I. Title page
IV Prevalence &Pathogenesis of type 3 diabetes mellitus
V Proposed Treatment for type 3 diabetes (AD)
VI Metformin and type 3 diabetes mellitus
VII The intestinal microbiota and type 3 diabetes mellitus
VIII Probiotics, gut microbiota, and Alzheimer's disease
Chapter 1. Introduction
Dementia is a multifaceted syndrome with a significant public health, social, and economic burden; there are forty-four million people affected by the disease worldwide according to the most recent estimate. The number is projected to double by the year 2030 and to triple by 2050 (1,2).
Alzheimer's disease ( AD, or type-3 diabetes mellitus) and vascular dementia are the most common forms of dementia. Lifestyle risk factors including obesity and type 2 diabetes increase the risk for the development of both vascular and nonvascular dementia in later life. Previous literature reported that people with diabetes mellitus had 70% greater risk for dementia development (3). Traditionally, type-2 diabetes and AD (type-3 diabetes) have been thought as independent disorders; recent literature suggests possible links that could lead to common effective modalities of treatment. Furthermore, the highly innervated pancreas shares many features with the brain at molecular levels (4).
Metformin is recommended as the first line for the treatment of patients with type 2 diabetes mellitus due to its effectiveness, favorable effects on lipids and cardiovascular risks, and safety profile. The previous restriction of the use of metformin in patients with the moderate renal disease is loosened by the Food and Drug Organization(5,6). Thus the use of this valuable and affordable drug is expected to increase.
The American Diabetes Association recommended the periodic measurement of vitamin B12 and supplementation as needed to reflect the recent evidence showing the association of long-term use of metformin and B12 deficiency (6). Although the role of vitamin B12 deficiency in the development of dementia is well-established, the role of metformin in B12 deficiency and dementia remain to be elucidated (7,8).
Insulin resistance is considered as a primary factor for the association of diabetes mellitus and dementia. However, the role of insulin sensitizer in the prevention of dementia remains unclear(9). Furthermore, there is an increasing concern about the role of metformin in cognitive disorders (10). Thus we conducted this narrative review, in this study we reviewed the literature to assess the interaction of Alzheimer's disease, the gut, and its microbiome, and to assess the role of metformin and other drugs used for type 1&2 diabetes mellitus as possible therapies for the AD. The role of microbiota and fecal transplantation on cognitive disorders was also discussed.
Chapter 2.Prevalence &Pathogenesis of type 3 diabetes mellitus
Dementia is characterized by global progressive cognitive dysfunction including learning, memory, speech, comprehension, orientation, and judgment. The most common form of dementia is Alzheimer's disease (AD) accounting for more than 60%. Due to the increasing aging population, the disease is on the rise. Currently, 36 million people were affected worldwide and the projection for the year 2050 is > 115 million. Dementia poses a significant burden on the patients, family, healthcare system, and the community as a whole (11-13).
Glucose is an essential energy source for human body function. The regulation of this vital energy involves the interaction of the liver, the pancreas, and brain. Glucose is converted to lactate by astrocytes; this lactate is essential for neuronal metabolism, the expression of genes involved in memory, and the formation of dendrites and synapses. The disruption of the physiological balance could result in metabolic compromise leading to diabetes including type-3 diabetes (AD). Age is an essential risk factor for both type-2 and type-3 diabetes mellitus, as the brain ages it becomes more liable to cell damage induced with high plasma sugar and this could explain the development of cognitive impairment observed in some patients with diabetes. The brain is highly susceptible to plasma glucose perpetuation, and both hypoglycemia and hyperglycemia are dangerous (14).
Alzheimer's disease (AD) a degenerative brain disease is also called type 3 diabetes. It is the most frequent cause of dementia and characterized by extracellular amyloid beta (Aβ) plaques and intraneuronal deposits of neurofibrillary tangles (NFTs). Due to the increasing age of the population, the disease is on the rise worldwide. The growing rate of AD among older adults is also associated with the uprise in obesity and type 2 diabetes mellitus. Thus many consider AD as a metabolic disease. The diseases share many features including risk factors, demographic profiles, and clinical and biochemical characteristics. Antioxidant, insulin and adiponectin were suggested as mechanisms linking the three disorders. Previous literature reported reduced insulin signal transductions in the brain. Furthermore, insulin injected (intranasal) has been shown to affect AD treatment. Also, oxidative stress induction by Aβ and NFTs and the reduced levels of adiponectin observed among patients with type 2 diabetes and obesity are suggested as causes for the metabolic dysfunction in both the brain and other organs linking AD to obesity and type 2 diabetes (15).
