Type 3 Diabetes is Sporadic Alzheimer’s disease: Mini-Review

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is a metabolic disease mediated by impairments in brain insulin responsiveness, glucose utilization, and energy metabolism, which lead to increased oxidative stress, inflammation, and worsening of insulin resistance. In addition, metabolic derangements directly contribute to the structural, functional, molecular, and biochemical abnormalities that characterize AD, including neuronal loss, synaptic disconnection, tau hyperphosphorylation, and amyloid-beta accumulation. Because the fundamental abnormalities in AD represent effects of brain insulin resistance and deficiency, and the molecular and biochemical consequences overlap with Type 1 and Type 2 diabetes, we suggest the term ‘Type 3 diabetes’ to account for the underlying abnormalities associated with AD-type neurodegeneration. In light of the rapid increases in sporadic AD prevalence rates and vastly expanded use of nitrites and nitrates in foods and agricultural products over the past 30–40 years, the potential role of nitrosamine exposures as mediators of Type 3 diabetes is discussed.

Alzheimer’s disease and brain glucose starvation

Sporadic Alzheimer’s disease (AD) is the most common cause of dementia in North America and its high incidence and prevalence rates now constitute an epidemic (de la Monte et al., 2009b). AD diagnosis is based on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) and DSM-IV criteria (Cummings, 2007). Although neuroimaging and biomarker panels are beginning to facilitate its detection and severity (Gustaw-Rothenberg et al., 2010), a definitive diagnosis can only be rendered by postmortem examination of the brain. AD presence and severity are gauged by the distribution and abundance of related and characteristic lesions, including neuronal loss, gliosis, insoluble aggregates of abnormally phosphorylated and ubiquitinated tau in the forms of neurofibrillary tangles, dystrophic neurites and neuropil threads, and neurotoxic amyloid-beta precursor protein peptides (AβPP-Aβ) as oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers are neurotoxic and inhibit synaptic plasticity (Walsh et al., 2002). Beyond these effects, AD is associated with degeneration and disconnection of synaptic terminals, disruption of the cortical laminar architecture, neuro-inflammation, and white matter fiber loss.

For decades, the dominant hypothesis was that neurodegeneration is caused by one or two of the specific lesions that characterize AD, e.g. AβPP-Aβ accumulation, pTau aggregation, or neuro-inflammation. However, a stream of human and experimental studies has provided convincing evidence that AD is a metabolic disease whereby the brain loses its capacity to efficiently utilize glucose for energy production and respond to critical trophic factor signals due to insulin as well as insulin-like growth factor (IGF) resistance (Baker et al., 2010; Craft, 2007; Hoyer, 2002, 2004b; Krikorian et al., 2010; Luchsinger, 2010; Neumann et al., 2008; Rivera et al., 2005; Schubert et al., 2004; Steen et al., 2005; Talbot et al., 2012; Watson and Craft, 2006). The molecular and biochemical consequences of insulin and IGF resistance in the brain are similar to those in other organs and tissues; however, in brain, insulin signaling impairments compromise neuronal survival, energy production, gene expression, plasticity and white matter integrity (de la Monte, 2011; de la Monte et al., 2009a). Since glucose is the primary fuel for the brain, deficits in glucose uptake and utilization cause the brain to “starve”. With the starvation comes oxidative stress, impairments in homeostasis, and increased cell death. Inhibition of insulin/IGF signaling mediates AD neurodegeneration due to increased: 1) activity of kinases that aberrantly phosphorylate tau; 2) accumulation of AβPP-Aβ; 3) oxidative and endoplasmic reticulum (ER) stress; 4) generation of reactive oxygen and reactive nitrogen species that damage proteins, RNA, DNA, and lipids; 5) mitochondrial dysfunction; and 6) signaling through pro-inflammatory and pro-apoptosis cascades (de la Monte, 2011, 2012; de la Monte et al., 2009a; de la Monte et al., 2012). In addition, insulin resistance down-regulates target genes needed for cholinergic function, further compromising neuronal plasticity, memory, and cognition (de la Monte, 2011; de la Monte et al., 2009a).

