Neuropathology of type 2 diabetes: a short review on insulin-related mechanisms
Introduction
There are two major types of diabetes. Type 1 (T1D), which affects primarily children results from dysfunction in insulin-producing pancreatic beta cells; and type 2 diabetes (T2D), which results from insulin resistance (reduced response to insulin), affects primarily adults, represents about 90% of all diabetes cases, and is the focus of this review. T2D causes micro- and macrovascular complications including peripheral neuropathy, nephropathy, retinopathy, cardiovascular disease (Cefalu, 2006, Wrighten et al., 2009), and cerebrovascular disease (CVD). Brain changes observed in T2D (white matter lesions, lacunar infarcts, and cortical atrophy) (Nelson et al., 2009, van Harten, 2006) are associated with cognitive dysfunction and worsened by vascular risk factors (hypertension and dyslipidemia) (Gold, 2007, van Harten, 2007). Alzheimer׳s disease (AD)-related neuropathology (neuritic plaques and neurofibrillary tangles [NFTs]) is also found in T2D. These brain abnormalities are also associated with the cognitive deficits and increased risk for dementia consistently observed in T2D, particularly in those carrying the apolipoprotein E-epsilon 4 (APOE ε4) allele (Peila et al., 2002). In view of the projected increase in percentage of the elderly population from 2015 to 2060—particularly those aged 65 and over (14.84% to 21.90%, respectively) and 85 and above (1.96% to 4.33%, respectively)—(US Census Bureau, 2012), and the projected prevalence of T2D (by 2030, 82 million of elderly over 64 years of age are projected to have T2D in developing countries and over 48 million in developed countries) (Wild, 2004), disentangling neuropathological complications deriving from T2D leading to cognitive impairment and disability is an intensifying public health and scientific concern.
This paper reviews the literature describing the neuropathology of T2D in brain tissue samples of animals and humans, with a focus on CVD and AD-type neuropathology. The contribution of insulin dysfunction and hyperglycemia in CVD and in AD-type neuropathology is discussed.
Considering the decades-long survival with T2D in humans, animal research is both time- and cost-effective. Although no animal models exhibit all T2D characteristics observed in humans—its pathophysiology, progression, and complications that lead to comorbidity and mortality—they provide a crucial window for understanding T2D pathophysiology (Cefalu, 2006), and will be included in this review. In this issue of European Neuropsychopharmacology, Brundel et al. reviews neuroimaging findings in T2D and thus those are excluded from this review.
Section snippets
Overview
One of the largest neuropathological studies of CVD in T2D dates back to 1973 with 5479 autopsies of which 677 were individuals with diabetes, primarily T2D. T2D cases presented with more infratentorial encephalomalacia (softening of brain tissue) as shown by at least three times as many infarctions in the pontine basis in various age groups (e.g., ages 56–65, 66–75, 76–85) (Aronson, 1973). That these infarcts were non-lethal and subclinical is supported by more recent postmortem T2D studies
Overview
While AGEs may be the important mechanisms involved in the association between hyperglycemia and CVD in T2D, disruption in insulin signaling appears to be implicated in the association of T2D with AD neuropathology. Peripheral insulin can cross the blood-brain barrier, thus increasing the amount of insulin and affecting its receptors in the brain. A small proportion of insulin is also synthesized in the brain, and its receptors are located in brain areas including the hippocampus and the
Conclusion
CVD is a well-established neuropathology associated with T2D. Mechanisms deriving from hyperglycemia (e.g., AGEs) underlie this increased prevalence of CVD in T2D. In contrast, a relationship of T2D to AD neuropathology has not been established despite substantial support for such a relationship from epidemiological studies, and from animal models. This discrepancy may depend on the fact that the vast majority of T2D patients are treated by T2D medications making it difficult to tease out the
Role of funding source
This study was supported by NIA Grants R01 AG034087 to Dr. Beeri and P50 AG005138 to Dr. Sano, the Helen Bader Foundation and the Irma T. Hirschl Scholar award to Dr. Beeri.
Contributors
Elizabeth Guerrero-Berroa: conducted the literature search and wrote the manuscript.
James Schmeidler: contributed to the writing and editing of the manuscript.
Michal Schnaider Beeri: led discussion of the original idea of the review and its organization, provided supervision and guidance, and contributed to the writing and editing of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
None.
Acknowledgment
None.
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