Characterization of the portal signal in a nonsteady hyperglycemic state in conscious dogs

N. Ogihara1, S. Ebihara1, W. Kawamura1, M. Okamoto1, T. Sakai1, K. Takiguchi1, T. Morita1, R. Uchida1, Y. Matsuyama2, Y. Hayashi3, Y. Arakawa3, and M. Kikuchi1

1 Department of Endocrinology and Metabolism, Institute for Adult Diseases, Asahi Life Foundation, Tokyo 160-0023; 2 Department of Health Science, Department of Biostatistics, Kyoto University School of Public Health, Kyoto 606-8501; and 3 Third Department of Internal Medicine, Nihon University, Tokyo 173-8610, Japan


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

To characterize the "portal signal" in a nonsteady hyperglycemic state, the kinetic relationship between net hepatic glucose balance (NHGB) and either hepatic glucose load (HGL) or plasma insulin level was determined during glucose infusion using a catheter technique in 36 conscious dogs. Glucose was infused intraportally (Po group) and peripherally (Pe group) at 39, 56, and 83 µmol · kg-1 · min-1 over 2 h. There was a linear relationship between mean NHGB and either mean HGL or plasma insulin levels at each rate in either delivery (HGL: Po r = 0.99, Pe r = 0.95; insulin: Po r = 99, Pe r = 0.79). The threshold levels for net hepatic glucose uptake were 3.8 and 11.7 mmol/l for plasma glucose and 65 and 392 pmol/l for plasma insulin, respectively. The slope of the regression line against the abscissa was four times larger in portal than in peripheral delivery (HGL: Po 0.20 vs. Pe 0.05, P < 0.05; insulin: Po 0.19 vs. Pe 0.04, P < 0.05). These results suggest that the portal signal overrules the threshold of glucose for hepatic uptake by increasing hepatic extraction rate in a nonsteady hyperglycemic state.

glucose delivery route; hepatic glucose load; insulin dependency; hepatic glucose uptake


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

NUMEROUS STUDIES HAVE DOCUMENTED that hepatic glucose uptake is dependent on hepatic glucose load (HGL), plasma insulin level, and route of glucose delivery. However, in most studies, either hyperinsulinemic or hyperglycemic clamps were used in the presence of constant glucose, insulin, glucagon, and/or somatostatin concentrations (1, 2, 6, 14-16). It has not been demonstrated yet whether the portal signal functions similarly in a nonsteady hyperglycemic state as in the case during a clamp state. Moore et al. (13) infused glucose at a gradually increasing rate via the portal and peripheral delivery routes in dogs, with insulin and glucagon being free to change. However, arterial and portal plasma glucose profiles were largely not different with time in either delivery. In many clamp studies, peripheral delivery was combined with portal delivery to keep hepatic load constant. However, the portal signal appears not to be associated with the magnitude of arterial-portal glucose gradients at high glucose load (16). Recently, it has been reported that somatostatin blocks activation of the glucose sensor (5). Furthermore, several studies have demonstrated that pulsatile insulin concentrations have greater effects on glucose uptake than a constant concentration (3, 7, 11, 17), and the initial acute rise in plasma insulin provokes a decrease in postprandial hyperglycemia (4, 10). Against this background, the present studies were undertaken to characterize the portal signal in a nonsteady hyperglycemic state. To this end, we determined the kinetic relationship between hepatic glucose disposal and HGL, plasma insulin levels, arterial-portal glucose gradients, or nonhepatic glucose uptake during intraportal and peripheral glucose infusion at the same rates.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. Experiments were carried out in 36 nondiabetic conscious beagles (7~12 kg) of either sex fed daily a commercial pellet of meat and chow (Labo D standard meat, Nosan Tokyo; 24% protein, 66.5% carbohydrate, 8.4% fat, and 1.1% fiber based on dry weight). The protocols were approved by the Institute's Animal Care Committee.

