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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 38-57

Insulin resistance and Alzheimer’s disease: the role of defective insulin signaling and inflammation


1 Geriatric Unit, Department of Internal Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Department of Neuropsychiatry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
3 Department of Medical Biochemistry, Medical Research Institute, University of Alexandria, Alexandria, Egypt
4 Department of Internal Medicine, Faculty of Mediciney, University of Alexandria, Alexandria, Egypt

Date of Submission26-Apr-2018
Date of Acceptance02-Feb-2019
Date of Web Publication22-Aug-2019

Correspondence Address:
MBBCh Ali M.A. Ramadan
Alex. Master Degree of Internal Medicine Assistant Lecturer Alexandria University Hospitals, Department of Internal Medicine Faculty of Medicine, University of Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejode.ejode_4_18

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  Abstract 

Introduction
Alzheimer’s disease (AD) is the most common form of dementia in the elderly, accounting for 60–80% of cases. The present study was to explore the role of insulin resistance and inflammatory processes in AD patients and to assess the effect of an insulin sensitizer (pioglitazone) on cognition and plasma levels of the amyloid beta derivative. Also, the study aimed to verify experimentally the effect of pioglitazone on the components of brain insulin signaling pathway and inflammatory pathway.
Materials and methods
We studied the impact of pioglitazone treatment on diabetic AD patients for 6 months with concomitant study of pioglitazone effect on insulin signaling pathway on diabetic AD rats.
Results
We report that pioglitazone 6 months treated patients has a positive effect on cognitive deficit, improve neurometabolic and decreasing neuroinflammation in diabetic AD patients, and it also was associated with a positive effect on insulin-signaling pathway plus its antioxidant effect on the brain of rats.
Conclusion
There is a strong association between AD and type 2 diabetes mellitus indicating that they share similar underlying pathophysiological mechanisms. Pioglitazone-treated diabetic AD patients were associated with improvement in cognition.

Keywords: Alzheimer’s disease, pioglitazone, treated, type 2 diabetes


How to cite this article:
Abou-Raya SN, Abdou AM, Kamel MA, Ramadan AM. Insulin resistance and Alzheimer’s disease: the role of defective insulin signaling and inflammation. Egypt J Obes Diabetes Endocrinol 2018;4:38-57

How to cite this URL:
Abou-Raya SN, Abdou AM, Kamel MA, Ramadan AM. Insulin resistance and Alzheimer’s disease: the role of defective insulin signaling and inflammation. Egypt J Obes Diabetes Endocrinol [serial online] 2018 [cited 2020 Jul 7];4:38-57. Available from: http://www.ejode.eg.net/text.asp?2018/4/2/38/265190




  Introduction Top


Alzheimer’s disease (AD) is the most common form of dementia in the elderly, accounting for 60–80% of cases. As the population ages, the overall burden of dementia is increasing worldwide. As the number of older Egyptians grow rapidly, so too will the numbers of new and existing cases of Alzheimer’s. United States develops Alzheimer’s every 65 s [1]. Regular physical activity and management of cardiovascular risk factors especially diabetes, obesity, smoking, and hypertension, reduce the risk of cognitive decline and may reduce the risk of dementia [2]. Insulin resistance, the compensatory hyperinsulinemia, and other components are associated with an increased risk of cardiovascular disease; endothelial dysfunction is a prominent feature of insulin resistance syndrome [3].

Insulin in the brain

The presence of insulin in the brain was first detected by Havrankova and colleagues, who used radioimmunoassay to determine high levels of insulin in brain extracts. Likewise, they reported that insulin content in the brain was independent of the peripheral insulin, since circulating insulin levels had no effect on the brain’s insulin concentration [4].

Brain insulin receptors

The molecular events through which insulin functions in the brain are the same as those operating in the periphery. However, certain insulin actions are different in the central nervous system, such as the hormone-induced glucose uptake due to a low insulin-sensitive glucose transporter (GLUT-4) activity, and because of the predominant presence of GLUT-1 and GLUT-3. In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects. Although the presence of insulin receptors (IRs) in many tissues in the periphery and their main function of mediating glucose transport into cells are well known, the existence of IRs within the brain was poorly understood [5].

