Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

Abstract

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.

Insulin effects on core neurotransmitter pathways involved in schizophrenia neurobiology: a meta-analysis of preclinical studies. Implications for the treatment

“…Several factors are involved in the regulation of insulin transport via the BBB as well as insulin signaling in the brain, including obesity, inflammation, glycemia, insulin resistance, levels of circulating triglycerides, and age [23,24]. In this framework, brain insulin resistance may arise from low levels of insulin in the central nervous system or resistance at the receptor level [23,25]. Of interest, brain insulin resistance may precede the onset of a full-blown diabetic state or represent an independent manifestation, as proved by the observation of a reduced response to ex vivo insulin stimulation in the hippocampal formation and the cerebellar cortex of patients affected by Alzheimer's Disease without diabetes [26].…”

Effect of circulating ceramides on adiposity and insulin resistance in patients with type 2 diabetes: An observational cross‐sectional study

“…The aforementioned can lead to a reduction in postprandial glucose storage, particularly in the skeletal muscle and liver 1–3 . IR is known to affect about 15.5%–46.5% of the human population 4,5 . A sedentary lifestyle, heredity, a high‐fat diet, obesity, type 2 diabetes mellitus (T2DM) and heart‐related pathologies have all been associated with IR 6–8 .…”

“… 1 , 2 , 3 IR is known to affect about 15.5%–46.5% of the human population. 4 , 5 A sedentary lifestyle, heredity, a high‐fat diet, obesity, type 2 diabetes mellitus (T2DM) and heart‐related pathologies have all been associated with IR. 6 , 7 , 8 Indeed, obesity‐mediated IR is common in individuals who live in areas defined by persistent energy surplus, a low basal metabolic rate or a combination of both.…”

Evidence for an alternative insulin transporter at the blood-brain barrier

“…Insulin signaling within the central nervous system (CNS) is important not only for regulation of metabolism but also cognition. CNS insulin signaling can become dysfunctional with age and in neurodegenerative diseases such as Alzheimer's disease [7] and insulin BBB interactions are impaired [7][8][9]. BBB transport of insulin could be a regulator of CNS insulin signaling since it is one of the mediators of CNS insulin levels [7].…”

“…CNS insulin signaling can become dysfunctional with age and in neurodegenerative diseases such as Alzheimer's disease [7] and insulin BBB interactions are impaired [7][8][9]. BBB transport of insulin could be a regulator of CNS insulin signaling since it is one of the mediators of CNS insulin levels [7]. Additionally, insulin interactions with the BBB are impaired in obesity [10,11].…”