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

2009 ◽  
Vol 3 (6) ◽  
pp. 1451-1459 ◽  
Author(s):  
W. Blair Geho ◽  
Hans C. Geho ◽  
John R. Lau ◽  
Theophilus J. Gana
Keyword(s):  
Glucose Uptake ◽  
Evaluation Studies ◽  
Phospholipid Bilayer ◽  
Oral Glucose ◽  
Formulation Development ◽  
Genetic Toxicology ◽  
Preclinical Evaluation ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Hepatic Glucose Uptake

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.

Insulin as a mediator of hepatic glucose uptake in the conscious dog

1982 ◽  
Vol 242 (2) ◽  
pp. E97-E101 ◽  
Author(s):  
A. D. Cherrington ◽  
P. E. Williams ◽  
N. Abou-Mourad ◽  
W. W. Lacy ◽  
K. E. Steiner ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Plasma Insulin ◽  
Marked Effect ◽  
Glucose Infusion ◽  
Hepatic Glucose Output ◽  
Intravenous Glucose ◽  
Conscious Dog ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Hepatic Glucose Uptake

The aim of this study was to determine whether a physiological increment in plasma insulin could promote substantial hepatic glucose uptake in response to hyperglycemia brought about by intravenous glucose infusion in the conscious dog. To accomplish this, the plasma glucose level was doubled by glucose infusion into 36-h fasted dogs maintained on somatostatin, basal glucagon, and basal or elevated intraportal insulin infusions. In the group with basal glucagon levels and modest hyperinsulinemia (33 +/- 2 micro U/ml), the acute induction of hyperglycemia (mean increment of 120 mg/dl) caused marked net hepatic glucose uptake (3.7 +/- 0.5 mg . kg-1 . min-1). In contrast, similar hyperglycemia brought about in the presence of basal glucagon and basal insulin levels described net hepatic glucose output in 56%, but did not cause net hepatic glucose uptake. The length of fast was not crucial to the response because similar signals (insulin, 38 +/- 6 micro U/ml; glucose increment, 127 mg/dl) promoted identical net hepatic glucose uptake (3.8 +/- 0.6 mg . kg-1 . min-1) in dogs fasted for only 16 h. In conclusion, in the conscious dog, a) physiologic increments in plasma insulin have a marked effect on the ability of hyperglycemia to stimulate net hepatic glucose uptake, and b) it is not necessary to administer glucose orally to promote substantial net hepatic glucose uptake.

scholarly journals Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake

2010 ◽  
Vol 299 (6) ◽  
pp. E887-E898 ◽  
Author(s):  
Katie Colbert Coate ◽  
Melanie Scott ◽  
Ben Farmer ◽  
Mary Courtney Moore ◽  
Marta Smith ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Large Animal Model ◽  
Oral Glucose ◽  
Large Animal ◽  
High Fructose ◽  
Hepatic Glucose ◽  
Glucose Tolerance Tests ◽  
Hepatic Glucose Uptake ◽  
Average Glucose

The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD ( n = 10) or chow control (CTR, n = 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ΔAUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by ≈30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0–90 min) and 2 (P2, 90–180 min). During P1, somatostatin, basal intraportal glucagon, 4 × basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mg·kg−1·min−1). Net hepatic glucose uptake during P1 and P2 was −0.4 ± 0.1 [output] and 0.2 ± 0.8 mg·kg−1·min−1 in the HFFD group, respectively, and 1.8 ± 0.8 and 3.5 ± 1.0 mg·kg−1·min−1 in the CTR group, respectively ( P < 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 ± 0.2 and 1.5 ± 0.4 mg·kg−1·min−1 in the HFFD and CTR groups, respectively ( P < 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis.

Dynamics of hepatic lactate and glucose balances during prolonged exercise and recovery in the dog

1987 ◽  
Vol 63 (6) ◽  
pp. 2411-2417 ◽  
Author(s):  
D. H. Wasserman ◽  
D. B. Lacy ◽  
D. R. Green ◽  
P. E. Williams ◽  
A. D. Cherrington
Keyword(s):  
Glucose Uptake ◽  
Glucose Production ◽  
Moderate Intensity ◽  
Hepatic Veins ◽  
Hepatic Glucose Output ◽  
Rapid Release ◽  
Hepatic Glucose ◽  
Lactate Output ◽  
Glucose Output ◽  
Hepatic Glucose Uptake

