Alzheimer’s disease has been called type 3 diabetes

Galantamine Inhibits Diabetes
Operating through the cholinergic anti-inflammatory pathway
By Will Block

Scientific research lends validity to the idea that the cholinergic anti-inflammatory pathway links diabetes with Alzheimer’s disease (AD). (See Fig. 1.) It follows then that if you diminish one (diabetes or Alzheimer’s), you might diminish the other (Alzheimer’s or diabetes). Curiously, AD has been thought of as type 3 diabetes (see “Is Alzheimer’s Disease a Type of Diabetes?” in the May 2005 issue, and “More Evidence that Alzheimer’s Is Type 3 Diabetes” in the February 2006 issue). In a new study published on August 11, 2015 in PLoS One, researchers leveled their sights on the potential antidiabetic effect of galantamine.1

The study was conducted at several Egyptian Universities where scientists unveiled the possible mechanisms and evaluated galantamine’s interaction with vildagliptin, an oral anti-hyperglycemic agent (anti-diabetic drug) shown to reduce hyperglycemia in type 2 diabetes mellitus.

However, vildagliptin has many adverse effects that have been observed in clinical trials including nausea, tremor, head­ache, dizziness, and even liver toxicity.


On almost all parameters,
galantamine’s effects surpassed those
of vildagliptin, while the combination
regimen showed the best effects.


Galantamine Lowered Diabetic Elevations

Using a diabetic rat model the researchers treated the rodents with galantamine and/or vildagliptin for 4 weeks. Galantamine lowered the induced elevation in body weight, food/water intake, serum levels of glucose, fructosamine, and the transaminase ratio (ALT/AST). This ratio represents the concentrations of the enzymes aspartate transaminase (AST) and alanine transaminase (ALT) in the blood, which may be used to help diagnose liver damage. As well, galantamine reduced acetylcholinesterase (AChE) in the tested organs of the rats. AChE breaks down the important neurotransmitter acetylcholine (ACh).


The study’s results clearly
proved that galantamine modulated
the glucose/lipid profile, through
its anti-oxidant, -apoptotic,
-inflammatory and -cholinesterase
properties.


Galantamine Also Lowered Lipid Profiles

Also, galantamine successfully modulated the lipid profile assessed in serum, liver and muscle, and increased serum insulin level, as well as increasing β-cell function, in a pattern similar to that of vildagliptin. What’s more, galantamine confirmed its antioxidant, antiinflammatory, and anti-apoptotic capabilities by altering the effect in the diabetic rat model on all the above-mentioned parameters.

Galantamine Enhanced Insulin and Wnt/β-Catenin Signaling Pathways

On the molecular level, galantamine and vildagliptin have enhanced the insulin and Wnt/β-catenin signaling pathways. Wnt signaling is a pathway involving a complex network of proteins that has been shown to be related to AD. On almost all parameters, the galantamine effects surpassed that of vildagliptin, while the combination regimen showed the best effects. The results of the study clearly proved that galantamine modulated the glucose/lipid profile, probably through its anti-oxidant, -apoptotic, -inflammatory and -cholinesterase properties.

Galantamine Surpassed the Drug Vildagliptin

On almost all parameters, the galantamine effects exceeded those of vildagliptin, while the combination regimen showed the best effects. These results clearly proved that galantamine modulated glucose/lipid profile possibly through its anti-oxidant, -apoptotic, -inflammatory and -cholinesterase properties. These properties could be attributed partly to the enhancement of insulin and Wnt/β-catenin signaling pathways. Galantamine can be strongly considered as a potential antidiabetic agent and as an add-on therapy with other oral antidiabetics.


Galantamine can be strongly
considered as a potential antidiabetic
agent and as an add-on therapy with
other oral antidiabetics.


Diabetes Correlates with Cognitive Dysfunctions

Figure 1 The Cholinergic Antiinflammatory Pathway is triggered by vagus nerve stimulation (VNS) and/or acetylcholine agonists (e.g., galantamine) or other agonists. It inhibits pro-inflammatory genes such as TNF, IL-6, and iNOS.
LEM1509Figure1_274.jpg
(click on thumbnail for full sized image)

Type 2 diabetes is connected to cognitive dysfunctions and central nervous system abnormalities. While the exact mechanism is not completely understood, the variation in AChE activity—an enzyme that has a fundamental role in learning and memory—can play a profound role. Of interest, AChE was found in tissues devoid of cholinergic innervations, indicating its potential non-cholinergic function, including response to stress and neurogenesis.