Alzheimer's disease is often called brain diabetes or type 3 diabetes mellitus because it showed reduced neuronal insulin receptors and insulin expression with the ultimate breakdown of insulin signaling pathway (the bases of insulin resistance). These observations led scientist to suggest that AD is a neuroendocrine disorder resembling type 2 diabetes mellitus in term of insulin resistance that leads to brain metabolic disturbances and cognitive impairment (16). Due to the shared cellular and molecular features in type 1, type 2 diabetes, and insulin resistance associated with cognitive decline and memory loss among the elderly population, the researchers proposed the term type 3 diabetes for Alzheimer's disease. The AD has composite features of insulin deficiency and insulin resistance (both type-1 and type 2 diabetes mellitus). Insulin is involved in the activation of glycogen synthase kinase 3β, to phosphorylate tau, the latter is involved in the formation of neurofibrillary tangles. Interestingly, insulin also plays a principal role in amyloid plaques formation (17). Another substance that can alter the mechanism involved in type 2 diabetes and Alzheimer's disease is Humanin a recently introduced, mitochondrial-derived peptide with neuroprotective effects (18).
Lifestyle modification could play an essential role in the prevention of AD. Previous literature showed that modifiable cardiovascular risk factors could increase the risk of the AD. Furthermore, physical inactivity and smoking constitute 37.7% of the population attributable (19). A lifestyle prevention program targeting both type 2 &3 diabetes mellitus is highly beneficial. The Mediterranean diet rich in fruits, vegetable, whole grain, moderate consumption of dairy products, polyunsaturated fatty acids, and low meat consumption has been shown to improve cognitive dysfunction. Mediterranean diet as a dietary pattern, the individual nutrients characteristic of this food, and other micronutrients like vitamins (C, E, and B-12) and flavonoids reduce oxidative stress and low grade inflammation and positively affect cognitive dysfunction (20). It is interesting to note that, the relationship between type-2 diabetes and type-3 diabetes is bidirectional. Patients with the AD are more susceptible to type-2 diabetes mellitus, AD-implicated brain dysfunction in the pathogenesis of T2DM could be possible. AD is also associated with chronic inflammation, oxidative stress and impaired cognition as well as metabolic alterations, including impaired neuronal insulin signaling, impaired cerebral energy metabolism, and reduced glucose metabolism. Whether these shared characteristics are due to obesity which is common in both type-3 and type-2 diabetes and if they are fixed or reversible needs further research. Obesity, type-2 diabetes and the chronic consumption of a high-fat diet (especially saturated fat) have been linked to reduced cognitive function in both animals and human studies, with some improvement with a healthier friendly diet Furthermore, AD mouse models crossed with genetic mouse models of diabetes (such as ob/ob and db/db), show early spatial learning and memory impairments(21).
Chapter 3. Proposed Treatment for type 3 diabetes (AD)
Patients with type -2 diabetes have higher rates of dementia (50-150% increased risk). AD is the commonest form of dementia and can be due to genes or sporadic. The latter is associated with seven modifiable risk factors namely: diabetes mellitus, obesity, physical inactivity, hypertension at middle age, smoking, lower level of education, and depression. Although a framework linking the neuropathological abnormalities in Alzheimer's disease is lacking, there is accumulating evidence that links the neuro-cognitive dysfunction to insulin deficiency and resistance. Given the above and the fact that most of the treatment of AD failed in the stage-3 trial, it could be possible that antihyperglycemic medications may be useful in AD (22).
Intranasal insulin spray: Trial on this type of therapy showed improvement in cognitive function especially among APOE-ε4 positive genotype. The dose was 201U; the APOE-ε4 negative genotype showed improvement at higher doses. The intranasal approach was used due to efficient insulin delivery through the olfactory and trigeminal perivascular channels and axonal pathways and a lower hypoglycemia risk (22). The side effects intranasal insulin are irritation, increasing blood pressure, and nasal mucosal damage. Delivering insulin directly to the brain could overcome these side effects, but the blood-brain barrier needs to be defeated (4).