Insulin effects on cognition and memory

It has been widely reported that the peripheral or central administration of insulin by Intracerebroventricular (ICV) or intrahippocampal routes to experimental animals has positive effects on memory and learning processes. The improvement in these activities is related with an increase in both IR expression and its signal transduction pathways in the hippocampus, and the loss of memory due to ischemic lesions in this structure can be avoided by insulin administration [6],[7].

Inflammation, insulin resistance, and the brain

There is experimental evidence to indicate that inflammatory responses are closely associated with the development of insulin resistance in peripheral and central tissues. Chronic inflammation may contribute to the appearance of insulin resistance and type 2 diabetes, as well as to the association of AD and type 2 diabetes mellitus (T2DM) [8],[9]. Alterations of some of the insulin-signaling pathways such as PI3K/Akt and GSK-3 are recorded in central inflammation and insulin resistance [10]. It is well accepted that neuroinflammation occurs in AD. Inflammation is needed for the expression of insulin resistance, as demonstrated by the inhibition of inflammatory pathways, which avoid diet-induced insulin resistance in experimental animals [11].

Relationships between alterations of insulin signaling and Alzheimer’s disease pathogenesis

Insulin resistance is a risk factor for AD, it being a common feature of AD patients with or without T2DM. Cognitive deficits are associated with insulin signaling abnormalities. The close relationship between these two pathological disturbances, because of the common presence of insulin resistance, has led to the use of the term type 3 diabetes, which means it is considered a neuropathogenic expression of AD [12].


  Materials and methods Top


The study was conducted on two phases: clinical and experimental.

Clinical study

The study was carried out on 60 aged male patients (65 years and above) divided into:
  1. Group I (control), which included 20 normal participants.
  2. Group II (diabetic), which included 20 insulin resistant type 2 diabetic patients.
  3. Group III (diabetic/AD), which included 10 insulin resistant participants with AD/diabetic (Mini-Mental State Exam score between 12 and 26).
  4. Group IV (pioglitazone treated), which included 10 insulin-resistant participants with AD/diabetic treated with pioglitazone for 6 months.


Alzheimer’s patients were recruited from the Geriatric Unit and Neurology Department, Faculty of Medicine, University of Alexandria. The two most commonly used criteria for the diagnosis of AD are those of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and those created by the National Institute on Aging and the Alzheimer’s Association [13],[14].

Cognitive assessment was done using:
  1. General Practitioner Assessment of Cognition [15].
  2. Folstein Mini-Mental Status Examination [16].
  3. Alzheimer’s Disease Assessment Scale-Cognitive [17].
  4. Mini-Cognitive Assessment Instrument [18].


The following laboratory investigations were done for control and cases:
  1. Fasting blood glucose.
  2. Postprandial blood glucose.
  3. Glycated hemoglobin.
  4. Fasting insulin concentration.
  5. Lipid profile [serum triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol].
  6. High-sensitivity C-reactive protein (hs-CRP).
  7. Plasma levels of the amyloid protein-beta (Aβ) derivative (Aβ1–17) as a useful marker for the diagnosis of AD [19].
  8. Insulin resistance index: calculated as the homeostasis model of assessment (HOMA-IR).
  9. Computed tomography of brain.


Experimental phase

The rats were divided into four main groups:

Group I (control), 10 normal healthy male rats.

Group II (diabetic), 10 diabetic rats [high fat diet (HFD) induced and streptozotocin (STZ) induced].

Group III (diabetic/AD), 10 diabetic rats (HFD induced and STZ induced) in which AD will be induced by CuSO4.

Group IV (pioglitazone treated): 10 diabetic rats (HFD induced and STZ induced) in which AD will be induced by CuSO4 and will be treated with pioglitazone for 1 month.

