Intranasal Insulin to Improve Memory Function in Humans

Benedict, Christian; Hallschmid, Manfred; Schultes, Bernd; Born, Jan; Kern, Werner

doi:10.1159/000106378

Cited by 152 publications

(101 citation statements)

References 100 publications

(57 reference statements)

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“…Metabolic hormones are emerging as important regulators of hippocampal function (28,(44)(45)(46)(47). GLP-1 has previously been shown to decrease glutamate-generated currents in cultured hippocampal neurons (48) and decrease hippocampal u wave duration in rats (30), and there is an impairment of synaptic plasticity and memory formation in GLP-1 receptor knockout mice (49).…”

Section: Discussionmentioning

confidence: 99%

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

et al. 2014

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Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the center for memory and learning. Diabetes is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on g-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01-1 nmol/L) transiently enhanced synaptic and tonic currents, and the effects were blocked by exendin (9-39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) amplitudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50, or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01-1 nmol/L GLP-1 and by 0.5-100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), inhibitory postsynaptic currents decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippocampal function and are consistent with GLP-1 receptor agonists enhancing GABA A signaling by pre-and postsynaptic mechanisms.In recent years, compelling evidence has emerged suggesting that diabetes mellitus increases the risk for cognitive impairments in the elderly (1-8). How this comes about is not resolved, but interestingly, the brain contains receptors for many metabolic hormones, among those receptors for insulin and the incretins. To date, with the exception of the hypothalamus, we know relatively little about how metabolic hormones affect neuronal activity and thereby brain function. The hippocampus is central for cognitive functions and is the center for memory and learning (9,10). It has prominent expression for receptors activated by metabolic hormones (10). Furthermore, via neurons in the septum, the hippocampus regulates the activity of a number of hypothalamic nuclei (11,12). Glucagon-like peptide-1 (GLP-1) is a gut hormone that is secreted by intestinal L cells in response to food intake, and the GLP-1 receptor is expressed in the hippocampus (10,13). GLP-1 crosses the blood-brain barrier, but it is also a neurotransmitter produced by neurons with cell bodies in the brainstem (12-15). The best known effects of GLP-1 are to stimulate insulin and inhibit glucagon secretion in a glucose-dependent manner in the pancreatic islets to regulate glucose homeostasis after a meal (13). Although the GLP-1 receptor is expressed in the hippocampus (10,16,17) and GLP-1 and its mimetics, e.g., exendin-4, liraglutide, might potentially be used to treat cognitive declines related to diabetes (6,7), to date not much is known about the effects of GLP-1 on neuronal signaling and, hence, how GLP-1 affects cognition and hippocampal regulation of metabolic homeostasis.

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Section: Discussionmentioning

confidence: 99%

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

et al. 2014

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“…Stimulation of brain insulin signaling has been suggested as a promising approach to prevent synapse deterioration and memory decline in AD (41,42). We thus next tested whether bolstering insulin signaling might also protect neurons from aberrant activation of the JNK/IRS-1pSer pathway triggered by AβOs.…”

Section: Introductionmentioning

confidence: 99%

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers

et al. 2012

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“…Insulin receptors are found throughout the CNS, although it is unclear whether brain insulin comes only from the blood through the blood-brain barrier (BBB) [1] or is also synthesized by CNS cells [2,3]. Insulin participates in a number of brain functions, such as regulation of food intake and body weight [4], and in cognition by modulating synaptic plasticity and long-term potentiation [5,6]. Diabetes mellitus type 2, which is mainly associated with insulin resistance, is a risk factor for dementia and AD [7].…”

Section: Introductionmentioning

confidence: 99%

Insulin Levels are Decreased in the Cerebrospinal Fluid of Women with Prodomal Alzheimer's Disease

Gil-Bea

Solas

Solomon

et al. 2010

JAD

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Abstract. Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1−42) levels and cognitive score. Furthermore, total-tau/(Aβ1−42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1−42 ratio for early AD diagnosis in women.

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Intranasal Insulin to Improve Memory Function in Humans

Cited by 152 publications

References 100 publications

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers

Insulin Levels are Decreased in the Cerebrospinal Fluid of Women with Prodomal Alzheimer's Disease

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