The effect of prehepatic insulin administration on alanine flux rates in diabetic dogs

Freyse, Ernst‐Joachim; Fischer, Uwe; Günther, Albrecht; Marx, Stephen; Keilacker, H

doi:10.1007/bf00292542

Cited by 17 publications

(26 citation statements)

References 36 publications

(34 reference statements)

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“…Isoglycaemic hyperinsulinaemic clamp data in normal and diabetic pigs after 4 weeks of peripheral and hepatic insulin delivery can remove between 50 and 75 % of insulin in the fasting state [55]. A lack of agreement exists among previous animal investigations, performed in rodents or dogs, concerning whether or not insulin delivery by the peripheral route results, as in our study, in raised [3,7,9,13,[17][18][19][20][21] or unchanged [2,6,11,[14][15][16] peripheral insulin levels. Studies in man comparing intraperitoneal and subcutaneous insulin delivery have similarly yielded conflicting results relating to the extent of systemic insulinisation [23][24][25][26][27][28]56].…”

Section: Discussioncontrasting

confidence: 63%

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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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Section: Discussioncontrasting

confidence: 63%

“…advantage was found [2,6,9,11,14,21]. Indeed some acute experiments have shown that peripherally delivered insulin is more effective than the same dose delivered portally [1,5].…”

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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“…Alanine reflects both carbohydrate and protein metabolism and thus is variably affected during insulin clamps (37). In depancreatized dogs, insulin decreases alanine levels (38). In our study, the greater suppression of alanine with peripheral than portal or half peripheral infusion can be explained by higher peripheral insulin levels.…”

Section: Discussionmentioning

confidence: 45%

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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“…Although insulin inhibits key enzymes of gluconeogenesis (1) and the mobilization of gluconeogenic substrates to the liver (2)(3)(4)(5), it is well established that insulin-induced hypoglycemia (IIH) provokes the release of hormones (6)(7)(8)(9)(10)(11), which stimulate hepatic gluconeogenesis (11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Rat liver responsiveness to gluconeogenic substrates during insulin-induced hypoglycemia

Souza

Borba-Murad

Ceddia

et al. 2001

Braz J Med Biol Res

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Hepatic responsiveness to gluconeogenic substrates during insulininduced hypoglycemia was investigated. For this purpose, livers were perfused with a saturating concentration of 2 mM glycerol, 5 mM Lalanine or 5 mM L-glutamine as gluconeogenic substrates. All experiments were performed 1 h after an ip injection of saline (CN group) or 1 IU/kg of insulin (IN group). The IN group showed higher (P<0.05) hepatic glucose production from glycerol, L-alanine and L-glutamine and higher (P<0.05) production of L-lactate, pyruvate and urea from L-alanine and L-glutamine. In addition, ip injection of 100 mg/kg glycerol, L-alanine and L-glutamine promoted glucose recovery. The results indicate that the hepatic capacity to produce glucose from gluconeogenic precursors was increased during insulin-induced hypoglycemia.

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The effect of prehepatic insulin administration on alanine flux rates in diabetic dogs

Cited by 17 publications

References 36 publications

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

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

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

Rat liver responsiveness to gluconeogenic substrates during insulin-induced hypoglycemia

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