Behavioral assessment of the rats

  1. Object recognition test [20].
  2. Morris water maze [21].


Biochemical assays

At the end of the experiment the rats were killed and the blood and brain tissues were obtained for the analysis of:
  1. Blood parameters:
    1. Fasting blood glucose.
    2. Fasting insulin concentration.
    3. Lipid profile (serum triglyceride, total cholesterol, HDL-cholesterol, and LDL-cholesterol).
    4. hs-CRP.
    5. Insulin resistance index: calculated as HOMA-IR.
  2. Brain insulin signaling parameters:
    1. Phospho-insulin receptor (P-IR) [22].
    2. Phospho-inositol 3 kinase [23].
    3. GLUT [24].



  Results Top


Human results

Age of the studied groups

There were no statistical significant differences between the studied groups as regards age ([Table 1] and [Figure 1]).
Table 1 Age and diabetic profile of the studied groups

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Figure 1 Age of the studied population.

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Diabetic profile of the studied groups

Fasting blood sugar (FBS) was significantly lower in the pioglitazone-treated group in relation to the other three groups ([Table 1] and [Figure 2]). Postprandial sugar was significantly lower in the pioglitazone-treated group in relation to diabetics without AD and diabetics with AD untreated groups ([Table 1] and [Figure 2]). The mean insulin was significantly higher in the pioglitazone-treated group in comparison to control and diabetic patients without AD ([Table 1] and [Figure 3]). HOMA was significantly lower in the pioglitazone-treated group in comparison to diabetic patients with AD and before treatment with pioglitazone ([Table 1] and [Figure 3]).
Figure 2 Fasting blood sugar (FBS) and postprandial blood sugar (PPS) of the studied groups.

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Figure 3 Insulin and HOMA-insulin resistance index of the studied groups. HOMA, homeostasis model of assessment.

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Glycated hemoglobin was significantly lower in the pioglitazone-treated group in comparison to diabetic patients with AD and before treatment with pioglitazone ([Table 1] and [Figure 4]).
Figure 4 Glycated hemoglobin (HBA1C) of the studied groups.

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Serum levels of amyloid β protein peptide (1–42) high-sensitive C-reactive protein in the studied groups

Comparing the mean of Aβ1–42 in different groups it was significantly lower in the pioglitazone-treated group in relation to diabetics with AD untreated. It was significantly higher in the pioglitazone-treated group in relation to control and diabetics without AD ([Table 2] and [Figure 5]). Comparing the mean of hs-CRP in different groups it was significantly higher in pioglitazone-treated in relation to control and diabetics without AD ([Table 2] and [Figure 6]).
Table 2 Serum levels of amyloid β protein peptide (1–42) high-sensitivity C-reactive protein in the studied groups

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Figure 5 Serum level of amyloid β peptide 1–42 (Aβ1–42) of the studied groups.

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Figure 6 Serum level of high-sensitivity C-reactive protein (hs-CRP) of the studied groups.

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Behavioral tests of the studied groups

Alzheimer’s Disease Assessment Scale-Cognitive was significantly lower in the pioglitazone-treated in relation to untreated diabetics with AD group, but was significantly higher in relation to control group and diabetics without AD group ([Table 3] and [Figure 7]). Folstein Mini-Mental Status Examination was significantly higher in the pioglitazone-treated group in relation to the same group before treatment and untreated diabetic with the AD group, but was significantly lower in relation to control group and diabetic without AD group ([Table 3] and [Figure 7]). Comparing General Practitioner Assessment of Cognition, Mini-Cognitive Assessment Instrument were significantly higher in the pioglitazone-treated group in relation to the same group before treatment and untreated diabetic with AD group but was significantly lower in relation to control group and diabetics without AD ([Table 3] and [Figure 8]).
Table 3 Behavioral tests of the studied groups

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Figure 7 ADAS-Cog and MMSE psychological test of the studied groups. ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive; MMSE, Folstein Mini-Mental Status Examination.

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Figure 8 GPCOG and Mini-Cog psychological test of the studied groups. GPCOG, General Practitioner Assessment of Cognition; Mini-Cog, Mini-Cognitive Assessment Instrument.

