Comparison of peripheral and portal (via the umbilical vein) routes of insulin infusion in IDDM patients

Shishko, P. I.; Kovalev, P. A.; Goncharov, Vitaliy G.; Zajarny, I. U.

doi:10.2337/diabetes.41.9.1042

Cited by 30 publications

(29 citation statements)

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“…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]. However, the systemic delivery of insulin which accompanies human pancreas transplantation has generally been found to lead to fasting peripheral hyperinsulinaemia [29][30][31][32][33][34][35][36][37].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Whether the defects in hepatic glycogen synthesis observed in the IDDM subjects after an overnight fast can be reversed by more aggressive treatment with insulin remains to be determined. Although it may be possible to normalize plasma glucose concentrations by giving more insulin, it is very difficult to normalize portal vein insulin concentrations by giving insulin peripherally without causing peripheral hyperinsulinemia, which has the potential for causing hypoglycemia (16,17).…”

Section: Discussionmentioning

confidence: 99%

Impaired net hepatic glycogen synthesis in insulin-dependent diabetic subjects during mixed meal ingestion. A 13C nuclear magnetic resonance spectroscopy study.

Hwang¹,

Perseghin²,

Rothman³

et al. 1995

J. Clin. Invest.

163

130

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Hepatic glycogen concentration was measured in six subjects with insulin-dependent diabetes mellitus (IDDM) and nine weight-matched control subjects using '3C nuclear magnetic resonance spectroscopy during a day in which three isocaloric mixed meals were ingested. The relative fluxes of the direct and indirect (3 carbon units -+ -+ glycogen) pathways of hepatic glycogen synthesis were also assessed using [1-3C]glucose in combination with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. Mean fasting hepatic glycogen content was similar in the two groups. After each meal, hepatic glycogen content increased, peaking 4-5 h after the meal in both groups. By 11:00 p.m. the IDDM subjects had synthesized only 30% of the glycogen that was synthesized by the control group [IDDM subjects, net increment = 44±20 (mean±SE) mM; control subjects, net increment = 144±14 mM; P < 0.05]. After breakfast the flux through the gluconeogenic pathway relative to the direct pathway of hepatic glycogen synthesis was 1.7-fold greater in the IDDM subjects (59±4%) than in the control subjects (35±4%, P < 0.0003). In conclusion, under mixed meal conditions, subjects with poorly controlled IDDM have a major defect in net hepatic glycogen synthesis and augmented hepatic gluconeogenesis. The former abnormality may result in an impaired glycemic response to counterregulatory hormones, whereas both abnormalities may contribute to postprandial hyperglycemia. (J. Clin. Invest. 1995. 95:783-787.)

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“…These studies were presented in part as a poster and published as an abstract at the 68th Annual Meeting of the American Diabetes Association, June [14][15][16][17] 2008, in San Francisco, California.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Hepatic-Directed Vesicle Insulin: A Review of Formulation Development and Preclinical Evaluation

Geho¹,

Geho

Lau³

et al. 2009

J Diabetes Sci Technol

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Hepatic-directed vesicle insulin (HDV-I), a novel investigational vesicle (<150 nm diameter) insulin delivery system that carries insulin and a specific hepatocyte-targeting molecule (HTM) in its phospholipid bilayer and has the ability to mimic a portal vein insulin infusion remotely [subcutaneous (SC) HDV-I] and noninvasively (oral HDV-I), has been developed. This review summarizes formulation development, subsequent refinements, and results of preclinical evaluation studies, including biodistribution, mechanistic, and toxicology studies of predominantly SC HDV-I, in various animal models. Studies conducted to date have confirmed the hepatocyte specificity of HDV and HDV-I and revealed that HDV-I can stimulate the conversion of hepatic glucose output to uptake at a dose that is <1% of the dose of regular insulin (RI) required for liver stimulation; suggest that the enhanced antihyperglycemic effect of HDV-I is due to hepatic glucose uptake; and in pancreatectomized dogs during an oral glucose tolerance test, HDV-I normalized blood glucose curves when compared to control curves in intact dogs and prevented secondary hypoglycemia in contrast to the same dose of RI. A 28-day SC HDV toxicity study in rats revealed no clinical, clinical laboratory, or histopathological findings, and the battery of three genetic toxicology studies was negative. Results support the hypothesis that HDV-I works by stimulating hepatic glucose uptake and/or glycogen storage in insulin-deficient animals. The ability to target the delivery of HDV-I to the liver reestablishes the liver as a major metabolic modulator of glucose metabolism. The future of HDV-I depends on the results of ongoing development and longer term clinical trials.

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Comparison of peripheral and portal (via the umbilical vein) routes of insulin infusion in IDDM patients

Cited by 30 publications

References 0 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

Impaired net hepatic glycogen synthesis in insulin-dependent diabetic subjects during mixed meal ingestion. A 13C nuclear magnetic resonance spectroscopy study.

Hepatic-Directed Vesicle Insulin: A Review of Formulation Development and Preclinical Evaluation

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