Effects of Portal and Peripheral Venous Insulin Infusion on Glucose Production and Utilization in Depancreatized, Conscious Dogs

Ishida, Toshihiko; Chap, Z.; Chou, Jesse; Lewis, Robert M.; Hartley, Craig J.; Entman, Mark L.; Field, James B.

doi:10.2337/diab.33.10.984

Cited by 37 publications

(11 citation statements)

References 16 publications

(21 reference statements)

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“…In addition, GP might be affected differently by hepatic arterial and portal venous insulin concentrations. The results ofmost (3)(4)(5)(6), but not all (7,8) ofthe studies where acute administration ofinsulin by either the portal or peripheral route was performed are consistent with some inhibitory effect of portal insulin levels on GP, especially at low insulin doses (5,6). The results ofthe studies involving chronic peripheral insulin delivery, as with pancreatic transplants (9,10), could be consistent with suppression of GP by either portal or peripheral insulin levels or both.…”

supporting

confidence: 71%

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

Giacca¹,

Fisher²,

Shi³

et al. 1992

J. Clin. Invest.

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It is generally believed that glucose production (GP) cannot be adequately suppressed in insulin-treated diabetes because the portal-peripheral insulin gradient is absent. To determine whether suppression of GP in diabetes depends on portal insulin levels, we performed 3-h glucose and specific activity clamps in moderately hyperglycemic (10 mM) depancreatized dogs, using three protocols: (a) 54 pmols kg-' bolus + 5.4 pmol* kg-' -min' portal insulin infusion (a = 7; peripheral insulin = 170±51 pM); (b) an equimolar peripheral infusion (a = 7; peripheral insulin = 294±28 pM, P < 0.001); and (c) a half-dose peripheral infusion (a = 7), which gave comparable (157±13 pM) insulinemia to that seen in protocol 1. Glucose production, use (GU) and cycling (GC) were measured using HPLC-purified 6-13Hj-and 2-13Hjglucose. Consistent with the higher peripheral insulinemia, peripheral infusion was more effective than equimolar portal infusion in increasing GU. Unexpectedly, it was also more potent in suppressing GP (73±7 vs. 55±7% suppression between 120 and 180 min, P < 0.001). At matched peripheral insulinemia (protocols 2 and 3), not only stimulation of GU, but also suppression of GP was the same (55±7 vs. 63±4%). In the diabetic dogs at 10 mM glucose, GC was threefold higher than normal but failed to decrease with insulin infusion by either route. Glycerol, alanine, FFA, and glucagon levels decreased proportionally to peripheral insulinemia. However, the decrease in glucagon was not significantly greater in protocol 2 than in 1 or 3. When we combined all protocols, we found a correlation between the decrements in glycerol and FFAs and the decrease in GP (r = 0.6, P < 0.01). In conclusion, when suprabasal insulin levels in the physiological postprandial range are provided to moderately hyperglycemic depancreatized dogs, suppression of GP appears to be more dependent on peripheral than portal insulin concentrations and may be mainly mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and by the suppressive effect of insulin on glucagon secretion. These results suggest that a portal-peripheral insulin gradient might not be necessary to effectively suppress postprandial GP in insulin-treated diabetics. (J. Clin. Invest. 1992. 90:1769-1777

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supporting

confidence: 71%

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

Giacca¹,

Fisher²,

Shi³

et al. 1992

J. Clin. Invest.

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“…A number of investigations have supported the concept that only portal insulin delivery can sustain normal insulin responsiveness [13,18,20]. Others, however, have yielded contradictory findings [2,4,7,11,14,17,19].…”

