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

Satya Dash, Changting Xiao, Cecilia Morgantini, Khajag Koulajian, Gary F. Lewis
2014 Diabetes  
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
more » ... f 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
doi:10.2337/db14-0685 pmid:25288674 fatcat:scfnkjgkejarfjzln4oxnvbi3a