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Brain Insulin Resistance in Alzheimer Disease and Its Potential Treatment With a Mediterranean Diet and GLP-1 Analogues: Page 3 of 5

Brain Insulin Resistance in Alzheimer Disease and Its Potential Treatment With a Mediterranean Diet and GLP-1 Analogues: Page 3 of 5

Our subsequent ex vivo stimulation studies have shown lesser, but significant, brain insulin resistance in the HF of patients with MCI (H-Y Wang et al, unpublished data, 2013). Given that nearly half the American populace aged 45 to 64 years has prediabetes (ie, peripheral insulin resistance but not hyperglycemia),7 it is likely that brain insulin resistance begins to develop with normal aging but accelerates in the transition from the preclinical to the MCI stage of AD. Peripheral hyperglycemia is not necessary for development of brain insulin resistance, because that occurred in our patients with MCI or AD dementia even though they lacked a history of diabetes.

AD is not type 3 diabetes mellitus (T3D), but rather an insulin resistance syndrome

Many have interpreted the similarities between T2D and AD coupled with evidence of brain insulin resistance in the latter disorder as evidence that AD represents a third type of diabetes mellitus targeting the brain. This is misleading for at least 2 reasons. First, the term “diabetes” is inappropriate: the defining diagnostic feature shared by type 1 diabetes mellitus and T2D is not insulin resistance, but hyperglycemia, which is not a known feature of the brain in AD or animal models of that disorder. Second, while brain glucose metabolism is reduced in AD, that phenomenon appears unrelated to brain insulin resistance, which does not play a role in neuronal glucose uptake.9 The term “T3D” incorrectly implies, then, that the many deleterious effects of hyperglycemia and decreased cellular glucose uptake are playing a role in brain insulin resistance.

Rather than T3D, brain insulin resistance in AD is more aptly described as a neuronal form of Reaven insulin resistance syndrome,12 a condition characterized by insulin resistance coupled to at least a subset of its associated abnormalities in other tissues (eg, inflammation, dyslipidemia, and endothelial dysfunction). This syndrome, a core element of the more expansive metabolic syndrome, is not a separate medical disorder but rather an aspect of different clinical conditions (eg, T2D, cardiovascular disease, and essential hypertension).12 Our work suggests that both MCI and AD can be added to that list of medical conditions.

IRS-1 inhibition by Aβ and cytokines can trigger braininsulin resistance in AD

Aβ oligomers and several inflammatory cytokines (eg, tumor necrosis factor α and interleukin-6) activate a number of enzymes that serine phosphorylate IRS-1 and thereby inhibit its activation by the IR.9,13 Such phosphorylation is known to cause peripheral insulin resistance in adipocytes and skeletal muscle.14 Brain insulin resistance appears to have the same cause, because the previously noted reductions in insulin-induced IRS-1 activation seen in brains of persons with AD dementia occur in the presence of abnormally high basal levels of IRS-1 serine phosphorylation (IRS-1 pS).9 Basal phosphorylation at 2 sites, IRS-1 pS616 and IRS-1 pS636, are consistently elevated in insulin-resistant brain tissues and may thus be biomarkers of brain insulin resistance.9 Levels of IRS-1 pS616 and IRS-1 pS636 rise to some extent in brains of normal persons with advanced aging, consistent with the view that brain insulin resistance is a feature of normal aging that is markedly accelerated in AD. This process appears closely associated with cognitive decline, because levels of IRS-1 pS and other markers of impaired insulin signaling in the hippocampus are strongly and negatively associated with global cognition, episodic memory, and working memory scores of both persons without and patients with MCI and AD dementia.9

Brain insulin resistance can promote most AD pathologies and cognitive deficits

Insulin is best known as a pancreatic β cell hormone secreted in response to elevated plasma glucose levels after meals. The classic functions of such secretion are to stimulate glucose uptake by adipose and muscle tissue and to inhibit no longer needed free fatty acid release by adipose tissue and glucose production by the liver. But insulin is also synthesized in the brain, including the adult cerebral cortex and hippocampus,15 where the density of insulin receptors is appreciable in pyramidal cell layers.16 Indeed, most insulin in the brain, with the possible exception of the hypothalamus, seems locally derived since loss of pancreatic β cells or alterations in their insulin secretion has little, if any, effect on total levels of brain insulin.17 It is likely, then, that brain insulin resistance outside the hypothalamus reflects decreased responsiveness to locally derived, not pancreatic, insulin.

Unlike insulin in peripheral tissues, insulin in the brain does not control cellular uptake of glucose, although it might modulate such uptake.9 But insulin does far more than regulate glucose metabolism in both peripheral tissues and the brain. In the brain, it promotes most functions disrupted in AD, namely (1) Aβ clearance; (2) tau phosphorylation; (3) blood flow regulation; (4) inhibition of apoptosis, inflammatory responses, and lipid catabolism; (5) facilitation of transmitter receptor trafficking; (6) synaptic plasticity; and (7) memory formation.18,19

Brain insulin resistance consequently has the potential to cause or contribute to the full spectrum of AD pathology and symptoms. The rate at which insulin resistance develops in the brain may thus play a large role in determining the rate at which AD progresses.

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