Surgical procedures. Two weeks before the experiment, a laparotomy was performed in beagles under general anesthesia (35 mg/kg pentobarbital sodium), and polyethylene catheters (Nipro; Heparin Infusion Line, Osaka, Japan) were inserted into a mesenteric vein, the portal vein, the left common hepatic vein, and a femoral artery. The mesenteric catheter used for blood sampling was inserted via the superior mesenteric vein, and the tip was placed at the point where the vessel enters the liver. The tip of the other mesenteric catheter, used for glucose infusion into the portal vein, was placed ~4 cm downstream from the root of the superior mesenteric vein. The tip of the hepatic vein catheter used for blood sampling was placed 1 cm inside the left common hepatic vein. The femoral catheter used for blood sampling was inserted through an incision made in the left inguinal region. After the procedures, the catheters were filled with saline containing heparin (50 U/ml; Novo Nordisk Pharma, Copenhagen, Denmark). Probes of an ultrasonic range-gated, pulsed Doppler flowmeter (Instrumentation Development Laboratories, Bayler College of Medicine, Houston, TX) were placed around the portal vein and the hepatic artery. The gastroduodenal branches of the hepatic artery were ligated to prevent outflow from bypassing the liver. The free ends of the catheters and wires of the Doppler flow probes were exteriorized below the base of the skull. Only dogs with good appetite and normal blood count and serum enzymes were studied. On the day of experiment, 2 wk after surgery, the catheter contents were aspirated, the catheters were flushed with saline, and a catheter was inserted percutaneously into the left cephalic vein for the peripheral infusion of glucose. Each dog rested quietly in a Pavlov harness for the duration of the study.

Experimental design. Before the experiments, animals were fasted for 18 h but had access to water. Each experiment consisted of a 60-min basal period followed by a 120-min glucose infusion period. The nondiabetic animals were randomly assigned to either protocol 1 [portal (Po) group] or protocol 2 [peripheral (Pe) group]. In protocol 1, glucose was infused via the superior mesenteric vein at rates of 39, 56, or 83 µmol · kg-1 · min-1, respectively. In protocol 2, the animals received glucose via the cephalic vein at the same rates. The experiments were carried out in a randomized fashion in each group of six dogs for the respective rates in either protocol. Blood samples were taken at -40, -30, -20, -10, 0, 2, 4, 6, 8, 10, 15, 30, 45, 60, 75, 90, 105, and 120 min.

Analytical procedures. Plasma glucose concentration was determined by a Beckman glucose analyzer (Fullerton, CA). Immunoreactive insulin was measured by the Phadeseph Insulin Test (Pharmacia Diagnostics, Uppsala, Sweden). Immunoreactive glucagon was determined with a commercially available kit (Daiich, Tokyo, Japan).

Calculations. Net hepatic glucose balance (NHGB) is defined as the difference between the load of glucose leaving the liver (LOADOUT) and that entering it (LOADIN). LOADOUT was calculated using the equation [G]HV · FHV, where [G]HV represents blood glucose concentration in the hepatic vein, and FHV is hepatic vein blood flow rate: FHA + FPV, in which FHA is the flow rate of the hepatic artery and FPV that of the portal vein. LOADIN was calculated according to two different methods: 1) directly, according to the equation LOADIN = [G]A · FHA + [G]PV · FPV, in which [G]A and [G]PV represent blood glucose concentration in an artery and the portal vein, respectively; and 2) indirectly, according to the equation LOADIN = [G]A · FHV + GIRPV - GUG, where GIRPV is the intraportal glucose infusion rate and GUG is the uptake of glucose by the gastrointestinal tract according to the formula: GUG = ([G]A - [G]PV) · FPV during peripheral glucose infusion. As a result, NHGB is calculated 1) directly, as LOADOUT - LOADIN = [G]HV · FHV - ([G]A · FHA+ [G]P · FP), with positive values representing net output of glucose by the liver and negative values representing net glucose uptake; and 2) indirectly, as LOADOUT - LOADIN = [G]HV · FHV - ([G]A · FHV + GIRPV - GUG) = ([G]HV - [G]A) · FHV - GIRPV + GUG. To assure the glucose mixing in the portal vein, we calculated NHGU with formulas 1 and 2. The difference in NHGU between the two formulas was <= 11% (Table 1). Timed net hepatic fractional extraction of glucose (NHFEG) was calculated by NHGU divided by HGL (%) at each time point during glucose infusion. Overall NHFEG was determined by cumulative areas under the curves (AUCs) of NHGU divided by cumulative AUCs of HGL (%). Net nonhepatic glucose uptake was calculated as glucose infusion rate minus mean AUCs of NHGU. The trapezoidal rule was used to determine the AUC.

