Inhaled Insulin Is Associated with Prolonged Enhancement of Glucose Disposal in Muscle and Liver in the Canine

Edgerton, Dale S.; Cherrington, Alan D.; Neal, Doss W.; Scott, Melanie; Lautz, Margaret; Brown, Nancy J.; Petro, Jeff; Hobbs, C.H.; Leach, Chet; Parigi, Angelo Del; Strack, Thomas

doi:10.1124/jpet.108.146985

Cited by 4 publications

(1 citation statement)

References 32 publications

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“…The results of this study are in agreement with previous data in animal models. Edgerton et al administered to dogs human insulin via inhalation (Exubera®; n = 9) or infusion (Humulin R; n = 9) using an infusion algorithm that yielded matched plasma insulin kinetics between the two groups to determine whether this insulin effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients [25]. Somatostatin was infused to prevent insulin secretion, and glucagon was infused to replace basal plasma levels of the hormone.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of Inhaled Insulin on Whole Body Glucose Metabolism in Subjects with Type 2 Diabetes Mellitus

Mehta¹,

Gastaldelli

Balas³

et al. 2019

IJMS

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In the current study we investigate the mechanisms of action of short acting inhaled insulin Exubera®, on hepatic glucose production (HGP), plasma glucose and free fatty acid (FFA) concentrations. 11 T2D (Type 2 Diabetes) subjects (age = 53 ± 3 years) were studied at baseline (BAS) and after 16-weeks of Exubera® treatment. At BAS and after 16-weeks subjects received: measurement of HGP (3-3H-glucose); oral glucose tolerance test (OGTT); and a 24-h plasma glucose (24-h PG) profile. At end of study (EOS) we observed a significant decrease in fasting plasma glucose (FPG, 215 ± 15 to 137 ± 11 mg/dl), 2-hour plasma glucose (2-h PG, 309 ± 9 to 264 ± 11 mg/dl), glycated hemoglobin (HbA1c, 10.3 ± 0.5% to 7.5 ± 0.3%,), mean 24-h PG profile (212 ± 17 to 141 ± 8 mg/dl), FFA fasting (665 ± 106 to 479 ± 61 μM), post-OGTT (433 ± 83 to 239 ± 28 μM), and triglyceride (213 ± 39 to 120 ± 14 mg/dl), while high density cholesterol (HDL-C) increased (35 ± 3 to 47 ± 9 mg/dl). The basal HGP decreased significantly and the insulin secretion/insulin resistance (disposition) index increased significantly. There were no episodes of hypoglycemia and no change in pulmonary function at EOS. After 16-weeks of inhaled insulin Exubera® we observed a marked improvement in glycemic control by decreasing HGP and 24-h PG profile, and decreased FFA and triglyceride concentrations.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Action of Inhaled Insulin on Whole Body Glucose Metabolism in Subjects with Type 2 Diabetes Mellitus

Mehta¹,

Gastaldelli

Balas³

et al. 2019

IJMS

View full text Add to dashboard Cite

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Drug Delivery Systems in Domestic Animal Species

Brayden

Oudot

Baird

2010

Comparative and Veterinary Pharmacology

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Delivery of biologically active agents to animals is often perceived to be the poor relation of human drug delivery. Yet this field has a long and successful history of species-specific device and formulation development, ranging from simple approaches and devices used in production animals to more sophisticated formulations and approaches for a wide range of species. While several technologies using biodegradable polymers have been successfully marketed in a range of veterinary and human products, the transfer of delivery technologies has not been similarly applied across species. This may be due to a combination of specific technical requirements for use of devices in different species, inter-species pharmacokinetic, pharmacodynamic and physiological differences, and distinct market drivers for drug classes used in companion and food-producing animals. This chapter reviews selected commercialised and research-based parenteral and non-parenteral veterinary drug delivery technologies in selected domestic species. Emphasis is also placed on the impact of endogenous drug transporters on drug distribution characteristics in different species. In vitro models used to investigate carrier-dependent transport are reviewed. Species-specific expression of transporters in several tissues can account for inter-animal or inter-species pharmacokinetic variability, lack of predictability of drug efficacy, and potential drug-drug interactions.

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Intranasal Insulin Suppresses Endogenous Glucose Production in Humans Compared With Placebo in the Presence of Similar Venous Insulin Concentrations

et al. 2014

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Intranasal insulin (INI) has been shown to modulate food intake and food-related activity in the central nervous system in humans. Because INI increases insulin concentration in the cerebrospinal fluid, these effects have been postulated to be mediated via insulin action in the brain, although peripheral effects of insulin cannot be excluded. INI has been shown to lower plasma glucose in some studies, but whether it regulates endogenous glucose production (EGP) is not known. To assess the role of INI in the regulation of EGP, eight healthy men were studied in a single-blind, crossover study with two randomized visits (one with 40 IU INI and the other with intranasal placebo [INP] administration) 4 weeks apart. EGP was assessed under conditions of an arterial pancreatic clamp, with a primed, constant infusion of deuterated glucose and infusion of 20% dextrose as required to maintain euglycemia. Between 180 and 360 min after administration, INI significantly suppressed EGP by 35.6% compared with INP, despite similar venous insulin concentrations. In conclusion, INI lowers EGP in humans compared with INP, despite similar venous insulin concentrations. INI may therefore be of value in treating excess liver glucose production in diabetes.Dysregulation of insulin-mediated suppression of hepatic glucose production (HGP) is a hallmark of type 2 diabetes (1). It is well established that activation of hepatic insulin receptors with ensuing activation of downstream insulin signaling pathways lowers hepatic glucose output by decreasing gluconeogenesis and increasing glycogen synthesis (1). In addition to the direct action of insulin on hepatocytes, insulin can indirectly affect HGP by altering free fatty acid (FFA) flux and suppressing glucagon secretion (2-4). Animal studies have indicated that insulin may also indirectly regulate hepatic glucose output via effects on the central nervous system (CNS)-the so-called brain-liver axis (1,5,6).Injection of insulin into the third cerebral ventricle in mice activates K ATP channels in the mediobasal hypothalamus (via activation of the insulin receptorphosphoinositide 3-kinase pathway), which activates second-order neurons in the brain stem. This in turn lowers expression of gluconeogenic enzymes and glucose production by the liver, an effect that is abrogated by surgical resection of the hepatic branch of the vagus nerve (6). CNS insulin action in the dorsal vagal complex has more recently been shown to regulate HGP via activation of the insulin-insulin receptor-extracellular signalrelated kinase pathway (7). These brain-liver axis effects are observed in the absence of changes in plasma insulin concentration (5-7). A brain-liver axis also has been

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Inhaled Insulin Is Associated with Prolonged Enhancement of Glucose Disposal in Muscle and Liver in the Canine

Abstract: Diabetic

Cited by 4 publications

References 32 publications

Mechanism of Action of Inhaled Insulin on Whole Body Glucose Metabolism in Subjects with Type 2 Diabetes Mellitus

Mechanism of Action of Inhaled Insulin on Whole Body Glucose Metabolism in Subjects with Type 2 Diabetes Mellitus

Drug Delivery Systems in Domestic Animal Species

Intranasal Insulin Suppresses Endogenous Glucose Production in Humans Compared With Placebo in the Presence of Similar Venous Insulin Concentrations

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