The present experiments were undertaken to assess dynamics of hepatic lactate and glucose balance in the over-night-fasted dog during 150 min of moderate-intensity treadmill exercise and 90 min of exercise recovery. Catheters were implanted chronically in an artery and portal and hepatic veins 16 days before experimentation. 3–3H-glucose was infused to determine hepatic glucose uptake, as well as tracer-determined glucose production by isotope dilution (Ra). At rest, net hepatic lactate output was 0.33 +/- 0.15 mg.kg-1.min-1 and increased to 2.26 +/- 0.82 mg.kg-1.min-1 after 10 min of exercise, after which it fell such that the liver was a net lactate consumer by the end of exercise and through recovery. In contrast to the rapid release of lactate, net hepatic glucose output rose gradually from 2.58 +/- 0.20 mg.kg-1.min-1 at rest to 8.87 +/- 0.85 mg.kg-1.min-1 after 60 min of exercise, beyond which it did not change significantly until the cessation of exercise. Hepatic glucose uptake at rest was 1.38 +/- 0.42 mg.kg-1.min-1 and did not change appreciably during exercise or recovery. Absolute hepatic glucose output (net glucose output plus uptake) rose from 3.96 +/- 0.45 mg.kg-1.min-1 at rest to 10.20 +/- 1.09 mg.kg-1.min-1 after 60 min of exercise and was 9.65 +/- 1.15 mg.kg-1.min-1 at 150 min of exercise. Ra rose from 3.34 +/- 0.21 mg.kg-1.min-1 to 7.58 +/- 0.73 and 8.59 +/- 0.77 mg.kg-1.min-1 at 60 and 150 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Quantitative Determination of Hepatic Glucose Uptake Using an Innovative Approach

1991 ◽  
Vol 37 (Supplement) ◽  
pp. S35-S42 ◽  
Author(s):  
Ryuzo KAWAMORI ◽  
Minoru KUBOTA ◽  
Masahiko IKEDA ◽  
Munehide MATSUHISA ◽  
Masashi KUBOTA ◽  
...  
Keyword(s):  
Quantitative Determination ◽  
Glucose Uptake ◽  
Innovative Approach ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake

scholarly journals Nonhepatic response to portal glucose delivery in conscious dogs

2000 ◽  
Vol 279 (6) ◽  
pp. E1271-E1277 ◽  
Author(s):  
Mary Courtney Moore ◽  
Po-Shiuan Hsieh ◽  
Doss W. Neal ◽  
Alan D. Cherrington
Keyword(s):  
Glucose Uptake ◽  
Glucose Infusion ◽  
Glucose Load ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
The Difference ◽  
Arterial Plasma ◽  
Arterial Blood Glucose ◽  
Blood Glucose Concentrations ◽  
Hepatic Glucose Uptake

The glycemic and hormonal responses and net hepatic and nonhepatic glucose uptakes were quantified in conscious 42-h-fasted dogs during a 180-min infusion of glucose at 10 mg · kg−1 · min−1 via a peripheral (Pe10, n = 5) or the portal (Po10, n = 6) vein. Arterial plasma insulin concentrations were not different during the glucose infusion in Pe10 and Po10 (37 ± 6 and 43 ± 12 μU/ml, respectively), and glucagon concentrations declined similarly throughout the two studies. Arterial blood glucose concentrations during glucose infusion were not different between groups (125 ± 13 and 120 ± 6 mg/dl in Pe10 and Po10, respectively). Portal glucose delivery made the hepatic glucose load significantly greater (36 ± 3 vs. 46 ± 5 mg · kg−1 · min−1 in Pe10 vs. Po10, respectively, P < 0.05). Net hepatic glucose uptake (NHGU; 1.1 ± 0.4 vs. 3.1 ± 0.4 mg · kg−1 · min−1) and fractional extraction (0.03 ± 0.01 vs. 0.07 ± 0.01) were smaller ( P < 0.05) in Pe10 than in Po10. Nonhepatic (primarily muscle) glucose uptake was correspondingly increased in Pe10 compared with Po10 (8.9 ± 0.4 vs. 6.9 ± 0.4 mg · kg−1 · min−1, P < 0.05). Approximately one-half of the difference in NHGU between groups could be accounted for by the difference in hepatic glucose load, with the remainder attributable to the effect of the portal signal itself. Even in the absence of somatostatin and fixed hormone concentrations, the portal signal acts to alter partitioning of a glucose load among the tissues, stimulating NHGU and reducing peripheral glucose uptake.

Intrahepatic glucose: a requirement for neonatal ODC induction by specific hormones

1984 ◽  
Vol 247 (2) ◽  
pp. E243-E250
Author(s):  
G. Evoniuk ◽  
C. Kuhn ◽  
S. Schanberg
Keyword(s):  
Glucose Uptake ◽  
Intragastric Administration ◽  
Nutritional Deprivation ◽  
Rat Pups ◽  
Absolute Requirement ◽  
Whole Milk ◽  
Hepatic Glucose ◽  
Nutrient Administration ◽  
Hepatic Glucose Uptake

We have shown previously that short-term nutritional deprivation causes a tissue-specific loss of liver ornithine decarboxylase (ODC) induction after isoproterenol, phenylephrine, or glucagon administration in rat pups. To examine the role of nutrition in the regulation of hepatic ODC, we tested the ability of intragastric nutrient administration to reverse nutritionally related deficits in the ODC response to hormonal challenge. Intragastric whole milk was effective in restoring ODC induction and accumulation of its immediate product, putrescine, in response to isoproterenol administration. Glucose was shown to mediate this effect by the ability of intragastric skimmed milk, lactose, galactose, or D-glucose to return ODC induction, and the inability of casein, sucrose, fructose, L-glucose, or pyruvate plus lactate to do so. D-Glucose also reestablished ODC induction by phenylephrine and glucagon. Parenteral administration of D-glucose produced results comparable to those obtained after intragastric administration. Isoproterenol induction of ODC was prevented when hepatic glucose uptake was blocked by phlorizin but not by blockade of central nervous system glucose uptake with 2-deoxyglucose. We conclude that intrahepatic glucose is an absolute requirement for hepatic ODC induction by isoproterenol, phenylephrine, or glucagon in preweanling rats.