                              
View this table:
[in this window]
[in a new window]
 
Table 1.   Comparison of direct and indirect calculations of NHGU

Because canine red blood cells can act as glucose carriers, the most accurate assessment of gut glucose balance is obtained using blood glucose values. Plasma glucose values were used to determine the arterial-venous difference accurately, and then they were corrected to whole blood glucose by use of a blood glucose-to-plasma glucose ratio, verified independently: [G]BLOOD = 0.86[G]PLASMA + 0.15, r = 0.98, where [G]BLOOD is whole blood glucose concentration and [G]PLASMA is plasma glucose.

Statistical analysis. Data are given as means ± SE. Analysis of variance (ANOVA) with a repeated-measures design was utilized to evaluate changes over time within the groups at the respective infusion rate. Unpaired t-tests were used for comparison of the data at the particular rates between the two delivery routes. Paired t-tests were used for the comparison in NHGU between the direct and indirect measurements and between net NHGU and nonhepatic glucose uptake. The time course data were plotted at 13 time points during glucose infusion with each delivery rate. The mean data over 120 min during glucose infusion with the respective infusion rates were expressed as cumulative AUCs up to the arbiter time point divided by the minute number. The method of least squares was used to obtain a linear regression equation. A P value < 0.05 was accepted as significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Blood glucose levels during intraportal or peripheral glucose infusion. Figure 1 shows changes in plasma glucose, insulin, and glucagon levels in a femoral artery when groups of six dogs were infused with glucose intraportally (left) or peripherally (right) over 120 min at the rate of 39, 56, or 83 µmol · kg-1 · min-1. As shown in Fig. 1, top left, during intraportal infusion, plasma glucose increased gradually to a maximum at 60 min of 1.7, 1.9, and 2.5 times basal level at increasing doses and declined thereafter. Mean plasma glucose levels over 120 min increased dose dependently (P < 0.05) (Table 2). Similar plasma glucose excursions were observed in the portal vein and the hepatic vein (data not shown).


View larger version (36K):
[in this window]
[in a new window]
 
Fig. 1.   Arterial plasma glucose (top), insulin (middle), and glucagon levels (bottom) during basal and intraportal (left) or peripheral (right) glucose infusion periods at the rates of 39, 56, or 83 µmol · kg-1 · min-1. Data represent means ± SE for each group of 6 dogs.


                              
View this table:
[in this window]
[in a new window]
 
Table 2.   Plasma glucose, insulin, and glucagon concentrations in the femoral artery during basal and glucose infusion period in conscious dogs

As shown in Fig. 1, top right, when glucose was infused into a cephalic vein, plasma glucose rose dose dependently to a maximum by 60 min of 1.5, 2.1, and 3.1 times basal level and leveled off thereafter. Mean plasma glucose levels increased with increasing infusion rates (P < 0.05) and tended to be greater in peripheral than in portal delivery, but the difference did not reach significance (Table 2). Changes in portal and hepatic venous levels were similar to those in arterial levels (data not shown), but the mean portal plasma glucose level was two times higher in portal than peripheral delivery.

Plasma insulin levels. Figure 1, middle, depicts the plasma insulin profiles during either glucose infusion. Basal plasma insulin levels were not different (Table 2). Plasma insulin increased gradually to a peak at 120 min of 3.4, 7.7, and 10.2 times basal level during intraportal delivery and 4.9, 8.9, and 7.9 times basal level at 45-105 min during peripheral delivery. Mean plasma insulin levels increased with increasing rates (P < 0.05) without any difference between the delivery routes (Table 2). Portal and hepatic venous insulin excursions changed similarly throughout the experimental period, but mean plasma insulin levels in the portal vein were about twice as high as those in the artery.

