Rapid reversal of the effects of the portal signal under hyperinsulinemic conditions in the conscious dog

Hsieh, Po‐Shiuan; Moore, Mary Courtney; Neal, Doss W.; Emshwiller, Maya; Cherrington, Alan D.

doi:10.1152/ajpendo.1999.276.5.e930

Cited by 22 publications

(27 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In response to a hyperglycemic, hyperinsulinemic challenge, the liver reacts by switching from net glucose output to net uptake. Previous studies have demonstrated that activation of the portal signal by portally administered glucose in combination with hyperinsulinemia results in hepatic glucose uptake of 4 -5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 (8). Thus, the hepatic response in the IVC group was predictable, with nearly 5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 of glucose taken up at 30 min.…”

mentioning

confidence: 89%

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

et al. 2005

Self Cite

View full text Add to dashboard Cite

The results of the present study, using the conscious beagle dog, demonstrate that inhaled insulin (INH; Exubera) provides better glycemic control during an intraportal glucose load than identical insulin levels induced by insulin (Humulin) infusion into the inferior vena cava (IVC). In the INH group (n ‫؍‬ 13), portal glucose infusion caused arterial plasma glucose to rise transiently (152 ؎ 9 mg/dl), before it returned to baseline (65 min) for the next 2 h. Net hepatic glucose uptake was minimal, whereas nonhepatic uptake rose to 12.5 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 (65 min). In the IVC group (n ‫؍‬ 9), arterial glucose rose rapidly (172 ؎ 6 mg/dl) and transiently fell to 135 ؎ 13 mg/dl (65 min) before returning to 165 ؎ 15 mg/dl (125 min). Plasma glucose excursions and hepatic glucose uptake were much greater in the IVC group, whereas nonhepatic uptake was markedly less (8.6 ؎ 0.9 mg ⅐ kg ؊1 ⅐ min ؊1 ; 65 min). Insulin kinetics and areas under the curve were identical in both groups. These data suggest that inhalation of Exubera results in a unique action on nonhepatic glucose clearance. Diabetes 54:1164 -1170, 2005 I nsulin delivered by inhalation is an alternative to injected insulin for patients with diabetes. Clinical studies comparing subcutaneous administration of insulin (Humulin) with insulin inhalation (Exubera) suggest that there is a unique glucose-lowering effect associated with inhaled insulin (1). Previous studies in dogs have shown that inhaled insulin has a higher and earlier peak of arterial insulin that clears more rapidly than subcutaneous insulin. Despite the similar arterial and hepatic insulin areas under the curve (AUCs) in the two groups, a 20% greater glucose infusion rate was required to maintain euglycemia in the inhaled insulin group relative to the subcutaneous insulin group (2). This finding was consistent with the unique glucose-lowering effect of inhaled insulin seen in human studies.The difference in glycemic control resulting from inhalation verses subcutaneous administration of insulin could be explained by the different pharmacokinetic insulin profiles resulting from the two routes of administration, or by some unique aspect of insulin delivery by inhalation. To distinguish between these possibilities, we delivered insulin by inhalation (Exubera) or through infusion (Humulin) into the inferior vena cava (IVC) to create an identical pharmacokinetic profile to that resulting from insulin inhalation. We then examined the effects of both routes of insulin delivery on glucose disposal during a simulated oral glucose load. To further clarify the mechanism by which glucose disposal might be enhanced, we compared the role of the liver and nonhepatic tissues in glucose uptake. RESEARCH DESIGN AND METHODSExperiments were conducted on 22 healthy, conscious, 18-h-fasted, male beagle dogs (weight 8 -10 kg). Before the study, they were fed a standard diet once a day, and water was provided ad libitum. The surgical facility met the standards published by the American Association for the Accredi...