Thiazolidinediones: Due to the unwanted effects, there is a restriction of these drugs and black box warning in some countries. A large trial recruiting 500 patients with AD showed cognitive improvement among APOE-ε4-negative patients (23). The extracellular accumulation ofamyloid β in the brain and the subsequent robust inflammatory response triggered are controlled by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ).Skerrett et al. in their animal study (24) observed that both LXRs andPPARγ agonists were associated with a lower deposition of amyloid β. Furthermore, the combination of the two agonists had a higher positive effect on cognitive dysfunction. A literature review (25) published in the year 2011 recommended against the use of PPARγ in the management of AD due to lack of efficacy and safety concerns. A randomized controlled trial (26) conducted among patients with mild cognitive dysfunction( not included in the previous review search) reported the improvement in cognitive dysfunction among patients taking pioglitazone, but no improvement in plasma Aβ40/Aβ42 ratio. A more recent (searched through December 2014 and published 2016) meta-analysis (27) stated that, in spite of the insufficient evidence for the current use, PPAR-γ agonists might be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm. Another meta-analysis (28) conducted in the same period concluded similar findings. On the other hands, some studies (29) questioned the effects of PPAR-γ agonists on AD. More studies (30) stated the beneficial effects of PPAR-γ agonists in restoring cerebrovascular dysfunctions. Recent literature (31) suggested combination therapy for the treatment of AD due to the interaction of several subcellular factors affecting astrocytes, neurons, and capillaries. The available drugs are lithium, valproate, pioglitazone, erythropoietin, and prazosin. With some studies showing some success using pioglitazone (32,33), the TOMMORROW Trial (34) will incorporate 6000 cognitively normal subjects and randomize them to either pioglitazone or placebo. The translocase of outer mitochondrial membrane 40 homolog gene (TOMM40 gene) which is linked to APOE4 and has been shown to predict the age of late-onset AD will be targeted (35).
GLP-1R agonists and DPP-IV inhibitors:GLP-1R agonists are an attractive option because they activate pathways common to bypassing IRs and boost insulin-related signaling pathways through G protein-dependent signaling. GLP-1 like preceptors agonists are structurally not similar and bind to different receptors. They readily cross the blood-brain barriers and less likely to cause hypoglycemia, so no problem with dosing.Animal studies showed thatExendin-4 and liraglutide restored impaired insulin signaling, exerting neuroprotective effects on neurons and synapses, improving cognition, and decreasing Aβ accumulation in the brain. Furthermore, GLP-1 agonists increase cell proliferation and facilitate neuronal network repair (36,37). Amylin secreted by pancreatic cells has limited endogenous utility due to precipitation and plaques and oligomers formation. Abnormal Amylin has been reported in the brain of patients with AD, and sometimes localized with Aβ amyloid. Amylin receptors are widely distributed in the brain substance and can readily cross the blood-brain barrier, so it is suggested to have widespread implications for mood, memory anxiety, and satiety, Pramlintide soluble, non aggregating synthetic analog of amylin that lower plasma glucose by insulin release, glucagon inhibition, decreased gastric emptying, and reduced appetite has been shown to improve cognition, and inhibit inflammation and oxidative stress in the hippocampus and cortex in animals models (38,39). The minimal side effects, excellent safety profile, and tolerability of this drug are appealing for the study and treatment of Alzheimer's disease. A recent prospective study conducted among elderly diabetic patients with and without dementia showed that sitagliptin (a DPP-IV inhibitor) is associated improved cognitive dysfunction in both study groups (40).A multi-center observational study (41) conducted in Japan investigated various diabetes medications use among patients with diabetes and dementia. The study assessed the family support, ease of use, resources, and an obstacle to insulin and other medications. The authors concluded that DPP-IV inhibitors were the appropriate drugs for patients suffering from both diabetes mellitus and dementia.
Insulin secretagogues (Glimiperide and glipizide):
In addition to pancreas stimulation, Glimiperide has extra-pancreatic functions through which it suppressesamyloid beta (Aβ) plaques and neurofibrillary tangles leading to improvement in cognitive abilities:
- Increase glucose uptake
- PPARγ activation
- Activation of GPI-anchored proteins
- suppression of BACE1 activity
The above actions indicated the promising effect of Glimiperide in the treatment of AD associated with type-2 diabetes mellitus (42-44)
Other proposed treatments:
Insulin-degrading enzyme (IDE) and Neprilysin (NEP): by degradation of Aβ plaques. The latter together with tau-neurofibrillary tangles are the basis of AD pathology, the degradation of Aβ plaques could prevent their adverse effects on insulin coding genes and insulin signaling to decrease insulin resistance, low-grade inflammation, and neurocognitive dysfunction observed in patients with Alzheimer's disease (45).