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Serum lipid profile of the studied groups

Triglycerides were significantly lower in the pioglitazone-treated group in relation to diabetic patients with AD without treatment and before treatment in the same group. It was significantly higher in pioglitazone-treated group in relation to control group ([Table 4] and [Figure 9]). Cholesterol was significantly lower in pioglitazone-treated group in relation to diabetic patients without AD, diabetic patients with AD, and before treatment. Cholesterol was significantly higher in the pioglitazone-treated group in relation to the control group ([Table 4] and [Figure 9]).
Table 4 Serum lipid profile of the studied groups

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Figure 9 Serum level of triglycerides and total cholesterol of the studied groups.

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HDL-cholesterol was significantly higher in the pioglitazone-treated group in relation to diabetic patients without AD and untreated diabetic patients with AD, but it was significantly lower in the pioglitazone-treated group in relation to the control group ([Table 4] and [Figure 10]). LDL-cholesterol was significantly lower in the pioglitazone-treated group in relation to diabetic patients without AD, untreated diabetic patients with AD, and before treatment but it was significantly higher in the pioglitazone-treated group in relation to the control group ([Table 4] and [Figure 10]).
Figure 10 Serum level of HDL cholesterol and LDL cholesterol of the studied groups. HDL, high-density lipoprotein; LDL, low-density lipoprotein.

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Experimental results

Body weight

The results of body weight are summarized in [Table 5] and [Figure 10]. T2DM rats maintained on HFD showed significantly higher body weight than control rats while AD rats showed lower body weight than diabetic rats. The treatment of AD rats with pioglitazone results in significant increase in body weight compared with untreated rats ([Table 5] and [Figure 11]).
Table 5 Body weight (g) and glucose homeostasis parameters of studied groups of rats

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Figure 11 Body weight of control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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FBS was significantly lower in pioglitazone-treated rats than FBS in diabetic rats without AD and untreated diabetic rats with AD but FBS was significantly higher in pioglitazone-treated rats than in control rats ([Table 5] and [Figure 12]).
Figure 12 Fasting blood sugar of control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Insulin was significantly lower in pioglitazone-treated rats than in diabetic rats without AD and untreated diabetic rats with AD, but there is no significant difference between pioglitazone-treated rats and control. HOMA-insulin resistance index was significantly lower in pioglitazone treated rats than in diabetic rats without AD and untreated diabetic rats with AD, but it was significantly higher in pioglitazone-treated rats than in control rats ([Table 5] and [Figure 13]).
Figure 13 Serum insulin level (μIU/ml) and HOMA-insulin resistance index of control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer disease; HOMA, homeostasis model of assessment.

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Serum levels of high-sensitivity C-reactive protein and brain content of amyloid β-protein peptide (1–42) and Nrf2 in the studied groups of rats

hs-CRP was significantly lower in pioglitazone-treated rats in comparison to untreated diabetic rats with AD, but significantly higher in relation to control and diabetic rats without AD ([Table 6] and [Figure 14]). Aβ1–42 was significantly lower in pioglitazone-treated rats in relation to untreated diabetic rats with AD, but significantly higher in relation to control and diabetic rats without AD ([Table 6] and [Figure 15]). Nrf2 was significantly lower in pioglitazone-treated rats in relation to control rats, but it was significantly higher in relation to diabetic untreated AD rats ([Table 6] and [Figure 16]).
Table 6 Serum levels of high-sensitivity C-reactive protein and brain content of amyloid β protein peptide (1–42) and Nrf2 in the studied groups of rats

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Figure 14 Serum level of hs-CRP of control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease; hs-CRP, high-sensitivity C-reactive protein.

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Figure 15 Brain level of Aβ1-42 of control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease; Aβ1-42, amyloid β protein peptide (1–42).

