cells Review Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease Jesús Burillo 1,2,3,† , Patricia Marqués 1,3,† , Beatriz Jiménez 1,2,3,† , Carlos González-Blanco 1,3,† , Manuel Benito 1,2,3,‡ and Carlos Guillén 1,2,3, * ,‡   Citation: Burillo, J.; Marqués, P.; Jiménez, B.; González-Blanco, C.; Benito, M.; Guillén, C. Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease. Cells 2021, 10, 1236. https://doi.org/10.3390/ cells10051236 Academic Editor: Victoriano Baladrón Received: 13 April 2021 Accepted: 13 May 2021 Published: 18 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biochemistry, Complutense University, 28040 Madrid, Spain; jburillo@ucm.es (J.B.); pmarques@ucm.es (P.M.); bejime02@ucm.es (B.J.); carlgo23@ucm.es (C.G.-B.); mbenito@ucm.es (M.B.) 2 Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28040 Madrid, Spain 3 Mechanisms of Insulin Resistance (MOIR2), General Direction of Universities and Investigation (CCMM), 28040 Madrid, Spain * Correspondence: cguillen@ucm.es † These authors contribute equally to this review. ‡ These authors contribute equally to this review. Abstract: Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction. Keywords: insulin resistance; T3DM; mTOR; ER stress; autophagy; inflammation 1. Introduction Diabetes is a metabolic disease that is characterized by the appearance of chronic hyperglycemia because of pancreatic β cell failure by different mechanisms. This decline of β cells occurs in all types of diabetes, but it is an essential mechanism in the main forms of diabetes; type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [1]. According to American Diabetes Association (ADA), diabetes can be classified into different categories: Type 1 diabetes mellitus (T1DM); type 2 diabetes mellitus (T2DM); gestational diabetes mellitus (GDM); other causes of the disease, including monogenic diabetes, such as maturity-onset diabetes of the young (MODY), or secondary to the use of different drugs or chemical compounds [2]. T1DM is known as “insulin dependent” and represents 5–10% of the total amount of diabetics. The etiology of the disease is an autoimmune attack towards pancreatic β cells. Although there are several genetic predispositions related to the disease [3,4], it is also considered the existence of an environmental component, which is poorly understood [5,6]. T2DM is known as “insulin independent” and represents the majority of all diabetics (90–95%). The main characteristic of the disease is the appearance of insulin resistance, which is a defect in insulin signaling and a correct coupling of insulin with its receptor. It can be distinguished 2 phases in the disease progression. During the first one, there is insulin resistance, and concomitantly, a compensatory mechanism in pancreatic β cells, associated with hyperinsulinemia [7,8]. Although T2DM is considered non-insulin dependent, it is known that as the disease progresses, many patients need insulin because of pancreatic β cell destruction. Then, β cell function maintenance is a key treatment strategy [9]. Although β cell death is one of the main events of pancreatic β cell failure, some authors indicate that dedifferentiation is another important mechanism for β cell dysfunction [10]. In this regard, Cells 2021, 10, 1236. https://doi.org/10.3390/cells10051236 https://www.mdpi.com/journal/cells