1 Departments of Physiology and 2 Medicine, and 3 Division of Comparative Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and 4 Department of Medicine, Juntendo University, Tokyo 113-0033, Japan
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ABSTRACT |
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In our previous studies in nondiabetic
dogs and humans, insulin suppressed glucose production (GP) by both an
indirect extrahepatic and a direct hepatic effect. However, insulin had
no direct effect on GP in diabetic depancreatized dogs under conditions
of moderate hyperglycemia. The present study was designed to
investigate whether insulin can inhibit GP by a direct effect in this
model under conditions of euglycemia. Depancreatized dogs were made
euglycemic (~6 mmol/l), rather than moderately hyperglycemic (~10
mmol/l) as in our previous studies, by basal portal insulin infusion. After ~100 min of euglycemia, a hyperinsulinemic euglycemic clamp was
performed by giving an additional infusion of insulin either portally
(POR) or peripherally at about one-half the rate (1/2 PER) to match the
peripheral venous insulin concentrations. The greater hepatic insulin
load in POR resulted in greater suppression of GP (from 16.5 ± 1.8 to 12.2 ± 1.6 µmol · kg1 · min
1)
than 1/2 PER (from 17.8 ± 1.9 to 15.6 ± 2.0 µmol · kg
1 · min
1,
P < 0.001 vs. POR), consistent with insulin having a
direct hepatic effect in suppressing GP. We conclude that the direct effect of insulin to inhibit GP is present in diabetic depancreatized dogs under conditions of acutely induced euglycemia. These results suggest that, in diabetes, the prevailing glycemic level is a determinant of the balance between insulin's direct and indirect effects on GP.
peripheral and hepatic effects of insulin; direct and indirect effects of insulin; hyperglycemia; free fatty acids
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INTRODUCTION |
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INSULIN HAS A STRONG INHIBITORY EFFECT on glucose production (GP). This inhibition is in part direct, i.e., due to hepatic sinusoidal insulin's interaction with the hepatocyte insulin receptor (18, 19, 28, 29, 31, 32), and in part indirect, due to peripheral insulin's actions on extrahepatic tissues (1, 18, 19, 23, 28, 29, 31, 32). These actions consist mainly of the antilipolytic effect of insulin in the adipose tissue (16, 17, 24, 25, 30). In nondiabetic animals and humans, the importance of either the direct or the indirect regulation of GP by insulin has been differently emphasized (2, 4). Undoubtedly, however, under normal physiological conditions, the impact on GP of even a small direct effect of insulin is magnified by the greater hepatic than peripheral insulinization.
Individuals with type 1 diabetes are treated with subcutaneous injections of insulin, which result in peripheral absorption of insulin and thus a level of hepatic insulinization that is not greater than peripheral insulinization. To the extent that the direct effect of insulin plays a role in the suppression of GP, peripheral hyperinsulinemia should be required to elevate the hepatic sinusoidal levels to adequately suppress GP. Because hyperinsulinemia has been associated with atherosclerosis (27) and recently also with some types of cancer (11), it is important to determine whether the nonphysiological route of insulin administration can contribute to hyperinsulinemia in diabetes.
However, GP may be differently regulated by hepatic and peripheral insulin effects in nondiabetic vs. diabetic individuals. In moderately hyperglycemic depancreatized dogs, we could not detect any direct effect of insulin, as we found that suppression of GP was proportional to peripheral, but not hepatic, insulin load at both high physiological and low insulin levels (9, 10). In humans with type 2 diabetes and moderate hyperglycemia, we found that the direct effect of insulin on steady-state GP was also undetectable (14).
The lack of a direct effect of insulin on suppression of GP in diabetic dogs and humans may be due to hyperglycemia and/or to chronic effects of the diabetic state. The aim of the present study was to determine whether, with correction of hyperglycemia, we would be able to detect a direct effect of insulin on GP in depancreatized dogs, similar to nondiabetic dogs.
We studied depancreatized dogs in which euglycemia (~6 mmol/l) was acutely induced by basal portal insulin replacement, and we performed a hyperinsulinemic euglycemic clamp by giving an additional infusion of insulin either portally (POR) or peripherally at approximately one-half the rate (1/2 PER) to match the peripheral insulin levels, assuming that hepatic insulin extraction was ~50%. Our hypothesis was that POR would have suppressed GP to a greater extent than 1/2 PER.