show abstract

mentioning

confidence: 89%

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…A potential benefit of the enteral route is that when only glucose is delivered via the enteral route in the acute setting it enhances net hepatic glucose uptake (NHGU) to a greater extent than when glucose is delivered via a peripheral route; this route-dependent effect has been termed the "portal signal" (7,20). The portal signal can rapidly (Ͻ15 min) augment NHGU; it does not require the presence of hyperglycemia or hyperinsulinemia (11). Surprisingly, when TEN is administered chronically in unstressed animals, which should activate the portal signal, NHGU is not any greater than that seen with TPN alone (1).…”

mentioning

confidence: 99%

Route-dependent effect of nutritional support on liver glucose uptake

Chen¹,

Torres-Sanchez²,

Hosein³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

The liver is a major site of glucose disposal during chronic (5 day) total parenteral (TPN) and enteral (TEN) nutrition. Net hepatic glucose uptake (NHGU) is dependent on the route of delivery when only glucose is delivered acutely; however, the hepatic response to chronic TPN and TEN is very similar. We aimed to determine whether the route of nutrient delivery altered the acute (first 8 h) response of the liver and whether chronic enteral delivery of glucose alone could augment the adaptive response to TPN. Chronically catheterized conscious dogs received either TPN or TEN containing glucose, Intralipid, and Travasol for either 8 h or 5 days. Another group received TPN for 5 days, but ϳ50% of the glucose in the nutrition was given via the enteral route (TPNϩEG). Hepatic metabolism was assessed with tracer and arteriovenous difference techniques. In the presence of similar arterial plasma glucose levels (ϳ6 mM), NHGU and net hepatic lactate release increased approximately twofold between 8 h and 5 days in TPN and TEN. NHGU (26 Ϯ 1 vs. 23 Ϯ 3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and net hepatic lactate release (44 Ϯ 1 vs. 34 Ϯ 6 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in TPNϩEG were similar to results for TPN, despite lower insulin levels (96 Ϯ 6 vs. 58 Ϯ 16 pM, TPN vs. TPNϩEG). TEN does not acutely enhance NHGU or disposition above that seen with TPN. However, partial delivery of enteral glucose is effective in decreasing the insulin requirement during chronic TPN.intestine; glycogen IN STRESSED STATES (trauma, injury, or infection) nutritional support is often provided to patients either via the parenteral (TPN) or enteral (TEN) route. Prior studies suggest that when the nutrition (either TPN or TEN) is given continuously for 5 days liver glucose uptake is markedly augmented; the liver removes ϳ45% of the exogenous glucose (1). Even more surprisingly, substantial liver glucose uptake occurred in the absence of hyperglycemia (ϳ6.7 mmol/l) and in only mild hyperinsulinemia (102 pmol/l) (1). Recently, our group (3) observed that the enhancement in the capacity of the liver to take up glucose (i.e., adaptive response) begins within 5 h after initiation of TPN and is nearly fully manifest by 24 h.The enteral route is the preferred route for delivery of exogenous nutrients (12,14). In postsurgical and stressed patients, isocaloric enteral nutrition can be given without significant accompanying hyperglycemia (22, 23) compared with that shown with TPN. A potential benefit of the enteral route is that when only glucose is delivered via the enteral route in the acute setting it enhances net hepatic glucose uptake (NHGU) to a greater extent than when glucose is delivered via a peripheral route; this route-dependent effect has been termed the "portal signal" (7,20). The portal signal can rapidly (Ͻ15 min) augment NHGU; it does not require the presence of hyperglycemia or hyperinsulinemia (11). Surprisingly, when TEN is administered chronically in unstressed animals, which should activate the portal signal, NHGU is not any greater than that seen with TPN...

show abstract

“…However, it has vasoactive effects in skeletal muscle in vivo, causing the channeling of blood away from the vessels supplying oxygen and nutrients to skeletal muscle ("nutritive flow") and into other vessels (those supplying connective tissue and associated adipocytes, creating "nonnutritive flow") and reducing muscle and hindlimb nutrient uptake (8,30). Finally, it is worth noting that our laboratory (1,17,18) has previously observed a reciprocal relationship between hepatic and peripheral glucose uptake, such that when NHGU is stimulated by the presence of the "portal signal," there is a concomitant decrease in non-HGU. Thus the presence of an integrated mechanism for partitioning glucose disposal among the tissues in the postprandial state may explain the tendency toward suppression of non-HGU concomitant with stimulation of NHGU in the FLUV group.…”

