The potential role of pancreatic γ-aminobutyric acid (GABA) in diabetes mellitus: A critical reappraisal

Al-Kuraishy, Hayder M; Hussian, Nawar R; Al-Naimi, Marwa S; Al-Gareeb, Ali I; Al-Mamorri, Farah; Al-Buhadily, Ali K

doi:10.4103/ijpvm.ijpvm_278_19

Cited by 25 publications

(11 citation statements)

References 46 publications

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“… 65 Inhibition of NEP leads to beneficial systemic effects by regulating insulin sensitivity, lipid metabolism, satiety and pancreatic β cell function. 66 , 67 , 68 , 69 , 70 …”

Section: Mechanistic Role Of Nep Inhibitors In ...mentioning

confidence: 99%

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon‐like peptide 1 (GLP‐1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP‐1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.

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“… 65 Inhibition of NEP leads to beneficial systemic effects by regulating insulin sensitivity, lipid metabolism, satiety and pancreatic β cell function. 66 , 67 , 68 , 69 , 70 …”

Section: Mechanistic Role Of Nep Inhibitors In ...mentioning

confidence: 99%

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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“…T2D is an endocrine disease due to the development of insulin resistance (IR) and pancreatic β dysfunction leading to hyperglycaemia and cardiometabolic disorders. 46 , 47 Of note, T2D is associated with the development of neurodegenerative diseases. Interestingly, there is a mutual association between T2D and epilepsy, and vice versa.…”

Section: The Mechanistic Role Of Metformin In Epilepsymentioning

confidence: 99%

New insights on the potential anti‐epileptic effect of metformin: Mechanistic pathway

Alnaaim,

Al‐kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well‐controlled disease by anti‐epileptic agents (AEAs) in about 69%. However, 30%–40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA‐approved drugs that have an anti‐seizure activity to the anti‐epileptic regimen is logical. The anti‐diabetic agent metformin has anti‐seizure activity. Nevertheless, the underlying mechanism of the anti‐seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti‐seizure activity by triggering adenosine monophosphate‐activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain‐derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti‐seizure mechanism of metformin. Also, metformin reduces α‐synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

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“…Было установлено, что ГАМК определяется практически во всех тканях и органах. В тканях поджелудочной железы содержание ГАМК сопоставимо с таковым в ГМ и высоко экспрессируется в α- и β-клетках островков Лангерганса [ 6 ][ 11 ]. Содержание ГАМК в β-клетках у пациентов с СД 1 и 2 типа снижается, и нарушается секреция инсулина [ 12 ][ 13 ].…”

Section: роль гамк в регуляции углеводного обменаunclassified

“…В островках поджелудочной железы в инсулин-продуцирующих β-клетках экспрессируются ГАМКА- и ГАМКВ-рецепторы, которые кодируются разными внутриклеточными путями и формируют различные механизмы передачи сигналов [ 6 ][ 12 ][ 14 ][ 15 ]. После высвобождения ГАМК влияет на активность α- и β-клеток поджелудочной железы через ионотропные ГАМКА-рецепторы и метаботропные ГАМКB-рецепторы.…”

Section: роль гамк в регуляции углеводного обменаunclassified

“…Участие Ca2+ и CREB и зависимая от них активация глюкозой IRS-2 β-клеток важна для пластичности ответа β-клеток на повышенную потребность в инсулине. ГАМК-индуцированная активация CREB одновременно связана с повышенным уровнем экспрессии транскрипта IRS-2 [ 6 ][ 15 ][ 20 ].…”

Section: роль гамк в регуляции углеводного обменаunclassified

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Synergistic effects of GABA and hypoglycemic drugs

Tyurenkov,

Faibisovich,

Bakulin

2023

Probl Endokrinol (Mosk)

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Diabetes mellitus (DM) is the leading cause of premature death and disability. Despite a significant number of drugs, the effectiveness of therapy aimed at normalizing the level of glycemia and preventing complications does not fully satisfy doctors and patients. Therefore, the search for new approaches for the prevention and treatment of DM and its complications continues. Significant resources are used to develop new drugs, but recently the possibility of using «old» widely available drugs with newly discovered pleiotropic properties has been substantiated. These may include preparations of gammaaminobutyric acid (GABA) and agents that directly or indirectly activate GABAergic transmission, which have a pronounced pancreatic protective effect, which has been widely discussed in foreign literature over the past 10–15 years. However, there are few such publications in the domestic literature.It has been established that the content of GABA in β-cells in patients with type 1 and type 2 diabetes is reduced and this correlates with the severity of the disease. Genetic suppression of GABA receptors causes a significant decrease in the mass of β-cells and glucose-stimulated insulin secretion, which confirms the importance of GABA in ensuring glucose homeostasis and the advisability of replenishing the GABA deficiency in DM with its additional administration. It has been established that in animals with DM, GABA suppresses apoptosis and stimulates the regeneration of β-cells, increases β-cell mass and insulin production.Experimental data have been obtained indicating a synergistic effect of GABA when combined with glucagon-like peptide-1 (GLP-1) receptor agonists, DPP-4 inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, when a more pronounced pancreoprotective effect is observed, due to decrease in oxidative and nitrosative stress, inflammation, increase in the level of Klotho protein, Nrf-2 activity and antioxidant defense enzymes, suppression of NF-kB activity and expression of pro-inflammatory cytokines. As a result, all this leads to a decrease in apoptosis and death of β-cells, an increase in β-cell mass, insulin production and, at the same time, a decrease in glucagon levels and insulin resistance.The review substantiates the feasibility of using GABA and drugs with a positive GABAeric effect in combination with new generation antidiabetic agents: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors in order to increase their antidiabetic potential.The search was carried out in the databases Pubmed, eLibrary, Medline. Keywords: diabetes mellitus, gamma-aminobutyric acid, glucagon-like peptide-1, GLP-1 receptor agonists, glucose-dependent insulinotropic peptide, dipeptidyl peptidase inhibitors, sodium-glucose cotransporter 2 inhibitors. The search was carried out from 2000 to 2022, but the review presents the results studies published mainly in the last 3 years, due to the requirements of the journal for the maximum amount of work and the number of sources.

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The potential role of pancreatic γ-aminobutyric acid (GABA) in diabetes mellitus: A critical reappraisal

Cited by 25 publications

References 46 publications

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

New insights on the potential anti‐epileptic effect of metformin: Mechanistic pathway

Synergistic effects of GABA and hypoglycemic drugs

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