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

1999 ◽  
Vol 276 (5) ◽  
pp. E930-E937 ◽  
Author(s):  
Po-Shiuan Hsieh ◽  
Mary Courtney Moore ◽  
Doss W. Neal ◽  
Maya Emshwiller ◽  
Alan D. Cherrington
Keyword(s):  
Glucose Uptake ◽  
Infusion Rate ◽  
Experimental Period ◽  
Glucose Infusion ◽  
Glucose Load ◽  
Conscious Dog ◽  
The Third ◽  
Hepatic Glucose ◽  
Rapid Reversal ◽  
Hepatic Glucose Uptake

Experiments were performed on two groups of 42-h-fasted conscious dogs ( n = 6/group). Somatostatin was given peripherally with insulin (4-fold basal) and glucagon (basal) intraportally. In the first experimental period, glucose was infused peripherally to double the hepatic glucose load (HGL) in both groups. In the second experimental period, glucose (21.8 μmol ⋅ kg−1⋅ min−1) was infused intraportally and the peripheral glucose infusion rate (PeGIR) was reduced to maintain the precreating HGL in the portal signal (PO) group, whereas saline was given intraportally in the control (CON) group and PeGIR was not changed. In the third period, the portal glucose infusion was stopped in the PO group and PeGIR was increased to sustain HGL. PeGIR was continued in the CON group. The glucose loads to the liver did not differ in the CON and PO groups. Net hepatic glucose uptake was 9.6 ± 2.5, 11.6 ± 2.6, and 15.5 ± 3.2 vs. 10.8 ± 1.8, 23.7 ± 3.0, and 15.5 ± 1.1 μmol ⋅ kg−1⋅ min−1, and nonhepatic glucose uptake (non-HGU) was 29.8 ± 1.1, 40.1 ± 4.5, and 49.5 ± 4.0 vs. 26.6 ± 4.3, 23.2 ± 4.0, and 40.4 ± 3.1 μmol ⋅ kg−1⋅ min−1in the CON and PO groups during the three periods, respectively. Cessation of the portal signal shifted NHGU and non-HGU to rates similar to those evident in the CON group within 10 min. These results indicate that even under hyperinsulinemic conditions the effects of the portal signal on hepatic and peripheral glucose uptake are rapidly reversible.

Pathway and carbon sources for hepatic glycogen repletion in dogs

1991 ◽  
Vol 260 (2) ◽  
pp. E194-E202 ◽  
Author(s):  
A. Mitrakou ◽  
R. Jones ◽  
Y. Okuda ◽  
J. Pena ◽  
N. Nurjhan ◽  
...  
Keyword(s):  
Carbon Sources ◽  
Hepatic Uptake ◽  
Hepatic Glycogen ◽  
Oral Glucose ◽  
Indirect Pathway ◽  
Hepatic Glucose ◽  
Glycogen Repletion ◽  
Hepatic Glucose Uptake ◽  
Labeling Pattern

The present studies were undertaken to quantitate the relative contributions of the indirect and direct pathways for hepatic glycogen repletion and to determine the role of splanchnic tissues in provision of C precursors used for the indirect pathway. For this purpose, we administered oral glucose (1.4 g/kg) enriched with [1-14C]glucose to 18-h fasted dogs and measured net hepatic and net gastrointestinal glucose, lactate, and alanine balance, hepatic and gastrointestinal fractional extraction [( 3H]lactate), release and uptake of lactate, as well as the total amount of hepatic glycogen formed from the oral glucose and the 14C labeling pattern of the glycogen-glucose C. Although net hepatic glucose uptake (8.7 +/- 0.6 g, 27% of the oral load) exceeded the amount of glycogen formed from the oral glucose (6.3 +/- 1.1 g), analysis of radioactivity in C-1 of the glycogen glucose indicated that nearly 50% of the glycogen was formed by the indirect pathway. Net hepatic uptake of lactate (1.4 +/- 0.1 g) and alanine (1.5 +/- 0.1 g) could account for greater than 90% of glycogen formed by the indirect pathway if all of the lactate and alanine taken up by the liver had been incorporated into glycogen. Release of lactate and alanine by splanchnic tissues approximated the amount of lactate and alanine taken up by the liver. However, in addition to taking up lactate, the liver also produced nearly as much lactate as the gastrointestinal tract (1.8 +/- 0.2 vs. 2.0 +/- 0.3 g, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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