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MATERIALS AND METHODS |
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Experimental animals and preparation. The animal model and preparation were the same as in our previous studies (9, 10). All procedures were in accordance with the Canadian Council of Animal Care Standards and were approved by the Animal Care Committee of the University of Toronto. The studies were performed on six postabsorptive, depancreatized male dogs (model of type 1 diabetes mellitus) weighing 25-35 kg. Before surgery, atropine (0.02 mg/kg) and acepromazine (0.1 mg/kg) were administered to prevent throat secretions and to sedate the animal, respectively. After general anesthesia was induced by an intravenous dose of sodium thiopental (25 mg/kg), the dogs were intubated for assisted ventilation. Anesthesia was maintained through 0.5% halothane in carrier gas consisting of 60% nitric oxide (Canox, Toronto, ON, Canada) and 40% oxygen (Canox).
The abdominal cavity was opened with a midline laparotomy. The pancreas was completely removed, and care was taken to preserve duodenal vascularization through the pancreatoduodenal vessels. In all dogs, a Silastic cannula (0.05 in. ID, Baxter Healthcare, McGaw Park, IL) was inserted into the portal vein through a branch of the splenic vein and advanced until the tip was ~1.0 cm beyond the point of confluence of the splenic vein with the portal vein, i.e., ~5 cm from the branching point of the portal vein into its left and right bifurcations to the liver. Three Silastic cannulas (one 0.05 in. ID and two 0.03 in. ID) were inserted into the jugular vein and advanced into the superior vena cava. In addition, a Silastic cannula (0.05 in. ID) was inserted into the carotid artery and advanced into the aortic arch. The carotid cannula served for arterial sampling, and the jugular and portal cannulas served for infusions. The cannulas were tunneled subcutaneously and exteriorized at the back of the neck. They were filled with heparin (1,000 U/ml Hepalean; Organon Teknika, Ontario, Canada) and bandaged around the dog's neck. An analgesic (buprenorphine) was administered intravenously during the surgery and intramuscularly after surgery (0.02 mg/kg). In addition, a small dose of NPH insulin (Iletin II NPH insulin; Eli Lilly, Indianapolis, IN) was injected subcutaneously to regulate glycemia. The cannulas were regularly flushed (every 3-4 days) with saline and filled with heparin to maintain patency. The dogs received a mixture of dry chow mixed with canned meat once a day. The food was supplemented with folic acid and iron. In addition, pancreatic enzymes (Cotazym; Organon Canada, Toronto, ON, Canada) were given orally to replace the lost exocrine function of the pancreas. Regular porcine (Iletin II regular insulin; Eli Lilly) and NPH porcine insulin were injected subcutaneously. The insulin dose was adjusted to maintain glycosuria <1%, as in our previous studies (9, 10). Body weight, body temperature, hematocrit, stools, and food intake were monitored regularly. Paired experiments were carried out in random orderExperimental protocol.
On the morning of the experiment (Fig.
1), the dogs were hyperglycemic (>20
mmol/l) due to their reduced NPH insulin dose the day before. At the
onset of the experiment, regular porcine insulin was initially infused
intraportally at a high dose. The dose was then gradually reduced to
basal levels with the goal of obtaining constant euglycemia (5-7
mmol/l in dogs). When glucose levels decreased below 16 mmol/l (i.e.,
~80 min after the insulin infusion was started), a bolus of tracer
(7.77 × 107 dpm of [3-3H]glucose; New
England Nuclear, Boston, MA) followed by a continuous tracer infusion
(5.55 × 105 dpm/min) was given to enable the
measurements of GP and glucose utilization (GU).
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Laboratory methods.