AChE Activated by Diabetes; Inhibited by Galantamine

In the PLoS One study, induced diabetes activated the AChE enzyme in brain, liver and muscle tissues of the diabetic rats, while the administration of the cholinesterase inhibitor galantamine reduced AChE in all tissues, as expected. This effect points to a possible antidiabetic mechanism of galantamine through inhibition of AChE enzyme. Nevertheless, vildagliptin showed a subtle, yet significant reduction, but only in the cerebral enzyme. The addition of vildagliptin to galantamine showed a marked decrease in AChE activity that was less than the highest dose of galantamine in all tissues tested and even less than the normal level in the brain.

Galantamine Decreased Food Intake

The diabetic rat model develops the classical diabetic picture of type 2 diabetes: elevating fructosamine and sharply reducing pancreatic insulin stores with the consequent decrease in basal insulin. On the other hand, galantamine dose-dependently decreased food intake in diabetic rats in agreement with an earlier study.2 This effect can be accredited to both the improved insulin level and to the stimulation of the vagal tone, which was shown to decrease appetite, food consumption, and weight gain.

Moreover, stimulation of the presynaptic alpha7 nicotinic acetylcholine receptor (α7nAChR) by galantamine emphasizes the importance of the central cholinergic signaling in controlling food intake. Conversely, vildagliptin had no influence on food intake, nor on weight gain.


Administration of the cholinesterase
inhibitor galantamine reduced AChE
in all tissues, as expected through
inhibition of the AChE enzyme.


Galantamine’s Antidiabetic Effects Due to Stimulation of the Cholinergic Antiinflammatory Pathway

In the PLoS One study, galantamine corrected the glucose homeostasis-related parameters. In cases of obesity and diabetes mellitus, the vagal tone is suppressed and the pathway is dysfunctional. The antidiabetic effects of galantamine can stimulate the antiinflammatory cholinergic pathway—being an inhibitor of AChE and an agonist of the α7 nicotinic acetylcholine receptor (α7nAChR)—besides activating the efferent vagus nerve. The latter serves as the neuronal pathway in the cross-talk between liver, pancreatic β-cells and adipose tissue, to modulate insulin secretion, pancreatic β-cell mass, energy expenditure regulation, glucose metabolism, hepatic glucose/glycogen production, systemic insulin sensitivity and fat distribution between liver and peripheral tissues.


Apart from the classical mechanism
of action, both galantamine and
vildagliptin increased the
phosphorylation of insulin receptors.


Mechanisms of Vildagliptin

Figure 2 Vildagliptin mediates its antidiabetic effect by inhibiting DPP-4 to augment intact GLP-1—gliptins, are a class of oral hypoglycemics that block DPP-4.
LEM1509Figure2_274.jpg
(click on thumbnail for full sized image)

Vildagliptin mediates its antidiabetic effect by inhibiting DPP-4 to augment intact GLP-1. Gliptins are a class of oral hypoglycemics that block DPP-4. (See Fig. 2) This in turn improves β-cell function and mass, increases insulin secretion, and reduces glucose excursions. The best-corrected glucose profile was seen in the combination-treated group; whether this effect is ascribed, even partly, to the activation of the vagus tone remains to be elucidated.

For the first time, the Egyptian study confirmed the influence of the two agents on the insulin-signaling trail. The activation and phosphorylation of Akt, along with the elevation of GLUT2 and GLUT4 (both glucose transporters), are responsible for the improved insulin sensitivity. Akt, also known as protein kinase B (PKB), plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration (see Fig. 3).

Phosphorylated insulin receptors and Akt corrects the function of GLUT2 in the liver to enhance glucose uptake on one side and to block gluconeogenesis and mediate glycogen synthesis on the other side. This pathway also enhances the translocation of GLUT4 to the cell membrane surface of skeletal muscle to increase muscular glucose uptake.


Some antioxidants, such as
curcumin and vitamin E
prevented the cognitive deficits
induced by the diabetic state through
the inhibition of AChE.


Wnt/β-Catenin and Insulin Pathway Enhancement

Figure 3 Simplified schematic illustration of the insulin > PI3K > p-Akt > AS160 induced increase in GLUT-4 glucose transporter expression and the effects of increased serum amino acids.
LEM1509Figure3_274.jpg
(click on thumbnail for full sized image)

Another pathway examined in the Egyptian paper was the Wnt/β-catenin. Again, both galantamine and vildagliptin enhanced this pathway when tested in liver and muscle, indicating another pathway for improvement of insulin sensitivity.