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Figure 16 Brain level of Nrf2 control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Lipid profile of the studied groups of rats

Triglycerides were significantly lower in pioglitazone-treated diabetic rats with AD in relation to diabetic rats without AD and untreated AD diabetic rats, but in comparing pioglitazone-treated diabetic rats with AD and control it was significantly higher ([Table 7] and [Figure 17]). Total cholesterol was significantly lower in pioglitazone-treated diabetic rats with AD in relation to untreated AD diabetic rats but it was significantly higher in pioglitazone-treated diabetic rats with AD in relation to control rats ([Table 7] and [Figure 17]). HDL-cholesterol was significantly lower in pioglitazone-treated diabetic rats with AD in relation to control rats ([Table 7] and [Figure 18]). LDL-cholesterol was significantly lower in pioglitazone-treated diabetic rats with AD in relation to untreated AD diabetic rats, but it was significantly higher in pioglitazone-treated diabetic rats with AD in relation to control rats ([Table 7] and [Figure 18]).
Table 7 Lipid profile of the studied groups of rats

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Figure 17 Serum triglycerides and total cholesterol levels in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Figure 18 Serum LDL-cholesterol and HDL-cholesterol levels in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

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Behavioral tests of the studied groups of rats

Object recognition test (discrimination index) was significantly lower in pioglitazone-treated diabetic rats with AD in comparison to control rats and diabetic rats without AD, but it was significantly higher in pioglitazone-treated diabetic rats with AD in comparison to untreated diabetic rats with AD ([Table 8] and [Figure 19]). Morris water maze (MWM) (trailing trail, s) in day 3 was significantly higher in pioglitazone-treated diabetic rats with AD in comparison to control rats and diabetic rats without AD, but it was significantly lower in pioglitazone-treated diabetic rats with AD in comparison to untreated diabetic rats with AD ([Table 8] and [Figure 20]). MWM (probe trail, %) was significantly lower in pioglitazone-treated diabetic rats with AD in comparison to control rats and diabetic rats without AD, but it was significantly higher in pioglitazone-treated diabetic rats with AD in comparison to untreated diabetic rats with AD ([Table 8] and [Figure 21]).
Table 8 Behavioral tests of the studied groups of rats

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Figure 19 Object recognition test of control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Figure 20 MWM (trailing) test in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Figure 21 MWM (probe trail) test in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Insulin signaling parameters

IR was significantly higher in pioglitazone-treated diabetic rats with AD in relation to diabetic rats without AD and untreated diabetic rats with AD, but it was significantly lower in pioglitazone-treated diabetic rats with AD in comparison to control ([Table 9] and [Figure 22]). P-IR was significantly higher in pioglitazone-treated diabetic rats with AD in relation to untreated diabetic rats with AD, but it was significantly lower in pioglitazone-treated diabetic rats with AD in relation to control ([Table 9] and [Figure 23]). GLUT-3 was significantly higher in pioglitazone-treated diabetic rats with AD in comparison to diabetic rats without AD and untreated diabetic rats with AD, but it was significantly lower in pioglitazone-treated diabetic rats with AD in comparison to control ([Table 9] and [Figure 24]). P-Akt (Thr308) was significantly higher in pioglitazone-treated diabetic rats with AD in relation to untreated diabetic rats with AD, but it was significantly lower in pioglitazone-treated diabetic rats with AD in relation to control ([Table 9] and [Figure 25]).
Table 9 Insulin signaling parameters

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Figure 22 Brain insulin receptor level in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Figure 23 Brain content of P-IR (Tyr 1162/1163) in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease; P-IR, Phospho-insulin receptor.

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Figure 24 Brain content of GLUT-3 in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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Figure 25 Brain content of p-Akt in control rats, diabetic rats, and AD rats treated or untreated with pioglitazone. AD, Alzheimer’s disease.

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  Discussion Top


In the human section of the present study, it was found that pioglitazone improves cognition of Alzheimer’s due to its multiple positive benefits including increasing insulin sensitivity, improving lipid profiles, and acting as an anti-inflammatory agent. The finding demonstrates the strong relationship between insulin resistance in diabetes type 2 and AD. Pioglitazone in the human section was found to have a positive neurometabolic effect that can be attributed to the effect of pioglitazone on several glucose parameters including FBS, postprandial blood sugar, the insulin level, and HOMA-insulin resistance index. In addition, pioglitazone has another positive neurometabolic effect explained by increased HDL-C and the decreased triglycerides, cholesterol, and LDL-C levels in the pioglitazone-treated group. Similarly, a pilot study with pioglitazone in AD patients with DM indicated that pioglitazone for 6 months improved cognition and cerebral blood flow in the parietal lobe compared with controls. Also, pioglitazone treatment resulted in a decrease in the fasting plasma insulin levels, indicating enhanced insulin sensitivity [25].