Insulin and IGF Actions in the Brain

In the central nervous system (CNS), insulin and IGF signaling pathways play critical roles in cognitive function. Insulin, IGF-1 and IGF-2 polypeptide and receptor genes are expressed in neurons (de la Monte and Wands, 2005) and glial cells (Broughton et al., 2007; Freude et al., 2009; Zeger et al., 2007) throughout the brain; their highest levels are in structures that are heavily targeted by neurodegeneration, particularly AD (de la Monte et al., 2009a; de la Monte and Wands, 2005). Insulin and IGFs regulate a wide range of neuronal functions through ligand-receptor binding and activation of intrinsic receptor tyrosine kinases. Subsequent interactions between phosphorylated receptors and insulin receptor substrate molecules mediate transmission of signals downstream, and thereby inhibit apoptosis, and stimulate growth, survival, metabolism, and plasticity (de la Monte et al., 2009a; de la Monte and Wands, 2005). The anti-apoptosis mechanisms that insulin/IGF-1 inhibit include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3β (GSK-3β), and nuclear factor kappa B (NF-κB) (de la Monte et al., 2009a). GSK-3β regulates Wnt signaling by phosphorylating β-catenin, leading to its degradation via the ubiquitin-proteasome pathway (Cadigan and Liu, 2006; Foltz et al., 2002). Since Wnt mediates synaptic plasticity (Contestabile et al., 2013; Tabatadze et al., 2012; Varela-Nallar and Inestrosa, 2013), impairments in insulin/IGF signaling compromise cross-talk with various Wnt functions in the brain. In essence, insulin/IGF pathways support neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, neurotransmitter function, and plasticity (Chesik et al., 2008; de la Monte and Wands, 2005; Gong et al., 2008; Liang et al., 2007). Correspondingly, impaired insulin/IGF signaling has dire effects on the CNS’s structural and functional integrity.

Evidence of Type 3 Diabetes (Brain Insulin and IGF Resistance and Deficiency) in AD

The concept that AD represents a metabolic disease stemmed from studies showing that deficits cerebral glucose utilization were present very early in the course of disease (Caselli et al., 2008; Langbaum et al., 2010; Mosconi et al., 2009; Mosconi et al., 2008), either prior to, or coincident with the initial stages of cognitive dysfunction (Hoyer, 2004a; Iwangoff et al., 1980). Deficits in cerebral glucose utilization and energy metabolism worsen with progression of cognitive impairment (Hoyer et al., 1991). Furthermore, human postmortem studies revealed that brains from clinically well-characterized patients with pathologically proven AD have molecular and biochemical evidence of insulin and IGF resistance and deficiencies, as well as impairments in signal transduction (Rivera et al., 2005; Steen et al., 2005).

Brain insulin/IGF resistance is manifested by reduced levels of insulin/IGF receptor binding and decreased responsiveness to insulin/IGF stimulation (Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012), while insulin/IGF deficiencies are associated with altered expression of insulin and IGF polypeptides in brain and cerebrospinal fluid (Hoyer, 2004a, b; Rivera et al., 2005; Steen et al., 2005). These findings support the concept that chronic deficits in insulin signaling mediate the pathogenesis of AD (Steen et al., 2005). Moreover, AD could be regarded as a brain disorder that has composite features of Type 1 (insulin deficiency) and Type 2 (insulin resistance) diabetes. To consolidate this concept, we proposed that AD be referred to as, “Type 3 diabetes” (Rivera et al., 2005; Steen et al., 2005). As insulin stimulates brain glucose uptake and utilization (de la Monte and Wands, 2005), metabolism, memory, and cognition (Benedict et al., 2004; Craft et al., 2003; Krikorian et al., 2010; Reger et al., 2006; Reger et al., 2008), insulin resistance/deficiency associated impairments in glucose metabolism disrupt brain energy balance, increasing oxidative stress, reactive oxygen species (ROS) production, DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades (de la Monte et al., 2009a; de la Monte and Wands, 2005). Correspondingly, experimental depletion or suppression of brain insulin receptor expression and function causes cognitive impairment and molecular and biochemical abnormalities seen in AD (de la Monte et al., 2011; Grunblatt et al., 2007; Hoyer et al., 2000; Labak et al., 2010; Lester-Coll et al., 2006).

Role of Insulin/IGF resistance in Brain Metabolic Dysfunction and Oxidative Stress in AD

Insulin and IGF signaling regulate glucose utilization, metabolism, and ATP synthesis needed for both homeostasis and dynamic modulation of cellular functions (de la Monte and Wands, 2005; Frolich et al., 1998). Consequently, brain insulin/IGF resistance and deficiency are accompanied by impairments in glucose utilization and disruption of energy metabolism, with attendant increases in oxidative stress, ROS production, DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades (de la Monte and Wands, 2006; Frolich et al., 1998; Hoyer, 2002, 2004b; Rivera et al., 2005; Steen et al., 2005). Moreover, as AD progresses, cerebral glucose utilization, responses to insulin signaling, and expression of insulin-responsive genes decline (Rivera et al., 2005; Talbot et al., 2012). Correspondingly, experimental depletion or suppression of brain insulin receptor expression and function causes cognitive impairment and AD-type neurodegeneration (de la Monte et al., 2011; Grunblatt et al., 2007; Hoyer et al., 2000; Labak et al., 2010; Lannert and Hoyer, 1998; Lester-Coll et al., 2006).