An earlier study found that the development of type 2 diabetes results from abnormalities in the Wnt signaling pathway, which regulates hormone gene expression and metabolic homeostasis. Instead, the two agents increased phosphorylation, thus inactivating GSK-3β and hence, preventing the proteosomal degradation of β-catenin. (See Fig. 4.) The salvaged β-catenin is translocated to the nucleus to team up with TCF and activates Wnt target gene expression.

The Wnt pathway also plays a role in mediating incretin hormone functions, which can add to the vildagliptin antidiabetic mechanism. Such a pathway regulates the synthesis of proglucagon and consequently of GLP-1 and GIP via the bipartite transcription factor β-catenin/ TCF.

Another Explanation: Corrected Lipids

Improvement of the deranged insulin signaling, with consequent low glucose level induced by galantamine, lends another explanation for the corrected lipid panel observed herein. In previous studies, hyperglycemia was reported to increase added lipogenesis markedly by increasing sterol regulatory element-binding protein-1c (SREBP-1c).

Although the effect of galantamine on SREBP-1c was not tested here, an earlier study reported a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor, SREBP-1c, and the parasympathetic response in cardiomyocytes. The authors found that the cardiomyocytes of SREBP-1c KO mice responded far less to the parasympathomimetic drug, carbamylcholine, compared with the wild type animals. The activation of the Wnt signaling by galantamine can additionally verify this assumption, where inhibited GSK-3β and activated β-catenin drastically decreased the lipogenic factor SREBP-1c.

Vildagliptin Effect on Lipids Comparable to Galantamine

Similar to galantamine, the effect of vildagliptin on lipid profile may be indebted to the activation of insulin/Wnt signaling pathways, as well as to the maintenance of persistent levels of active GLP-1 and GIP. The two incretin hormones reduce fasting lipolysis in adipose tissue and lower stored triglycerides in muscle, liver and pancreas. Previous studies also reported a decrease in serum TC, TGs, and LDL-C in patients treated by vildagliptin. Combining both agents showed better impact on lipid profile in the tested organs, highlighting, thus, the positive interaction between both drugs. Once again, bear in mind that one has significant side effects (vildagliptin) while the other (galantamine) has few.

Oxidative stress is one arm of type 2 diabetes pathogenesis—the biological mechanism(s) that lead to a diseased state—which can directly or indirectly disrupt functions of cellular macromolecules and activate cellular stress-sensitive signaling pathways. Among the causes of diabetes is the nuclear transcription factor Nrf2 that controls the expression and the induction of a battery of defensive genes encoding detoxifying enzymes and antioxidants, by which mammalian cells can sense and adapt to oxidative stresses.

Exhaustion of the Nuclear Transcription Factor

Figure 4 Canonical Wnt-β-catenin pathway. Wnt signaling pathway is shown in the “OFF” (a) and “ON” (b) states. In the absence of a Wnt signal, the destruction complex phosphorylates and ubiquinates β-catenin, being therefore destroyed by the proteasome. In the presence of a Wnt signal, as the dishevelled protein (Dsh) recruits the Axin and inhibits GSK-3, β-catenin is not phosphorylated and therefore not destroyed. It can translocate to the nucleus and activate transcriptions genes.
LEM1509Figure4_274.gif
(click on thumbnail for full sized image)

The present diabetic model nearly exhausted Nrf2 in both liver and muscle in a prior study. The authors stated that on the molecular level, Nrf2-mediated antioxidant response plays a paradoxical role in insulin secretion. Under low levels of harmful stimuli, β-cells can adapt adequately by activating the Nrf2 system to minimize oxidative damage-related impairment of insulin secretion. However, under chronic exposure conditions, the adaptive endogenous antioxidant capacity is curtailed and can interfere with glucose-dependent endogenous reactive oxygen species (ROS) signaling (see Fig. 5). Consequently, a detrimental decrease in glucose stimulated insulin secretion occurs, as in the current model, which in turn confounds the Nrf2 system. The imbalanced redox system further entailed the elevation of lipid peroxides and the decay in the total antioxidant capacity (TAC) level.

