Endocrinol Nutr. 2014;61(4):173---175

ENDOCRINOLOGÍA Y NUTRICIÓN

www.elsevier.es/endo

EDITORIAL

Type 3 diabetes mellitus. The revival of inhaledinsulin?�

Diabetes mellitus tipo 3. ¿El renacer de la insulina inhalada?

Francesc Formigaa,∗, Manuel Pérez-Maraverb

a Programa de Geriatría, Servicio de Medicina Interna, Hospital Universitari de Bellvitge, IDIBELL, L′Hospitalet de Llobregat,Barcelona, Spainb Servicio de Endocrinología y Nutrición, Hospital Universitari de Bellvitge, IDIBELL, L′Hospitalet de Llobregat, Barcelona, Spain

Type 2 diabetes mellitus (DM) and dementia are two condi-tions highly prevalent today and probably interrelated. Theterm type 3 diabetes has therefore been proposed to tryand provide a view integrating the potential pathogeneticmechanisms shared by DM and Alzheimer disease (AD).1---3

Significant epidemiological evidence relating DM anddementia has accumulated in the past decade.1---3 Accordingto a recent complete meta-analysis, patients with DM havea relative risk of 1.464 of suffering AD. A greater impactof diabetes on dementia has been reported in people whoalso have a genetic predisposition, and also when diabetes isdiagnosed earlier in life. Impact is lower in older groups, butdiabetes continues to be a risk factor even in people aged85 years.5 It should be noted that current epidemiologicalstudies were not especially designed to assess the relation-ship between diabetes and dementia, and have thereforesome limitations which are expected to be solved with futureevidence from the Edinburgh Type 2 Diabetes Study.6

Various hypotheses have been proposed to explain therelationship between DM and dementia, from the effectof acute hyperglycemia itself (which may affect working

� Please cite this article as: Formiga F, Pérez-Maraver M. Diabetesmellitus tipo 3. ¿El renacer de la insulina inhalada?. Endocrinol Nutr.2014;61:173---175.

∗ Corresponding author.E-mail address: fformiga@bellvitgehospital.cat (F. Formiga).

memory and attention) to the effect of chronic hyper-glycemia, which may cause and aggravate macrovasculardisease, more related to vascular dementia, and microvas-cular disease.1---3 Chronic hyperglycemia may also involveincreased oxidative stress, mitochondrial dysfunction, andproduction of advanced glycation end-products.2

A very interesting theory considers hyperinsulinemia andinsulin resistance as a potential risk factor for AD, becausethey may cause neuron apoptosis and promote formationof extracellular �-amyloid deposits.1---3 Under normal con-ditions, excess �-amyloid may be removed through thelipoprotein receptor-related protein 1 (which decreasesif insulin resistance exists) or by a degradation processin which insulin-degrading enzyme (IDE) is involved. Ifchronic peripheral hyperinsulinemia exists, insulin trans-port across the blood-brain barrier will decrease. This isimportant because, among other effects in the brain, insulinpromotes learning and long-term memory, stimulates ace-cylcholinesterase expression responsible for acetylcholine,and decreases phosphorylation of tau proteins.7,8 Insulinactivates IDEs and, when effective insulin levels are low,IDE activation may be lower, and a greater harmful accu-mulation of �-amyloid may therefore occur.2 Thus, possiblediabetes 3 would be defined as the condition occurring whenhyperinsulinemia in response to insulin resistance leads to adecrease in cerebral insulin and poor regulation of IDE. �-Amyloid would accumulate due to its decreased degradationby IDE, among other mechanisms.2,9

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