Rapamycin (mTOR): Mtor is an essential component of a complex protein which is a critical role in some signaling pathways necessary for cellular metabolic homeostasis, insulin secretion, insulin resistance pancreatic β-cell function, stem cell proliferation and differentiation, and programmed cell death with apoptosis and autophagy. Rapamycin is very promising as a future regenerative therapy for patients with type 3 and types 2 diabetes, but obstacles are on the way:
- Mtor acts through many critical pathways including, phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP-activated protein kinase (AMPK). So Mtor may not function individually, but dependent on other pathways which could limit protective paths leading to unwanted side effects like reducing the efficacy of metformin which also involve the same pathway to work. Vasculopathy is another serious side effect which needs to be addressed in future studies. Mtor plays an important role in stem cell survival; again a delicate balance is warranted in apoptotic and autophagic pathways to reach the goal of regeneration of various cell types and avoiding cell death on the other hand (46)
Centrally active angiotensin-converting enzyme inhibitors (ACE-Is): ACE inhibitors are used in various medical conditions including heart failure, kidney disease, high blood pressure, and diabetes. Evidence exists that these agents could improve cognitive function in early-stage AD through a possible anti-inflammatory effect and not merely blood pressure lowering. Thus a timely introduction of centrally active ACE-I (e.g., captopril, fosinopril, lisinopril, perindopril, ramipril, or trandolapril) could be of help in prevention and deployment of AD (47).
A page on diet side effects including organ atrophy
Chapter 4. Metformin and type 3 diabetes mellitus
Theoretically, most antihyperglycemic medication can address insulin resistance, and insulin deficiency characterized AD, but metformin is preferred due to the following:
- Low risk of hypoglycemia and weight loss
- Favorable effects on lipids and blood pressure
- Anticancer effects
- The role of metformin in Alzheimer,s disease (type 3 diabetes) is controversial. Metformin has been shown to reduce vitamin B12 levels on chronic use (The American Diabetes Association recommended to check for Vitamin B12 level and treat when appropriate) which could lead to cognitive impairment, on the other hands decreasing insulin resistance and the favorable effects on gut microbiota may enhance cognitive function.
Animal studies on metformin and AD:
Animal experiments using mouse model showed that metformin reduces tau phosphorylation in the cortex and hippocampus, increases the amount of insoluble tau and the number of inclusions with β-sheet aggregates in the brain, and exacerbates hindlimb atrophy. The study suggests that brain insulin resistance is due to Aβ pathology and is independent of peripheral insulin resistance or type 2 diabetes mellitus (48,49). The studies pointed that in spite the markers of insulin resistance are impeded in tau protein the role of tauopathology in insulin resistance is unclear and seemed to work independently (49,50). More studies showed that insulin acts in type 2 diabetes only via inhibition of mitochondrial complexes and AMPK activation independent of insulin signaling (51,52). Furthermore and surprisingly, chronic metformin use increased the amount of insoluble tau and β-sheet inclusion in the cortex and hippocampus. The studies concluded that metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action. Another study conducted on C57B6/J mice found that metformin leads to an increased risk of the AD via the promotion and aggregation of β-amyloid (Aβ), in the cortex (53). Son et al. (54) conducted a study using SH-SY5Y cells and drew similar conclusions. Further reviews (55) on LAN5 neuroblastoma cells showed that metformin promotes aggregation of Aβ, induces oxidative stress, and mitochondrial damage through increments of APP and presenilin levels, proteins involved in the AD.McNeilly and colleagues (56) in their study on rats fed a high-fat diet, debated the occurrence of brain insulin resistance. The author stated that metformin affects the metabolic but not the cognitive function suggesting other pathways through which a high-fat diet affects the cognitive abilities. A more recent study (10) investigated the long-term effects of metformin on brain neurotrophins and cognition in aged male C57Bl/6 mice and concluded the following: in spite of metformin attenuation of decline motor function induced by a high-fat diet it should be approached with caution as it also decreased expression of the antioxidant pathway regulator.
Studies are showing favorable effects of metformin on cognitive functions: An experimental study (57) conducted on hippocampus cells showed that metformin mediated its protective effects through phospho-JNK but had no effect on phospho-p38 MAPK and phospho-ERK1/2. Furthermore, metformin protected against apoptosis. Chiang and colleagues (58) reported the same, but the finding of proactive role of metformin against Aβ protein aggregates was mediated at least in part through AMP-activated protein kinase (AMPK). A further study (59) using murine primary neurons from wild-type and human tau transgenic mice suggested another pathway for metformin protection against tauopathy (protein phosphatase 2A (PP2A). The investigators reported that:
- The tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an essential mediator of the observed effects
- Metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation