Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions

Heni, Martin; Kullmann, Stephanie; Ketterer, Caroline; Guthoff, Martina; Linder, Katarzyna; Wagner, Róbert; Stingl, Krunoslav; Veit, Ralf; Staiger, Harald; Häring, Hans‐Ulrich; Preißl, Hubert; Fritsche, Andreas

doi:10.1007/s00125-012-2528-y

Cited by 96 publications

(137 citation statements)

References 56 publications

(68 reference statements)

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“…In agreement with previous studies (20), there was a slight increase in plasma insulin levels after intranasal insulin administration. This is a result of spillover of exogenous intranasal insulin to the vascular system.…”

Section: Discussionsupporting

confidence: 93%

“…Lines represent fit line 6 CI from a model adjusted for age and BMI. P and r Previously, we estimated the effects of brain insulin on peripheral insulin sensitivity by fasting insulin-to-glucose ratios (20). These data suggested that intranasal insulin might immediately cause peripheral insulin resistance followed by an insulin-sensitizing effect.…”

Section: Discussionmentioning

confidence: 99%

“…They showed lowered postprandial blood insulin levels (19) and lowered blood insulin-to-glucose ratio after intranasal insulin administration (20). However, whether peripheral insulin sensitivity was genuinely altered by central insulin action could not be shown unequivocally in humans.…”

mentioning

confidence: 99%

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Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

et al. 2014

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Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on wholebody insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

et al. 2014

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“…Recent studies in humans showed that INI administered at a higher dose of 160 IU can acutely lower plasma glucose and alter peripheral insulin sensitivity (11,14,15), an effect postulated to occur via insulin delivery to the CNS. However, the higher dose of INI (160 IU) transiently increased peripheral insulin concentration (9,14,15), which may contribute to the acute effects of INI on peripheral glucose metabolism and insulin sensitivity (11,14,15).…”

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confidence: 99%

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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“…Recently it has been suggested that changes in insulin action in the brain not only affect the regulation of appetite and body weight but are also crucial in controlling glucose metabolism [1][2][3]. There is evidence in humans that brain insulin resistance is not the consequence of peripheral metabolic changes but may itself contribute to the development of diabetes and obesity [4][5][6]. By recording brain activity with magnetoencephalography during a euglycaemichyperinsulinaemic stepwise clamp, we showed in adult humans that obesity, peripheral insulin resistance, age and genetic background are all associated with impaired central insulin sensitivity [7,8].…”

Section: Introductionmentioning

confidence: 99%

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity

et al. 2014

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Aims/hypothesis Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. Methods Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. Results Maternal insulin increased from a fasting level of 67±25 pmol/l (mean ± SD) to 918±492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4±0.3 to 7.4±1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297±99 to 235±84 ms (p=0.01) and then remained stable until 120 min (235±84 vs 251±91 ms, p=0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r=0.68, p=0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283±79 ms) than those of insulin-sensitive mothers (178±46 ms, p=0.03). Conclusions/interpretation Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.

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Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions

Cited by 96 publications

References 56 publications

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

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

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity

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