Plasma glucagon levels. Plasma glucagon declined dose dependently to a nadir at 30-60 min via either route (Fig. 1, bottom). Mean plasma glucagon levels were suppressed by 32, 23, and 32% during portal delivery and by 28, 45, and 51% during peripheral delivery; these differences were not significant within doses and between delivery routes except for the middle rate (Table 1). Basal glucagon levels were slightly lower in the order of portal vein, hepatic vein, and artery, and portal and hepatic venous glucagon decreased from basal levels to the same extent during glucose infusion in either delivery (data not shown).

Hepatic blood flow. As shown in Table 3, blood flows were higher during portal than during peripheral delivery. Portal vein blood flow tended to decrease, whereas hepatic arterial blood flow did not change in either delivery route. Neither blood flow increased with increasing glucose delivery rates in either route. Portal vein blood flow was 3.4-4.6 times higher than hepatic arterial blood flow during portal delivery and 3.0-3.2 times higher during peripheral delivery.

                              
View this table:
[in this window]
[in a new window]
 
Table 3.   Hepatic arterial and portal vein blood flows during basal and intraportal and peripheral glucose infusion periods in conscious dogs

HGL. Figure 2, top, shows changes in HGL during basal and glucose infusion periods. Basal HGL was not significantly different at any rate or route except for the middle rate (Table 4). As shown in Fig. 2, top left, during intraportal glucose infusion, HGL increased dose dependently to a maximum at 45-60 min of 2.0, 2.1, and 2.9 times basal load. The maximal values and mean AUCs of HGL increased with increasing rates (P < 0.05; Table 4). Portal glucose infusion rates corresponded to 21, 22, and 24% of mean HGL, respectively. There was a moderate correlation between HGL and plasma insulin level (r = 0.41, P < 0.005).


View larger version (37K):
[in this window]
[in a new window]
 
Fig. 2.   Hepatic glucose load (top) and net hepatic glucose balance (bottom) during intraportal (left) and peripheral (right) glucose infusion at the rate of 39, 56, or 83 µmol · kg-1 · min-1. Data represent means ± SE for each group of 6 dogs.


                              
View this table:
[in this window]
[in a new window]
 
Table 4.   Hepatic glucose load and hepatic glucose balance during basal and intraportal or peripheral glucose infusion periods in conscious dogs

As depicted in Fig. 2, top right, during peripheral glucose infusion, HGL rose to a peak at 20-60 min of 1.4, 2.0, and 2.5 times basal. The maximal values and mean HGL were raised with increasing rates (P < 0.05; Table 4). Peripheral glucose infusion rates corresponded to 33, 42, and 35% of mean HGL, respectively. Mean HGL was 1.6, 1.9, and 1.4 times greater during intraportal than peripheral delivery at the respective rate (P < 0.05). There was an approximately linear relationship between HGL and portal insulin levels in either delivery (Po r = 0.92; Pe r = 0.91).

NHGB. As illustrated in Fig. 2, bottom, there was a great difference in NHGB, net release, or net uptake, according to the delivery routes. As shown on the left, as soon as glucose was delivered into the portal vein, the liver switched from net glucose release to net consumption of glucose. NHGU attained the earlier and higher maximum with increasing doses [20.6 ± 8.3 (tmax = 2 min); -39.4 ± 3.3 (2 min); and -70.0 ± 7.8 µmol · kg-1 · min-1 (20 min), respectively]. Mean NHGU increased with increasing rates (P < 0.05). The latter corresponded to 46, 53, and 59% of the intraportally infused glucose (Table 5). In contrast, as shown in Fig. 2, bottom right, when glucose was given peripherally, the liver ceased gradually to release glucose by 30 min and removed only negligible amounts of glucose thereafter, if at all.

