Efficient delivery of glucose to brain cells is critical for brain function [12]. Glucose uptake by the brain cells appears to be independent of insulin; however neurons are known to express receptors for insulin and insulin related peptide (insulin-like growth factor 1 [IGF-1]) [12]. Both insulin and IGF-1 play important roles in neuronal development and affect cognition [12]. Insulin resistance and consequent abnormal blood glucose levels as observed in type 2 diabetes mellitus can have detrimental effects on brain and cognitive function [1314]. Fluctuation in glucose levels or peaks, which is common in diabetes, increases the risk for cognitive decline. Targeting glucose peaks has been proposed as therapeutic strategy for prevention of diabetes-associated cognitive dysfunction [14]. In laboratory animals, glucose lowering compounds such as metformin, thiazolidinediones and compounds targeting the glucagon like peptide-1 receptor have beneficial effects on cognition [10]. It was reported that agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcriptional factor, improved brain function in a rat model of streptozotocin-induced diabetes [15]. Decreased activity of PPARγ and its cofactor peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) causes mitochondrial dysfunction and oxidative stress in the settings of type 2 diabetes mellitus and in brain disorders. Glucose lowering thiazolidinediones, such as rosiglitazone and pioglitazone, act as agonist for PPARγ and improve cognitive function. Glucagon-like peptide 1 (GLP-1) receptor agonists are known elicit neuroprotective effects in animal models of stroke, Alzheimer's disease (AD) and Parkinson's disease [16]. GLP-1 receptor agonists reduced neuro-inflammation and increased neuro-survival [16]. Metformin reduces tau hyper-phosphorylation by inducing protein phosphatase 2A (PP2A) activity, a major tau phosphatase [17].

Elevated levels of plasma triglycerides and cholesterol may play a role in diabetes-associated risk for poor cognition function [1819]. Pharmacological interventions to ameliorate dyslipidemia may influence the progression of cognitive decline in individuals with diabetes and cerebrovascular disease [1819]. Cholesterol modulates the activity of enzymes involved (β and γ-secretases) in amyloid precursor protein (APP) processing and thus it can affect production of amyloid β (Aβ) protein. Because β and γ-secretases enzymes are membrane bound enzymes, the high cholesterol content in membrane lipid rafts could facilitate clustering of these enzymes with their substrate, thereby promoting cleavage of precursors of Aβ protein into amyloidogenic forms [20].

Cerebrovascular complications in individuals with diabetes are frequently linked to the presence of hypertension [2122]. The use of anti-hypertensive medications may diminish the risk of dementia in diabetic patients by 4% to 24% [23]; however, the underlying molecular mechanisms remain unknown [24].

Cerebrovascular accumulation of toxic lipids, advanced glycation end products (AGEs) and aggregated proteins trigger inflammatory responses and secretion of inflammatory mediators in the circulation [25262728]. Inflammatory responses are associated with blood-brain barrier (BBB) breakdown [29]. BBB injury further exposes brain parenchyma to neurotoxic blood proteins, thrombin, fibrin, plasmin, hemoglobin, and iron from lysed red blood cells. A leaky BBB causes abnormal neuronal activity [29] that plays a role in diabetes-associated neurological deficits [30].

Chronically elevated levels of C-reactive proteins, interleukin 6 (IL-6), fibrinogen, and tumor necrosis factor α are strongly correlated with cognitive decrement in diabetic patients [31323334]. Reducing systemic inflammation promotes brain health [31323334].

Macrovascular disease such as myocardial infarction or stroke negatively affects cognitive performance [835]. Microvascular abnormalities are also frequent in patients with type 2 diabetes mellitus [835]. Patients with diabetes and individuals with normal metabolic function showing retinal microvascular abnormalities are at high risk of cognitive decline [36]. Due to similarities between retina cells and cerebrovascular cells, retinopathy can be used as a marker and therapeutic target for microangiopathy and cerebral small vessel disease [37]. It is speculated that cerebral small vessel disease might be due to long term endothelium dysfunction, capillary loss and subsequent ischemia leading to white matter disease and neurological deficits [252829]. White matter disease of vascular origin is commonly associated with vascular contributions to cognitive impairment and dementia (VCID) [252829].

Vascular endothelial cell dysfunction is linked to vascular accumulation of toxic lipids [26], AGEs [27] and aggregated proteins [25]. Interaction of AGEs with endothelial cells increases generation of reactive oxygen species (ROS) [27] and impairs the production of vasodilatory substances resulting in a reduced cerebral blood flow [38]. Elevated ROS damage cellular structures and activate matrix metalloproteinases enzyme, which further induce cytoskeletal reorganization and vascular remodeling [29]. Cytoskeletal reorganization increases the vascular permeability by disrupting tight junction proteins in endothelium, which increases energy depletion and alters neural viability [2938].

Amylin, or islet APP, is a pancreatic hormone that is synthesized and co-secreted with insulin by pancreatic β-cells and participates in the central regulation of satiety [39]. Individuals with pre-diabetic insulin resistance have hypersecretion of amylin (and insulin) leading to amylin oligomerization and pancreatic amylin amyloid. Amylin dyshomeostasis plays an important role in the development and progression of type 2 diabetes mellitus [394041]. Deposits of amylin amyloid were detected in extra-pancreatic tissues, including the heart [42], kidneys [43] and the brain [4445464748]. Because amylin amyloid is toxic [394041], the presence of amylin deposition in brains of individuals with AD suggests that the development of drugs that could limit amylin deposition in the brain may provide benefit to patients with AD or mild cognitive impairment.

Altered Ca²⁺ signaling contributes in brain dysfunction through multiple mechanisms [49]. Erickson et al. [50], showed that diabetes causes Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) modification at Ser²⁷⁹ through o-linked N-acetylglucosamine (O-GlcNAc). This modification of CaMKII has been detected both in hearts and brains of humans with type 2 diabetes mellitus [50].

Brain insulin resistance increases the activity of β-secretase and γ-secretase [5455] promoting cerebral Aβ deposition and tau hyperphosphorylation [51525354555657]. Intracerebroventricular administration of insulin increased learning ability in normal mice [5859]; however, a similar treatment showed no significant effect on brain function in diabetic mice [59]. Cerebral accumulation of Aβ and phosphorylation of tau in mice were reduced by pharmacological interventions that ameliorate insulin resistance [60].

In a rat model for type 2 diabetes mellitus transgenic for human islet amyloid polypeptide (the HIP rat) [25], the development of diabetes is associated with amylin-mediated vascular endothelial dysfunction leading to axonal demyelination, white matter rarefaction and neurological deficits [25]. Phenylalanine and tyrosine, two main precursors of neurotransmitters, were greatly decreased in brains of diabetic HIP rats compared to non-diabetic littermates [61]. These results [2561] indicate amylin dyshomeostasis as a direct molecular link between pancreatic pathology in diabetes and VCID.

In addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons [62]. Neuronal amylin formed adducts with 4-hydroxynonenal (4HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine IL-1β [62]. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin [62]. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4HNE [62]. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors [62]. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. Schematic view of effect of amylin dyshomeostasis on brain is shown in Fig. 2.