Section: : 1125-1134]mentioning

confidence: 99%

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

et al. 1997

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The normal portal-peripheral insulin gradient is absent in patients with insulin-dependent diabetes mellitus (IDDM) managed on conventional insulin therapy. The effect of this on intermediary metabolism has been studied widely in man and animals. However, results have been conflicting and considerable uncertainty still exists regarding the importance of the gradient for the maintenance of overall metabolic homeostasis.In animal models the metabolic importance of the portal-systemic gradient has been examined using a variety of techniques including direct cannulation combined with exogenous insulin infusion, islet and pancreatic transplantation, and diversion of pancreatic venous drainage . In some studies control of hepatic glucose output or blood glucose concentrations was superior with the portal route of insulin delivery, [3,8,15,16,18,20] while in others no Diabetologia (1997Diabetologia ( ) 40: 1125Diabetologia ( -1134 The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM Summary A pig model of insulin-dependent diabetes was used to examine the importance of the portal-systemic insulin gradient for whole-body metabolic control. Six pigs had jugular vein, portal vein, and carotid artery cannulae implanted before being made diabetic (150 mg kg − 1 streptozotocin). Each animal received 4 weeks of portal and 4 weeks of peripheral insulin delivery in random order. The blood glucose target range was 5-10 mmol ⋅ l − 1 , and serum fructosamine and fasting and postprandial blood glucose concentrations were not different between peripheral and portal insulin infusion. Insulin requirement was not different between the 4 week infusion periods, but fasting peripheral insulin levels after peripheral delivery (124 ± 16 (mean ± SEM) pmol ⋅ l − 1 ) were significantly higher (p < 0.05) than in portally infused (73.8 ± 5.4 pmol ⋅ l − 1 ) or pre-diabetic control animals (68.4 ± 3.6 pmol ⋅ l − 1 ). Basal hepatic glucose output was also higher (p < 0.05) in peripherally (4.2 ± 0.4 mg ⋅ kg − 1 ⋅ min − 1 ) than in portally infused animals (2.9 ± 0.4 mg ⋅ kg). Clamp glucose metabolic clearance rate was, however, not different between the peripheral and portal insulin delivery routes (8.1 ± 1.0 vs 9.0 ± 0.7 ml ⋅ kg), although both were significantly lower (p < 0.05) than that measured in prediabetic control animals (11.7 ± 1.0 ml ⋅ kg. Lipid profiles and subfractions were similar in all three groups. It is concluded that the portal route of delivery is superior to the peripheral in maintaining more appropriate insulin concentrations and control of hepatic glucose output, although in the absence of euglycaemia it is still associated with significant metabolic abnormalities. [Diabetologia (1997[Diabetologia ( ) 40: 1125[Diabetologia ( -1134

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“…In the short term, during insulin infusions the liver has been found to be more sensitive to increasing insulin levels than the periphery (1)(2)(3)(4), suggesting that it is the initial site at which glycemia may be regulated. Evidence as to relative efficiency of portal and peripheral delivery of insulin in the regulation of both glucose and other aspects of metabolism is not entirely consistent.…”

Section: Introductionmentioning

confidence: 99%

The effect of systemic venous drainage of the pancreas on insulin sensitivity in dogs.

Radziuk

Barron²,

Najm³

et al. 1993

J. Clin. Invest.

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To assess the metabolic consequences of the diversion of the pancreatic venous drainage to the systemic circulation, the pancreaticoduodenal and gastrosplenic veins were anastomosed to the inferior vena cava in nine normal dogs. This procedure maintained the integrity of the entire pancreas while shunting the hormonal output ofthe pancreas to the periphery. The metabolic effects were assessed from the sensitivity to insulin during a euglycemic hyperinsulinemic glucose clamp using an insulin infusion of 800 IAU/kg per min. The studies were controlled by their duplication in seven dogs identically treated but with the pancreatic veins reanastomosed to the portal vein. No differences in systemic insulin levels or insulin sensitivity before and after surgery were seen under these circumstances. After diversion, however, basal insulin levels rose from 4.5±1.0 to 11.5±2.5 gU/ml. Basal glucose metabolic clearance rate (MCR) rose to 3.0±0.4 from 2.0±0.3 ml/kg per min. On insulin infusion, maximal stimulation of MCR within the 2-h infusion period was to 15.2±2.5 ml/kg per min preoperatively and to 7.2±0.8 ml/kg per min after diversion. Using ratios of MCR-to-insulin concentration as an index of insulin sensitivity, it was demonstrated that this index decreased by at least 50% after diversion. These data imply that portal venous drainage of the pancreas is an important factor in the determination of peripheral insulin sensitivity. (J. Clin. Invest. 92:1713-1721

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Effects of Portal and Peripheral Venous Insulin Infusion on Glucose Production and Utilization in Depancreatized, Conscious Dogs

Cited by 37 publications

References 16 publications

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

The effect of systemic venous drainage of the pancreas on insulin sensitivity in dogs.

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