                              
View this table:
[in this window]
[in a new window]
 
Table 5.   Comparion of hepatic and nonhepatic glucose uptake between portal and peripheral delivery

Relationship between NHGB and HGL. Figure 3 depicts a linear relationship between mean AUCs of NHGU and HGL over 120 min during glucose delivery at the respective rates in either delivery route (Po r = -0.99, P < 0.01; and Pe r = -0.95, P < 0.01). When the line relating them was extrapolated to the HGL axis, it intersected at 103 and 228 mmol · kg-1 · min-1 in portal and peripheral delivery, respectively. These HGL values corresponded to 3.8 and 11.7 mmol/l for plasma glucose levels. The slope of the regression line was three times larger in portal than in peripheral delivery (0.21 vs. 0.07, P < 0.05). NHFEG, the ratio of NHGU to HGL, immediately reached maximum and sustained the level thereafter during intraportal glucose infusion. Mean AUCs of NHFEG were 11.5 ± 0.4, 11.0 ± 1.1, and 15.6 ± 1.5% at the corresponding rates.


View larger version (19K):
[in this window]
[in a new window]
 
Fig. 3.   Relationship between mean net hepatic glucose balance and hepatic glucose load over 120 min during intraportal and peripheral glucose infusion at the rate of 39, 56, or 83 µmol · kg-1 · min-1. Data represent means ± SE for each group of 6 dogs. r, Correlation coefficient.

Relationship between NHGB and plasma insulin level. As illustrated in Fig. 4, an approximately linear relationship was also achieved between mean NHGB and plasma insulin levels over 120 min during portal and peripheral delivery at the respective rates (Pe r = 0.76, P < 0.05; Po r = 0.99, P < 0.01). The intercepts of the regression line on the insulin axis were 392 and 65 pmol/l during portal and peripheral delivery, respectively. Thus the threshold insulin value for hepatic glucose uptake in portal delivery was one-sixth that in peripheral delivery. The slope of the regression line of NHGB against insulin axis was about four times larger in portal than in peripheral delivery (Po 0.19 vs. Pe 0.044). A similar linear relationship was also observed between NHGB and portal insulin levels in either delivery (Po r = 0.99; Pe r = 0.98).


View larger version (19K):
[in this window]
[in a new window]
 
Fig. 4.   Relationship between mean net hepatic glucose balance and arterial plasma insulin concentration over 120 min during intraportal and peripheral glucose infusion at the rate of 39, 56, or 83 µmol · kg-1 · min-1. Data represent means ± SE for each group of 6 dogs.

Relationship between NHGB and arterial-portal glucose gradient. As shown in Fig. 5, a linear relationship was observed between mean NHGU and negative arterial-portal glucose gradients over 120 min during glucose delivery at each rate in either delivery route (Po r = 0.98, Pe r = 0.99). NHGU was negligible at positive arterial-portal glucose gradients during peripheral glucose load.


View larger version (22K):
[in this window]
[in a new window]
 
Fig. 5.   Relationship between mean net hepatic glucose balance and arterial-portal glucose gradients over 120 min during intraportal and peripheral glucose infusion at the rate of 39, 56, or 83 µmol · kg-1 · min-1. Data represent means ± SE for each group of 6 dogs.

Relationship between NHGU and nonhepatic glucose uptake. Table 5 shows the comparison of mean NHGU and nonhepatic glucose uptake over 120 min during portal glucose delivery at each rate. Contrary to NHGU, nonhepatic glucose uptake decreased dose dependently. As a consequence, nonhepatic glucose uptake was smaller than NHGU except for the low dose.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In this study, we show approximately linear relationships between mean NHGB and HGL over 120 min during glucose delivery at the respective rates via either route (Fig. 3). The regression line indicates that the threshold of plasma glucose for hepatic glucose uptake was largely at basal level for portal delivery, whereas it was over twice the basal level for peripheral delivery, and the slope of the regression line was about four times larger in portal than in peripheral delivery. Thus the portal signal appears to open the slope and overrule the glucose threshold for hepatic glucose uptake. In other words, the liver removes glucose newly entering the portal vein by raising the rate of glucose extraction by the portal signal. The correlation coefficient appeared to be similar in either route to those reported in the clamp study by Myers et al. (14). During peripheral infusion, the threshold and the slope were comparable in both studies. This means that the low slope may be a proper nature of peripheral delivery and is not limited to hepatic glucose output. During portal delivery, the threshold of plasma glucose was at nearly basal level in both studies, but the slope was four times larger in our study. With these results taken together, we believe that the portal signal is operative more sensitively in a nonsteady hyperglycemic state than in a hyperglycemic hyperinsulinemic clamp state if the portal signal was represented as the degree of the angle. In general, NHFEG (NHGU/HGL) is used as a measure of hepatic glucose extraction. The observed mean NHFEG values (11.0-15.6%) were comparable to those reported by Galassetti et al. (8), Horikawa et al. (9), and Moore et al. (12). However, our study indicates that NHGU can be expressed as such a linear equation of HGL with an intercept that NHFEG is inappropriate to evaluate hepatic extraction rate.