Brain glucose uptake and utilization are mediated by glucose transporter (GLUT) proteins, whose expression and function are regulated by insulin. GLUT4 is abundantly expressed along with insulin receptors, in medial temporal structures, which are notable targets of AD. Insulin stimulates GLUT4 expression and protein trafficking from the cytosol to the plasma membrane to modulate glucose uptake and utilization (Gonzalez-Sanchez and Serrano-Rios, 2007). Therefore, insulin stimulation of GLUT4 is critical for regulating neuronal metabolism and energy production which are needed for memory and cognition. Despite evidence for brain insulin resistance and deficiency in AD, postmortem brain studies have not detected reduced levels of GLUT4 expression (Steen et al., 2005). Instead, the well-documented deficits in brain glucose utilization and energy metabolism vis-a-vis brain insulin/IGF resistance could be mediated by impairments in GLUT4 trafficking between the cytosol and plasma membrane (Winocur et al., 2005).

Deficiencies in energy metabolism caused by inhibition of insulin/IGF signaling promote oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokine activation (de la Monte and Wands, 2002; Hoyer and Lannert, 1999; Hoyer et al., 2000). Oxidative stress leads to the generation and accumulation of ROS and reactive nitrogen species, which attack subcellular organelles and cause chemical modifications of DNA, RNA, lipids, and proteins. For example, adducts formed with macromolecules can compromise the structural and functional integrity of neurons due to loss of membrane functions, disruption of the cytoskeleton, dystrophy of synaptic terminals, deficits in neurotransmitter functions and plasticity, and perturbation of signaling pathways for energy metabolism, homeostasis, and cell survival.

Impaired insulin/IGF signaling and tau pathology in AD

Neurofibrillary tangles and dystrophic neurites are the main neuronal cytoskeletal lesions that correlate with severity of dementia in AD (Duyckaerts et al., 2009; Takashima, 2009). Mechanistically, the microtubule-associated protein, tau, gets hyper-phosphorylated due to inappropriate activation of proline-directed kinases such as GSK-3β. Consequently, tau misfolds and self-aggregates into insoluble fibrillar structures (paired helical filaments and straight filaments) that form neurofibrillary tangles, dystrophic neurites, and neuropil threads (Iqbal et al., 2009). Intra-neuronal accumulations of fibrillar tau disrupt neuronal cytoskeletal networks and axonal transport, leading to synaptic disconnection and progressive neurodegeneration (Iqbal et al., 2009). Besides fibrillar tau, pre-fibrillar tau can aggregate, forming soluble tau oligomers or insoluble granular tau, which also contribute to neurodegeneration by causing synaptic disconnection and neuronal death (Takashima, 2010). The eventual ubiquitination of hyper-phosphorylated tau (Arnaud et al., 2006), combined with dysfunction of the ubiquitin-proteasome system (Oddo, 2008), cause further accumulations of insoluble fibrillar tau, oxidative stress, and ROS generation, leading to increased neuronal apoptosis, mitochondrial dysfunction, and necrosis in AD (Mandelkow et al., 2003).

Growing evidence suggests that many of the aforementioned cellular aspects of AD neurodegeneration can be mediated by brain insulin/IGF resistance (de la Monte et al., 2000; de la Monte et al., 2001; de la Monte and Wands, 2002; Rivera et al., 2005; Steen et al., 2005; Xu et al., 2003). Tau expression and phosphorylation are regulated by insulin and IGF (Schubert et al., 2003; Schubert et al., 2004). In AD, brain insulin and IGF resistance reduces signaling through phosphoinositol-3-kinase (PI3K), Akt (Schubert et al., 2003; Schubert et al., 2004), and Wnt/β-catenin (Doble and Woodgett, 2003), and increases activation of GSK-3β (De Ferrari and Inestrosa, 2000; Fraser et al., 2001; Grilli et al., 2003; Mudher et al., 2001; Nishimura et al., 1999). GSK-3β over-activation is partly responsible for the hyper-phosphorylation of tau, which promotes tau misfolding and fibril aggregation (Bhat et al., 2003). In addition, AD tau pathology is mediated by impaired tau gene expression due to reduced insulin and IGF signaling (de la Monte et al., 2003). Consequences include failure to generate sufficient quantities of normal soluble tau vis-a-vis accumulation of hyper-phosphorylated insoluble fibillar tau, and attendant exacerbation of cytoskeletal collapse, neurite retraction, and synaptic disconnection.

