (r = -0.85, p less than 0.01) for 1-6 hr after operation. The ratio of peripheral to portal plasma glucagon was also inversely correlated to the logarithmic value of portal plasma glucagon (r = -0.59, p less than 0.01). In case of glucose infusion, plasma glucagon levels were not elevated after major hepatectomy. The data suggest that glucose deficiency after major hepatectomy in the dog may cause hyperglucagonemia with an enhanced glucagon requirement.     

Hepatic glucose metabolism during intraduodenal glucose infusion: impact of infection

We previously reported that infection decreases hepatic glucose uptake when glucose is given as a constant peripheral glucose infusion (8 mg. kg(-1) x min(-1)). This impairment persisted despite greater hyperinsulinemia in the infected group. In a normal setting, hepatic glucose uptake can be further enhanced if glucose is given gastrointestinally. Thus the aim of this study was to determine whether hepatic glucose uptake is impaired during an infection when glucose is given gastrointestinally. Thirty-six hours before study, a sham (SH, n = 7) or Escherichia coli-containing (2 x 10(9) organisms/kg; INF; n = 7) fibrin clot was placed in the peritoneal cavity of chronically catheterized dogs. After the 36 h, a glucose bolus (150 mg/kg) followed by a continuous infusion (8 mg. kg(-1). min(-1)) of glucose was given intraduodenally to conscious dogs for 240 min. Tracer ([3-(3)H]glucose and [U-(14)C]glucose) and arterial-venous difference techniques were used to assess hepatic and intestinal glucose metabolism. Infection increased hepatic blood flow (35 +/- 5 vs. 47+/-3 ml x g(-1) x min(-1); SH vs. INF) and basal glucose rate of appearance (2.1+/-0.2 vs. 3.3+/-0.1 mg x kg(-1) x min(-1)). Arterial insulin concentrations increased similarly in SH and INF during the last hour of glucose infusion (38+/-8 vs. 46+/-20 microU/ml), and arterial glucagon concentrations fell (62+/-14 to 30+/-3 vs. 624+/-191 to 208+/-97 pg/ml). Net intestinal glucose absorption was decreased in INF, attenuating the increase in blood glucose caused by the glucose load. Despite this, net hepatic glucose uptake (1.6+/-0.8 vs. 2.4+/- 0.9 mg x kg(-1) x min(-1); SH vs. INF) and consequently tracer-determined glycogen synthesis (1.3+/-0.3 vs. 1.0+/-0.3 mg. kg(-1) x min(-1)) were similar between groups. In summary, infection impairs net glucose absorption, but not net hepatic glucose uptake or glycogen deposition, when glucose is given intraduodenally.