Mean NHGU over a 120-min glucose delivery was linearly related to mean plasma insulin level during glucose delivery at the respective rate in either delivery route (r = 0.99; Fig. 4). However, there was a great difference in the intercepts and the slopes: the threshold insulin level for NHGU in portal delivery was one-sixth that of peripheral delivery, whereas the slope against the insulin axis was four times that of peripheral delivery. Thus no hepatic glucose uptake was promoted at mean arterial insulin levels of 380 pmol/l during peripheral glucose delivery. This result suggests that plasma insulin plays a minor role in hepatic glucose uptake relative to HGL. However tightly associated arterial-portal glucose gradients are with the increases in HGL and plasma insulin level, from the result described above it was difficult to dissociate effects of one from the other in our preparation.

It remains uncertain whether negative arterial-portal glucose gradients are a cause or a consequence of the portal signal. In this study, an approximately linear relationship was observed between mean NHGU and negative arterial-portal glucose gradients at the particular rates (Fig. 5). This result partly argues against the study of Pagliassotti et al. (16). Those authors showed that NHGU was raised with increasing arterial-portal glucose gradient but was saturated when the gradient was >0.8 mmol/l in the presence of fixed hepatic glucose and insulin load. Therefore, combined peripheral glucose administration with portal delivery is likely to affect the linear relationship between NHGU and arterial-portal glucose gradient.

Plasma glucose concentrations plateaued during peripheral delivery, whereas they declined during portal glucose delivery at the high dose, although plasma insulin continued to increase similarly in either delivery (Fig. 1). The plasma glucose profile may be the consequence of changes in HGL, NHGB, and/or nonhepatic glucose uptake. NHGU was negligible, and nonhepatic glucose uptake was equated with glucose delivery rates during peripheral delivery (Table 5). As a result, plasma glucose levels would have been equilibrated. On the other hand, plasma glucose level and HGL began to decrease 60 min after the commencement of portal glucose delivery (Figs. 1 and 2). Mean NHGU occupied ~60% of the glucose infusion rate during portal glucose infusion and overestimated nonhepatic glucose uptake was as low as ~40% of peripheral glucose infusion (Table 5). Together, the increase in hepatic glucose uptake and hepatic glycogen synthesis may have resulted in the decline in plasma glucose level with increasing plasma insulin level during portal delivery. However, it remains unclear why the plasma insulin level tends to rise despite the decline in plasma glucose.

We conclude that the portal signal operates more sensitively in a nonsteady hyperglycemic state than in a hyperglycemic hyperinsulinemic state, because it obliterates the glucose threshold for NHGU by increasing the rate of hepatic glucose extraction.


    ACKNOWLEDGEMENTS

We gratefully acknowledge Prof. E. Cerasi for careful reading of the manuscript and for helpful comments. We also express our sincere gratitude to K. Goshima for expert technical assistance and S. Abe for the scrupulous care of animals. We are also grateful to K. Honjo for linguistic consultation.


    FOOTNOTES

Address for reprint requests and other correspondence: M. Kikuchi, Dept. of Endocrinology and Metabolism, Institute for Adult Diseases, Asahi Life Foundation, 1-9-14, Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan (E-mail: m-kikuchi{at}asahi-life.or.jp).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

September 11, 2002;10.1152/ajpendo.00079.2002

Received 25 February 2002; accepted in final form 5 September 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Adkins, BA, Myers SR, Hendrick GK, Stevenson RW, Williams PE, and Cherrington AD. Importance of the route of intravenous glucose delivery to hepatic glucose balance in the conscious dog. J Clin Invest 79: 557-565, 1987[ISI][Medline].