Plasma glucose concentrations were measured by the glucose oxidase
method (13) on a glucose analyzer (Glucose Analyzer II; Beckman Instruments, Fullerton, CA). The radioimmunoassays for insulin
and glucagon were performed using kits from Pharmacia and Diagnostic
Products, respectively. The coefficients of variation of the assays are
<7 and <16%, respectively. The FFA concentrations were determined
with the fluorometric method of Miles et al. (20). For
determination of [3-3H]glucose radioactivity, plasma was
deproteinized in equal volumes of 5% (wt/vol) zinc sulfate and 0.3 N
barium hydroxide (BDH; Sigma Diagnostics, St. Louis, MO). An
aliquot of the supernatant was evaporated to dryness to eliminate
tritiated water. After addition of 1 ml of double-distilled water, 10 ml of liquid scintillation solution (Ready Safe; Beckman, Fullerton,
CA) were added, the tubes were vortexed, and radioactivity from
[3-3H]glucose was measured in a -scintillation counter
(Camberra Packard, Meriden, CT). Aliquots of the infused glucose tracer and of the labeled glucose infusate were diluted with nonradioactive plasma of the same dog and assayed together with the plasma samples.
Calculations. GP was calculated as the endogenous rate of appearance measured with [3-3H]glucose. A modified one-compartment model of Steele, which accounted for the mixture of labeled and unlabeled glucose infused during the euglycemic clamp, was used to calculate GP and GU (6). Data were smoothed with the optimal segments routine using the optimal error algorithm (3).
We calculated the first-pass hepatic insulin extraction (HIE) of portally delivered insulin using the formula
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Statistical analysis.
The data were expressed as means ± SE. Two-way analysis of
variance (ANOVA) was carried out for differences between experimental groups, as all experiments were paired. Data were also analyzed within
each group for differences between the experimental periods (basal:
from 40 to 0 min; clamp: from 0 to 180 min). Calculations were
performed with SAS software (SAS Statistical Analysis System, Cary, NC)
using "group" and "dog" and "period" and "dog" as
independent variables in the two-way ANOVA models. Significance was
accepted at P < 0.05.
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RESULTS |
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The following results are based on an n = 6 for
POR and 1/2 PER. The portal insulin dose required to maintain
euglycemia was 4.1 ± 1.0 (POR) and 4.2 ± 1.1 pmol · kg1 · min
1
(1/2 PER) [P = not significant (NS)], and the basal
peripheral insulin levels were ~60 pmol/l (also P = NS; Fig. 2A). The additional portal insulin infusion in the POR treatment raised the peripheral insulin levels to ~150 pmol/l, which was not different from the rise
in insulin levels observed with the additional peripheral insulin
infusion in 1/2 PER. The HIE was calculated to be 55.7%.
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The plasma glucose levels were maintained constant (~6 mmol/l) at basal euglycemia (5-7 mmol/l in dogs) (Fig. 2B). Plasma glucose specific activity was also maintained close to the basal levels (Fig. 2C).
The GINF necessary to maintain glycemia constant during the
hyperinsulinemic clamps was significantly greater in POR
(P < 0.001) than in 1/2 PER (Fig.
3A).
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As expected at matched peripheral insulin levels, GU was similar in the basal state and increased to a similar extent in response to insulin (Fig. 3B).
Basal endogenous GP was 16.5 ± 1.8 and 17.8 ± 1.9 µmol · kg1 · min
1
(P = NS) in the POR and 1/2 PER treatments,
respectively. When the additional insulin was given, GP was suppressed
to a level that was much lower (12.2 ± 1.6 µmol · kg
1 · min
1)
in POR than in 1/2 PER (15.6 ± 2.0 µmol · kg
1 · min
1,
P < 0.001 vs. POR; Fig.
4). In fact, with the 1/2 PER treatment, the GP suppression barely reached significance (P < 0.05).
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The basal FFA levels were similar in the POR and 1/2 PER groups. During
the hyperinsulinemic clamps, the FFA levels were suppressed to a
similar extent in both treatments (Table
1). The basal glucagon levels were also
similar in the basal state and during the clamps in both treatments
(Table 1).
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DISCUSSION |
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In this study in euglycemic depancreatized dogs, at matched
peripheral insulin levels, portal insulin infusion (POR treatment) was
more effective than half-rate peripheral insulin infusion (1/2 PER
treatment) in suppressing GP during a hyperinsulinemic clamp,
consistent with our previous findings in normal dogs (19) and humans (18). The 1/2 PER treatment, which only
marginally suppressed GP, resulted in peripheral insulin levels equal
to those of the POR treatment, but the hepatic sinusoidal insulin levels were presumably much lower than those in the POR treatment [50% lower assuming a portal-peripheral gradient of 2.5 (10) and 72% contribution of the portal flow to hepatic
blood flow (12)].