Section: Discussionmentioning

confidence: 98%

“…During the 1st h of glucose infusion, the non-HGU was corrected for the glucose required to fill the pool, using a pool fraction of 0.65 (9) and assuming that the volume of distribution for glucose equaled the volume of the extracellular fluid or ϳ22% of the dog's weight (32). For all glucose balance calculations, glucose concentrations were converted from plasma to blood values by using correction factors (ratio of the blood to the plasma concentration), as previously established in our laboratory (17,18,27).…”

Section: Methodsmentioning

confidence: 99%

Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Moore

DiCostanzo

Dardevet

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs. Am J Physiol Endocrinol Metab 287: E1057-E1063, 2004. First published August 17, 2004 doi:10.1152/ajpendo.00313.2004.-Intraportal delivery of serotonin enhanced net hepatic glucose uptake (NHGU) during a hyperinsulinemic hyperglycemic clamp, but serotonin elevated catecholamines and can cause gastrointestinal distress. We hypothesized that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine would enhance NHGU without side effects. Arteriovenous difference and tracer ([3-3 H]glucose) techniques were used in conscious 42-h-fasted dogs. Experiments consisted of equilibration (Ϫ120 to Ϫ30 min), basal (Ϫ30 to 0 min), and experimental (EXP; 0 -270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. Saline (SAL) was infused intraportally during 0 -90 min (P1), and fluvoxamine was infused intraportally at 0.5, 1, and 2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively, in the FLUV group (n ϭ 8). The SAL group (n ϭ 9) received intraportal saline during 0 -270 min. NHGU in SAL was 13.9 Ϯ 1.7 and 17.0 Ϯ 2.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in P3-P4, respectively, while NHGU in FLUV averaged 19.7 Ϯ 2.8 and 26.6 Ϯ 3.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.05 vs. SAL). Net hepatic carbon retention was greater (P Ͻ 0.05) in FLUV than in SAL (17.6 Ϯ 2.6 vs. 13.9 Ϯ 2.7 and 23.8 Ϯ 3.0 vs. 14.4 Ϯ 3.3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in P3-P4, respectively), and final hepatic glycogen concentrations were 50% greater in FLUV (P Ͻ 0.005). Nonhepatic glucose uptake was greater in SAL than in FLUV at 270 min (P Ͻ 0.05). Catecholamine concentrations remained basal, and the animals evidenced no distress. Thus fluvoxamine enhanced NHGU and hepatic carbon storage without raising circulating serotonin concentrations or causing stress, suggesting that hepatic-targeted SSRIs might be effective in reducing postprandial hyperglycemia in individuals with diabetes or impaired glucose tolerance. glycemia; liver; portal vein; hepatic glucose uptake; nonhepatic glucose uptake INTRAPORTAL INFUSION OF SEROTONIN (5-hydroxytryptamine, or 5-HT) enhanced net hepatic glucose uptake (NHGU) in conscious dogs during a hyperinsulinemic hyperglycemic clamp (22). These findings suggest that 5-HT might play a role in limiting postprandial glycemic excursions in individuals with type 2 diabetes or impaired glucose tolerance. Good control of glycemia has been documented to reduce the risk of diabetesrelated complications (35); because diabetes is a progressive disease, there is a need for a variety of pharmacological tools for diabetes treatment. Thus the effects of 5-HT on hepatic and whole body glucose metabolism are intriguing and invite further study.Plasma concentrations of catecholamines and cortisol increased during the portal 5-HT infusion (22), and high concentrations of 5-HT in humans are well known...

show abstract

Rapid reversal of the effects of the portal signal under hyperinsulinemic conditions in the conscious dog

Cited by 22 publications

References 23 publications

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

Route-dependent effect of nutritional support on liver glucose uptake

Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Contact Info

Product

Resources

About