The Antioxidant Effect of Galantamine

In the current study, both drugs conveyed their antioxidant potentials by enhancing the TAC and the transcriptional activation of Nrf2 along with reducing the lipid peroxide level. Previously, another study3 found galantamine to proffer a beneficial antioxidant effect through the reduction of lipid peroxidation and the replenishment of glutathione stores. The antioxidant effect may be related, at least in part, to the inhibition of AChE, where increased oxidative load parallels the activated AChE, as reported in several studies.

Vildagliptin too prevents stress-induced destruction of pancreatic β-cells, kidney and brain via reducing the levels of lipid peroxidation, and enhancement of the antioxidant defense system. The antioxidant effect of vildagliptin can elucidate, in part, the decreased AChE in brain, where it was reported previously that some antioxidants, such as curcumin and vitamin E prevented the cognitive deficits induced by the diabetic state through the inhibition of AChE.


Treatment with galantamine
reduced both apoptotic markers,
probably through reducing fatty acids
and/or inhibitiing AChE, where ample
evidence points to the involvement of
AChE in apoptosis.


Treatment with Galantamine Reduced Two Apoptotic Markers

Figure 5 Among the causes of diabetes is the nuclear transcription factor Nrf2, which controls the expression and the induction of a battery of defensive genes encoding detoxifying enzymes and antioxidants, by which mammalian cells can sense and adapt to oxidative stresses.
LEM1509Figure5_274.gif
(click on thumbnail for full sized image)

In type 2 diabetes, the altered glucose homeostasis is attended by an assortment of consequences; including mitochondrial dysfunction, which represents a crucial source of increased ROS and apoptosis. In the Egyptian study, the diabetes model increased the tested apoptotic biomarkers in liver and muscle. These results are in line with an earlier study, where the co-authors stated that in hepatocytes (liver cells), impaired mitochondria amplify the apoptotic signal pathway resulting in the release of several pro-apoptotic proteins into the cytosol, which in turn activates the downstream effector caspase-3. Additionally, apoptosis develops in myocytes (muscle cells) via lipotoxicity induced by high-saturated fatty acids documented in the current study and in a previous study, especially that induced by selective stressors as hyperglycemia. Though it was less pronounced than that of galantamine, vildagliptin proved its antiapoptotic capacity, possibly by inhibiting DPP-4. This effect is in line with recent findings in Parkinson’s disease model. Another report found that the DPP-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in type 2 diabetes and/or obesity.

Overproduction of ROS/free radicals and hyperglycemia coordinate an upsurge of an overabundance of cytokines, with the adipose tissue depots being the central node for driving local and systemic inflammation along with insulin resistance. However, in the Egyptian study, galantamine induced a shift towards an anti-inflammatory phenotype. The ability of galantamine to abate TNF-α level in non-diabetic models may be attributed to the stimulation of the cholinergic anti-inflammatory pathway via the activation of α7nAChR and/or elevation of adiponectin.

The Power of Galantamine as an Antidiabetic

In summary, the results of the Egyptian study demonstrate the capability of galantamine to alleviate type 2 diabetes and other components of the metabolic syndrome. These effects may be attributed to activation of the insulin and Wnt/β-catenin signaling pathways, beside its AChE inhibitory effect, antiinflammatory action, and antioxidant/antiapoptotic characters. The study points to the useful effect of galantamine as an add-on drug with antidiabetics, a common trend in the time being for the management of type 2 diabetes.

References

  1. Ali MA, El-Abhar HS, Kamel MA, Attia AS. Antidiabetic Effect of Galantamine: Novel Effect for a Known Centrally Acting Drug. PLoS One. 2015 Aug 11;10(8):e0134648. doi: 10.1371/journal.pone.0134648. eCollection 2015. PubMed PMID: 26262991.
  2. Satapathy SK, Ochani M, Dancho M, Hudson LK, Rosas-Ballina M, Valdes-Ferrer SI, Olofsson PS, Harris YT, Roth J, Chavan S, Tracey KJ, Pavlov VA. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 2011;17(7-8):599-606. doi: 10.2119/molmed.2011.00083. Epub 2011 Jul 1. PubMed PMID: 21738953; PubMed Central PMCID: PMC3146607.
  3. Melo JB, Sousa C, Garção P, Oliveira CR, Agostinho P. Galantamine protects against oxidative stress induced by amyloid-beta peptide in cortical neurons. Eur J Neurosci. 2009; 29(3):455–64.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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