**3. Neuroinflammation in Type 2 Diabetes Mellitus (T2DM)**

This section presents data and interpretation of the effect of T2DM on brain structure and function in relation to neuroinflammation. Brain tissue of T2DM patients exhibiting cognitive impairment contains deposits of amylin [islet amyloid polypeptide (IAPP)], a peptide hormone synthesized and co-secreted with insulin by pancreatic β cells [39]. Amylin deposition occurs following chronic over-secretion of amylin (hyper-amylinemia), common in humans with obesity or pre-diabetes insulin resistance. It is toxic, causes pancreatic islet inflammation and is thought to contribute to the development of T2DM [40,41]. Hyper-amylinemia and its consequent oligomerization mediate an inflammatory response, inducing neurological defects [39]. Using a rat model of overexpression of human amylin in the pancreas (the HIP rat) Luchsinger and Nelson et al. [42,43] observed psychomotor speed disturbances followed by full-blown T2DM (blood glucose > 10 nM) accompanied by a significant drop in cognition and memory. Janciauskiene and Ahren and Westwell-Roper et al. [44,45] reported elevation of the pro-inflammatory cytokines TNF-α and IL-6 and down-regulation of the anti-inflammatory cytokine IL-10 in brains from HIP rats. These data support the notion that "human" hyper-amylinemia promotes accumulation of brain oligomerized amylin which, in turn, might trigger an inflammatory response leading to neurological deficits. Using the same HIP rat, Srodulski et al. [39] further describe significantly reduced exploratory drive and impairment in the rotarod test, implicating that infusion of amylin decreases ambulation and locomotion ability in rats. The decline in long-term memory suggests a direct impact of hyper-amylinemia on hippocampal neurons. The authors also found activated microglia, particularly gathering around the small blood vessels in areas positive for amylin infiltration, implicative of neuroinflammation. The latter corroborate the study by Bahniwal et al [46]. They investigated the effects of elevated glucose concentrations (up to 30.5 mM) on functions of cultured human astrocytes in the presence of inflammatory stimuli. Using primary human astrocytes and U-118 MG astrocytoma cells, they found that high glucose increased mRNA expression of IL-6 and secretion of both IL-6 and IL-8 by astrocytes. High glucose also increased the susceptibility of undifferentiated human SH-SY5Y neuronal cells to injury by hydrogen peroxide.

Hyperglycemia in T2DM could contribute to worsening cognitive impairment [47]. This was seen in a rat model of vascular dementia caused by an impaired supply of blood to

the brain, and by chronic neuronal inflammation caused by the activation of brain microglia and astrocytes, which might further contribute to neuronal loss [48–50].

To conclude, T2DM might involve neuroinflammation. Hence, neuroinflammation inhibitors might be novel drugs for this disease. In the case of T2DM induced by brain injury, the list of such targets may also include antioxidants and neurotrophic factors. Since the studies described above imply that brain amylin accumulation might be a pathological substrate for diabetic patients with cognitive decline, reducing blood amylin levels might be another direction for drug design in T2DM. Additional studies are required to clarify the link between brain amylin pathology and impaired cognition, and to search for drugs that will protect the brain in T2DM patients.