Unlike our previous studies in depancreatized dogs at the same insulin dose (9) but under conditions of moderate hyperglycemia, the GINF rate was significantly greater in the POR treatment compared with the 1/2 PER treatment. GINF is dependent on both GU and GP, and with matched GU this observation indicated that GP was suppressed to a greater extent with POR than with 1/2 PER.
Indeed, unlike the previous study in hyperglycemic dogs, the suppression of GP in the euglycemic dogs was greater with POR than with 1/2 PER. The fact that a greater suppression of GP was found with POR leads to the conclusion that the greater hepatic insulin load in this treatment suppressed GP by a direct effect under conditions of euglycemia.
Because in the present study euglycemia was achieved by increasing the rate of the basal insulin infusion compared with the previous studies in depancreatized dogs when moderate hyperglycemia was achieved (9, 10), we cannot exclude that the higher insulin level itself or some other metabolic parameter that was improved by basal insulin replacement allowed the direct effect of insulin to become manifest. However, in our studies in nondiabetic dogs, the direct effect of insulin was, if anything, less evident at high rather than low insulin levels (19). Also, during the clamp period, glucose was the only parameter that was markedly different from what it was in the previous study when the same additional insulin dose was infused portally or peripherally (9). (Basal and clamp immunoreactive glucagon levels were lower in the present than in the previous study, in part because of the more specific antibody used in the radioimmunoassay; however, even if "true" 3,500-MW glucagon was lower in the present study, this should have diminished rather than potentiated the direct effect of insulin, as explained below.)
Glucose is known to have acute and profound effects on glycogen metabolism by suppressing glycogen phosphorylase and enhancing glycogen synthase activities (22). In in vivo studies by Rossetti et al. (26), hyperglycemia caused a marked inhibition of GP mainly through the suppression of glycogenolysis with no apparent changes in gluconeogenesis. Regarding insulin's effect on GP, Sindelar et al. (28) showed that, acutely, a selective elevation of hepatic sinusoidal insulin also inhibits GP through suppression of glycogenolysis but leaving gluconeogenesis intact. On the basis of the results of the present study, we hypothesize that, with glycogenolysis already maximally suppressed by hyperglycemia, hepatic insulin may not further suppress GP, whereas, with correction of hyperglycemia, glycogenolysis would be restored, allowing for the direct effect of insulin on glycogenolysis to become manifest. This hypothesis is also supported by the results of our studies (8, 15) and those of other authors (21) showing that glucagon, which is a stimulator of glycogenolysis, potentiates the direct effect of insulin.
In the present study, the direct effect of insulin was tested after only 100 min of achievement of euglycemia. The results are therefore consistent with an acute effect of the prevailing glucose level on insulin's direct effect rather than a chronic effect of improved control. An interesting question is whether there is also a chronic effect of the glucose level or of the diabetic state itself on insulin's direct effect in suppressing GP. It is possible that, with tighter glycemic control, hepatic sensitivity to insulin is improved, which could enhance insulin's direct effect on GP. To address this question, the results of the present study should be compared with those from dogs maintained under tighter glycemic control throughout the treatment period. However, in the present study, the difference in GP suppression was comparable to that seen in our previous studies in nondiabetic dogs (19), suggesting that the acute effect of euglycemia may be sufficient to restore insulin's direct effect on GP.
Other interesting questions are whether euglycemia restores insulin's direct effect on GP in type 2 diabetic humans, which is the threshold for hyperglycemia to diminish insulin's direct effect on GP, and whether diabetic and nondiabetic subjects rely mainly on insulin's indirect effect to inhibit GP when glucose levels are in the postprandial range. In our studies in type 2 diabetic humans maintained at their basal glucose levels (~9 mmol/l), the direct effect of insulin on steady-state suppression of GP was abolished; however, insulin still had a detectable direct suppressive effect on GP in the early periods of the clamp (14). The latter discrepancy with the dog data may be related to the 1 mmol/l difference in glycemia, to species difference, and/or to different experimental conditions (tolbutamide stimulation of endogenous insulin secretion in humans).
In summary, the present study shows that, in depancreatized dogs under conditions of basal euglycemia, at matched peripheral insulin levels, portal insulin infusion is more effective than half-rate peripheral insulin infusion in suppressing GP during a euglycemic clamp. This clearly indicates that the greater hepatic insulinization with portal insulin delivery has a direct effect of inhibiting GP. These results were obtained after only 100 min of euglycemia, which suggests that acute insulin-induced normalization of the prevailing plasma glucose level is capable of restoring insulin's direct effect on GP and therefore that hyperglycemia, rather than chronic effects of diabetic state, abolishes insulin's direct effect on GP in diabetic depancreatized dogs.
In conclusion, we have shown for the first time that the direct effect of insulin in suppressing GP is present in a model of type 1 diabetes under conditions of acutely induced euglycemia. These results have clinical implications, because if insulin had no direct effect on GP under any conditions in diabetes, peripheral insulin treatment of diabetic individuals would not result in peripheral hyperinsulinemia. Instead, our studies are consistent with the notion that deficiency of this direct effect due to hepatic hypoinsulinization during peripheral insulin delivery can account, in part, for the peripheral hyperinsulinemia of insulin-treated diabetes (hyperinsulinemia in this condition may also be due to insulin resistance). Because hyperinsulinemia has been associated with atherosclerosis (27) and recently also with some types of cancer (11) and because portal insulin delivery has the potential of normalizing plasma glucose levels while minimizing hyperinsulinemia, further investigation aimed at producing safe and relatively noninvasive portal insulin delivery systems appears to be justified.
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ACKNOWLEDGEMENTS |
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We thank L. Lam for excellent technical assistance.
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FOOTNOTES |
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* N. Gupta and H. Sandhu contributed equally to this article.
This study was supported by a grant to A. Giacca from the Canadian Diabetes Association. Support for personnel was also provided by the Medical Research Council of Canada and the Heart and Stroke Foundation of Canada.
Address for reprint requests and other correspondence: A. Giacca, Dept. of Physiology, Univ. of Toronto, Medical Sciences Bldg., Rm. 3363, Toronto, ON M5S 1A8, Canada (E-mail: adria.giacca{at}utoronto.ca).
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.
10.1152/ajpendo.00091.2002
Received 1 March 2002; accepted in final form 23 July 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ader, M,
and
Bergman RN.
Peripheral effects of insulin dominate suppression of fasting hepatic glucose production.
Am J Physiol Endocrinol Metab
258:
E1020-E1032,
1990
2.
Bergman, RN.
Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein?
Diabetologia
43:
946-952,
2000[ISI][Medline].
3.
Bradley, DC,
Steil GM,
and
Bergman RN.
Quantitation of measurement error with optimal segments: basis for adaptive time course smoothing.
Am J Physiol Endocrinol Metab
264:
E902-E911,
1993
4.
Cherrington, AD,
Edgerton D,
and
Sindelar DK.
The direct and indirect effects of insulin on hepatic glucose production in vivo.
Diabetologia
41:
987-996,
1998[ISI][Medline].
5.
DeBodo, RC,
Steele R,
Alszuler N,
Dunn A,
and
Bishop JS.
On the hormonal regulation of carbohydrate metabolism: studies with 14C glucose.
Recent Prog Horm Res
19:
445-488,
1963[ISI].
6.
Finegood, DT,
Bergman RN,
and
Vranic M.
Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates.
Diabetes
36:
914-924,
1987[Abstract].
7.
Finegood, DT,
Bergman RN,
and
Vranic M.
Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps.
Diabetes
37:
1025-1034,
1988[Abstract].
8.
Giacca, A,
Fisher SJ,
McCall RH,
Shi ZQ,
and
Vranic M.
Direct and indirect effects of insulin in suppressing glucose production in depancreatized dogs: role of glucagon.
Endocrinology
138:
999-1007,
1997
9.
Giacca, A,
Fisher SJ,
Shi ZQ,
Gupta R,
Lickley HL,
and
Vranic M.
Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.
J Clin Invest
90:
1769-1777,
1992[ISI][Medline].
10.
Giacca, A,
McCall R,
Chan B,
and
Shi ZQ.
Increased dependence of glucose production on peripheral insulin in diabetic depancreatized dogs.
Metabolism
48:
153-160,
1999[ISI][Medline].
11.
Giovannucci, E.
Insulin, insulin-like growth factors and colon cancer: a review of the evidence.
J Nutr
131:
3109S-3120S,
2001
12.
Greenway, CV,
and
Stark RD.
Hepatic vascular bed.
Physiol Rev
51:
23-65,
1971
13.
Kadish, AH,
and
Sternberg JC.
Determination of urine glucose by measurement of rate of oxygen consumption.
Diabetes
18:
467-470,
1969[ISI][Medline].
14.
Lewis, GF,
Carpentier A,
Vranic M,
and
Giacca A.
Resistance to insulin's acute direct hepatic effect in suppressing steady-state glucose production in individuals with type 2 diabetes.
Diabetes
48:
570-576,
1999[Abstract].
15.
Lewis, GF,
Vranic M,
and
Giacca A.
Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans.
Am J Physiol Endocrinol Metab
272:
E371-E378,
1997
16.
Lewis, GF,
Vranic M,
and
Giacca A.
Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans.
Am J Physiol Endocrinol Metab
275:
E177-E186,
1998
17.
Lewis, GF,
Vranic M,
Harley P,
and
Giacca A.
Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans.
Diabetes
46:
1111-1119,
1997[Abstract].
18.
Lewis, GF,
Zinman B,
Groenewoud Y,
Vranic M,
and
Giacca A.
Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans.
Diabetes
45:
454-462,
1996[Abstract].
19.
McCall, RH,
Wiesenthal SR,
Shi ZQ,
Polonsky K,
and
Giacca A.
Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs.
Am J Physiol Endocrinol Metab
274:
E346-E356,
1998
20.
Miles, J,
Glasscock R,
Aikens J,
Gerich J,
and
Haymond M.
A microfluorometric method for the determination of free fatty acids in plasma.
J Lipid Res
24:
96-99,
1983[Abstract].
21.
Mittelman, SD,
Fu YY,
Rebrin K,
Steil G,
and
Bergman RN.
Indirect effect of insulin to suppress endogenous glucose production is dominant, even with hyperglucagonemia.
J Clin Invest
100:
3121-3130,
1997
22.
Newgard, CB,
Brady MJ,
O'Doherty RM,
and
Saltiel AR.
Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1.
Diabetes
49:
1967-1977,
2000[Abstract].
23.
Prager, R,
Wallace P,
and
Olefsky JM.
Direct and indirect effects of insulin to inhibit hepatic glucose output in obese subjects.
Diabetes
36:
607-611,
1987[Abstract].
24.
Rebrin, K,
Steil GM,
Getty L,
and
Bergman RN.
Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin.
Diabetes
44:
1038-1045,
1995[Abstract].
25.
Rebrin, K,
Steil GM,
Mittelman SD,
and
Bergman RN.
Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs.
J Clin Invest
98:
741-749,
1996
26.
Rossetti, L,
Giaccari A,
Barzilai N,
Howard K,
Sebel G,
and
Hu M.
Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes.
J Clin Invest
92:
1126-1134,
1993[ISI][Medline].
27.
Ruige, JB,
Assendelft WJ,
Dekker JM,
Kostense PJ,
Heine RJ,
and
Bouter LM.
Insulin and risk of cardiovascular disease: a meta-analysis.
Circulation
97:
996-1001,
1998
28.
Sindelar, DK,
Balcom JH,
Chu CA,
Neal DW,
and
Cherrington AD.
A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog.
Diabetes
45:
1594-1604,
1996[Abstract].
29.
Sindelar, DK,
Chu CA,
Neal DW,
and
Cherrington AD.
Interaction of equal increments in arterial and portal vein insulin on hepatic glucose production in the dog.
Am J Physiol Endocrinol Metab
273:
E972-E980,
1997
30.
Sindelar, DK,
Chu CA,
Rohlie M,
Neal DW,
Swift LL,
and
Cherrington AD.
The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog.
Diabetes
46:
187-196,
1997[Abstract].
31.
Sindelar, DK,
Chu CA,
Venson P,
Donahue EP,
Neal DW,
and
Cherrington AD.
Basal hepatic glucose production is regulated by the portal vein insulin concentration.
Diabetes
47:
523-529,
1998[Abstract].
32.
Staehr, P,
Hother-Nielsen O,
Levin K,
Holst JJ,
and
Beck-Nielsen H.
Assessment of hepatic insulin action in obese type 2 diabetic patients.
Diabetes
50:
1363-1370,
2001