2.   Adkins-Marshall, BA, Myers SR, Hendrick GK, Williams PE, Triebwasser K, Floyd B, and Cherrington AD. Interaction between insulin and glucose-delivery route in regulation of net hepatic glucose uptake in conscious dog. Diabetes 39: 87-95, 1990[Abstract].

3.   Alzaid, AA, Dinneen SF, Turk DJ, Caumo A, Cobelli C, and Rizza RA. Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans. J Clin Invest 94: 2341-2348, 1994[ISI][Medline].

4.   Bruttomesso, D, Pianta A, Mari A, Valerio A, Marescotti M-C, Avogaro A, Tiengo A, and Del Prato S. Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients. Diabetes 48: 99-105, 1999[Abstract].

5.   Burcelin, R, Dolci W, and Thorens B. Portal glucose infusion in the mouse induces hypoglycemia. Evidence that the hepatoportal glucose sensor stimulates glucose utilization. Diabetes 49: 1635-1642, 2000[Abstract].

6.   DeFronzo, RA, Ferrannini E, Hendler R, Wahren J, and Felig P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA 75: 5173-5177, 1978[Abstract].

7.   Doeden, B, and Rizza R. Use of variable insulin infusion to assess insulin action in obesity: defects in both the kinetics and amplitude of response. J Clin Endocrinol Metab 64: 902-908, 1987[Abstract].

8.   Galassetti, P, Shiota M, Zinker BA, Wasserman DH, and Cherrington AD. A negative arterial-portal venous glucose gradient decreases skeletal muscle glucose uptake. Am J Physiol Endocrinol Metab 275: E101-E111, 1998[Abstract/Free Full Text].

9.   Horikawa, S, Ishida T, Igawa K, Kawanishi K, Hartley CJ, and Takahara J. Both positive and negative portal venous and hepatic arterial glucose gradients stimulate hepatic glucose uptake after the same amount of glucose is infused into the splanchnic bed in conscious dogs. Metabolism 47: 1295-1302, 1998[ISI][Medline].

10.   Kikuchi, M. Modulation of insulin secretion in non-insulin-dependent diabetes mellitus by two novel oral hypoglycemic agents, NN623 and A4166. Diabet Med 13: S151-S155, 1996[ISI][Medline].

11.   Mathews, DR, Naylor BA, Jones RG, Ward GM, and Turner RC. Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes 32: 617-621, 1983[Abstract].

12.   Moore, MC, Cherrington AD, Cline G, Pagliassotti MJ, Jones EM, Neal DW, Badet C, and Shulman GI. Sources of carbon for hepatic glycogen synthesis in the conscious dog. J Clin Invest 88: 578-587, 1991[ISI][Medline].

13.   Moore, MC, Hsien P-S, Neal DW, and Cherrington AD. Nonhepatic response to portal glucose delivery in conscious dogs. Am J Physiol Endocrinol Metab 279: E1271-E1277, 2000[Abstract/Free Full Text].

14.   Myers, SR, Biggers DW, Neal DW, and Cherrington AD. Intraportal glucose delivery enhances the effects of hepatic glucose load on net hepatic glucose uptake in vivo. J Clin Invest 88: 158-167, 1991[ISI][Medline].

15.   Myers, SR, McGuinness OP, Neal DW, and Cherrington AD. Intraportal glucose delivery alters the relationship between net hepatic glucose uptake and the insulin concentration. J Clin Invest 87: 930-939, 1991[ISI][Medline].

16.   Pagliassotti, MJ, Myers SR, Moore MC, Neal DW, and Cherrington AD. Magnitude of negative arterial-portal glucose gradient alters net hepatic glucose balance in conscious dogs. Diabetes 40: 1659-1668, 1991[Abstract].

17.   Paolisso, G, Scheen AJ, Giugliano D, Sgambato S, Albert A, Varricchio M, D'Onofrio F, and Lefebvre PJ. Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency. J Clin Endocrinol Metab 72: 607-615, 1991[Abstract].


Am J Physiol Endocrinol Metab 284(1):E148-E155
0193-1849/03 $5.00 Copyright © 2003 the American Physiological Society