The study demonstrates the positive effects of pioglitazone on neuroinflammation in humans that appear in the form of decreasing hs-CRP level and Aβ1–42 in the pioglitazone-treated diabetic AD patients in comparison to untreated diabetic AD patients.

In the present study, pioglitazone was found to have a positive effect on cognitive deficit noted in improved different behavioral tests in the pioglitazone-treated diabetic AD. These findings are in agreement with the results of Cheng et al. [26] study in which a recent meta-analysis on PPAR-γ agonists in AD suggests that only pioglitazone may offer an improvement in the early stages of AD and in mild-to-moderate AD.

Since, we cannot assess the different receptor changes in a live human brain, we did an experimental section where we were able to access and assess the receptor changes. The positive relationship was also confirmed again at the experimental level by using rats where induction of T2DM and AD was done.

In the experimental section, we found the same beneficial effect of pioglitazone as regards its positive neurometabolic and neuroinflammatory effects in treated diabetic AD rats in comparison to untreated diabetic AD rats. These effects were reflected in the decreased levels of hs-CRP, Aβ1–42, and improved different glucose homeostasis parameters of treated diabetic AD rats.

Also, improved cognitive deficits were evident in pioglitazone-treated diabetic AD rats. The positive effect of pioglitazone appeared at different behavioral tests in comparison to untreated diabetic rats with AD.

These significant findings in the experimental section can be explained by the same changes occurred in the human section plus the improvement of insulin signaling pathways in the brain in the form of increased number of IR, GLUT-3, P-IR, and Phospho-Akt in pioglitazone-treated diabetic rats with AD when compared with untreated diabetic rat AD brains. The experimental findings were supported by a recent preclinical study in which Fernandez-Martos et al. [27] reported that pioglitazone showed beneficial effects on the preclinical APPswe/PS1dE9 mice model of familial AD improving cognition and decreasing Aβ levels.

A recent study in which Galimberti and Scarpini found a very relevant effect of the drug reversing the damage that neuroinflammation causes in the structural plasticity of the dendrites. Thus, it has been observed that treatment with pioglitazone can reverse the loss of synaptic density induced by Aβ peptide generation [28]. Another support for the current study finding was the Sato et al. [25] study which showed that pioglitazone treated 3×Tg-AD mice for 4 months was associated with improvement in brain spatial learning impairment, TAU hyperphosphorylation, and neuroinflammation.

Zhang and colleagues found that pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-κB. In relationship to AD, the treatment with pioglitazone has been shown to reduce glial pro-inflammatory activity and the Aβ peptide levels due to the phagocytic activity of microglia [29].

In the Jahrling and colleagues study, pioglitazone has been shown to improve amyloid deposits. Moreover, these molecules can modify gene expression and restore both memory and cognition impairment in AD mouse models. Additionally, PPAR-γ stimulation also improves synapse density in cell cultures and reduces Aβ levels in AD transgenic mice [30].


  Conclusion Top


Insulin resistance and inflammation associated with diabetes are risk factors for the development of AD and the usage of the insulin sensitizer, pioglitazone for 6 months at a dose of 15–30 mg/day was associated with positive neurometabolic as well as positive effects on neuroinflammation and a positive effect on cognition in humans. Pioglitazone was associated with positive neurometabolic, positive effects on neuroinflammation, positive effect on cognitive deficit, positive antioxidant effect, and in improving insulin signaling pathways in the brain of rats.

Financial support and sponsorship

Nil.

Conflicts of interest

Although Pioglitazone caused improvement in cognition and decreased Aβ levels a large studies for longer time and higher doses still needed to confirm our results.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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