Insulin/IGF resistance and Amyloid-beta (AβPP-Aβ) neurotoxicity

AD is associated with dysregulated expression and processing of amyloid precursor protein (AβPP), resulting in the accumulation of neurotoxic AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils (plaques). Increased AβPP gene expression, together with altered proteolysis, lead to accumulations of 40 or 42 amino acid length AβPP-Aβ peptides that can aggregate. In familial AD, mutations in the AβPP, presenilin 1 (PS1), or PS2 genes, and inheritance of the Apoliprotein E ε4 (ApoE- ε4) allele promote AβPP-Aβ accumulation in the brain. In sporadic AD, which accounts for 90% or more of the cases, the causes of AβPP-Aβ accumulation are not well understood. However, recent evidence points to brain insulin/IGF resistance as both causal and consequential factors.

Studies have shown that insulin stimulation promotes trafficking of AβPP-Aβ from the trans-Golgi network where it originates, to the plasma membrane for extracellular secretion (Watson et al., 2003). In addition, insulin inhibits AβPP-Aβ’s intracellular accumulation and degradation by insulin-degrading enzyme (Gasparini et al., 2001; Gasparini et al., 2002). Impairments in insulin signaling disrupt AβPP processing and AβPP-Aβ clearance in the brain (Messier and Teutenberg, 2005). Accumulation of AβPP-Aβ further compromises insulin signaling by decreasing insulin’s binding affinity to its own receptor, worsening effects of insulin resistance (Ling et al., 2002; Xie et al., 2002). Furthermore, AβPP-Aβ oligomers inhibit neuronal transmission of insulin-stimulated signals by desensitizing and reducing the surface expression of insulin receptors. Finally, intracellular AβPP-Aβ directly interferes with PI3 kinase activation of Akt, impairing neuronal survival and increasing GSK-3β activation and hyper-phosphorylation of tau. As discussed, hyper-phosphorylated tau is prone to misfold, aggregate, and become ubiquitinated, prompting the formation of dementia-associated paired-helical filament-containing neuronal cytoskeletal lesions.

Potential mechanisms of brain insulin/IGF resistance in neurodegeneration

Although aging is clearly the dominant risk factor for AD, growing evidence suggests that brain insulin/IGF resistance is a major factor contributing to mild cognitive impairment, dementia, and AD (Craft, 2005b, 2006; de la Monte et al., 2009a; Hoyer et al., 1991; Rivera et al., 2005). Within the past several years, this field of research has greatly expanded due to growing information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment (Craft, 2005a, 2006, 2007; de la Monte et al., 2006; Lester-Coll et al., 2006; Rivera et al., 2005; Steen et al., 2005). A convincing argument could be made that AD, in its pure form, represents a brain form of diabetes mellitus (Craft, 2007; Hoyer, 2002; Hoyer et al., 1991; Rivera et al., 2005; Steen et al., 2005) since AD is often associated with progressive brain insulin resistance in the absence of Type 2 diabetes, obesity, or peripheral insulin resistance (de la Monte, 2011; de la Monte et al., 2009a; Rivera et al., 2005; Steen et al., 2005). Moreover, postmortem studies demonstrated that the molecular, biochemical, and signal transduction abnormalities in AD are virtually identical to those in Type 1 and Type 2 diabetes mellitus (Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).

The strongest evidence favoring the concept that AD is Type 3 diabetes comes from experimental studies in which rats were administered intracerebroventricular injections of streptozotocin, a pro-diabetes drug. Streptozotocin treated rats develop cognitive impairment with deficits in spatial learning and memory, brain insulin resistance and insulin deficiency, and AD-type neurodegeneration (Hoyer et al., 1999; Lester-Coll et al., 2006; Weinstock and Shoham, 2004). Therefore, targeted exposure to a pro-diabetes drug can cause neurodegeneration with structural, molecular, biochemical and functional abnormalities that closely mimic the pathology of AD in humans.

This line of research was extended based upon the facts that streptozotocin is a nitrosamine-related compound, and over the past several decades, Western societies have been assaulted by continuous and escalated contacts with environmental, agricultural, and food source nitrates and nitrites that result in increased nitrosamine exposures (de la Monte et al., 2009b). We found that experimental exposures to low, sub-mutagenic doses of the nitrosamines that can be found in processed and preserved foods, e.g. N-nitrosodiethylamine (NDEA), cause cognitive impairment, AD-type neurodegeneration, and brain insulin resistance (de la Monte et al., 2009c; Tong et al., 2010; Tong et al., 2009), similar to the effects of streptozotocin. Therefore, nitrosamine-related chemicals can cause Type 3 diabetes, mimicking the abnormalities seen in sporadic AD. We postulate that the rapid increases in prevalence rates of sporadic AD (Type 3 diabetes) are due to environmental exposures such as nitrosamines that contaminate highly processed and preserved foods and have become staples in our diets over the past 50 years (de la Monte and Tong, 2009). Further research is needed to better assess the impact of such exogenous mediators of neurodegeneration, and the spectrum of agents that can produce similar abnormalities leading to AD-type neurodegeneration.