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

Abstract

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

Central insulin-mediated regulation of hepatic glucose production [Review]

“…However, all the HGP-diminishing effects of intranasal insulin and oral diazoxide administration were in fact observed in healthy individuals [48,53,54], and they may not necessarily be reproducible in type 2 diabetes mellitus accompanied by obesity. The disturbance of central insulin action-mediated suppression of HGP has been reported in a rodent study using a high fat dietinduced obesity model [55], and dysfunction of central insulin action following high fat diet-induced obesity is reported to be due to inflammation of the hypothalamus and PI3K signal transduction failure caused by S6 kinase activation [55][56][57].…”

“…Indeed, it is possible to increase the cerebrospinal fluid insulin values without altering the peripheral blood insulin values by administrating 40 IU intranasal insulin to healthy individuals [52]. Intranasal administration of 40 IU insulin diminishes HGP under the condition of pancreatic clamp, which maintain a steady level of plasma insulin and glucagon by somatostatin administration [53]. Further, it has been reported that intrain hepatic glucose metabolism.…”

Nose-to-Brain delivery of insulin for Alzheimer’s disease

“…The FDA gave a Black Box Warning to the pulmonary administered insulin Exubera® since clinical studies reported a four-fold increase in the incidence of lung cancer among patients with a history of smoking. In 2007 Exubera® was discontinued and shifted back the interest to nasal insulin administration with very recent studies on beneficial metabolic effects of central insulin action [59,66,78]. Several companies continue their nasal insulin development programmes for the regimen of diabetes, all of them using different absorption enhancers like dodecyl-β-D-maltoside (Aegis therapeutics Inc.; [79]), micro crystalline cellulose (SNBL; [80]) and CriticalSorb™ (Critical Pharmaceuticals; [81]).…”

In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact

“…23,24 Moreover, intranasal insulin administration to healthy humans decreases endogenous glucose production. 25 Increased endogenous glucose production is the main source of hyperglycemia in individuals with diabetes 26 and thus a hallmark of underlying pathophysiology of this serious medical illness.…”