The Potential Role of Pancreatic γ-Aminobutyric Acid (GABA) in Diabetes Mellitus: A Critical Reappraisal.

BACKGROUND: Diabetes mellitus (DM) is an endocrine disorder characterized by hyperglycemia, polyuria, polydipsia, and glucosuria. γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the central nervous system (CNS) of humans and other mammals. GABA acts on two different receptors, which are GABA-A and GABA-B. Pancreatic ß-cells synthesize GABA from glutamic acid by glutamic acid decarboxylase (GAD). AIM: The objective of this study was to explore the potential role of pancreatic GABA on glycemic indices in DM. METHODS: Evidence from experimental, preclinical, and clinical studies are evaluated for bidirectional relationships between pancreatic GABA and blood glucose disorders. A multiplicity of search strategies took on and assumed included electronic database searches of Medline and Pubmed using MeSH terms, keywords and title words during the search. RESULTS: The pancreatic GABA signaling system has a role in the regulation of pancreatic hormone secretions, inhibition of immune response, improve ß-cells survival, and change α cell into ß-cell. Moreover, a GABA agonist improves the antidiabetic effects of metformin. In addition, benzodiazepine receptor agonists improve pancreatic ß-cell functions through GABA dependent pathway or through modulation of pancreatic adenosine and glucagon-like peptide (GLP-1). CONCLUSIONS: Pancreatic GABA improves islet cell function, glucose homeostasis, and autoimmunity in DM. Orally administered GABA is safe for humans, and acts on peripheral GABA receptors and represents a new therapeutic modality for both T1DM and T2DM. Besides, GABA-A receptor agonist like benzodiazepines improves pancreatic ß-cell function and insulin sensitivity through activation of GABA-A receptors.

Statins Therapy Improves Acute Ischemic Stroke in Patients with Cardio-metabolic Disorders Measured by Lipoprotein-Associated Phospholipase A2 (Lp-PLA2): New Focal Point.

BACKGROUND: Acute ischemic stroke (AIS) leads to neuronal and endothelial damage that activate the release of proinflammatory mediators such as lipoprotein-associated phospholipase A2 (Lp-PLA2), which lead to the development of brain edema injury. Most of statins produce differential effects on Lp-PLA2 activity and mass with a comparable reduction in low-density lipoprotein (LDL) serum levels. AIMS: The aim of this study is to evaluate the differential effect of different statins on the mass of level of Lp-PLA2 in patients with AIS. METHODS: A total of 69 patients with AIS aged 40-70 years compared with matched 39 healthy controls were involved in this case-control study. The AIS patients were divided according to the statins therapy into 39 patients on statins therapy (statins on), and 30 patients were not on the statins therapy (statins off). Anthropometric variables including weight, height, body mass index (BMI), and blood pressure profile were estimated. Besides, biochemical variables including lipid profile[total cholesterol (TC), triglyceride (TG), LDL, very low-density lipoprotein (VLDL), high-density lipoprotein (HDL)], Lp-PLA2 mass levels, high-sensitive C-reactive protein (Hs-CRP) were estimated. RESULTS: Patients with AIS had high Lp-PLA2 mass levels (P < 0.01) that positively correlated with high Hs-CRP, blood pressure, BMI, TC, TG, VLDL, LDL, and negatively correlated with HDL as compared with healthy controls. As well, statins on patients had lower Lp-PLA2 mass levels (9.82 ± 3.19 IU/mL) compared with statins off patients (16.55 ± 4.72 IU/mL), (P = 0.0001). Regarding the gender differences in the Lp-PLA2 mass level, it was higher in men patients with AIS compared with comparable females (P = 0.03). CONCLUSIONS: Lp-PLA2 mass level was higher in patients with AIS and linked with underlying poor cardio-metabolic disorders. Therefore, the Lp-PLA2 mass level is observed to be a surrogate biomarker of AIS mainly in patients with poor cardio-metabolic disorders. Statin therapy improves the Lp-PLA2 mass level and the poor cardio-metabolic profile in patients with AIS.

New insight into the effect of lycopene on the oxidative stress in acute kidney injury.

OBJECTIVE: To evaluate the nephroprotective effect of lycopene (LPN) in acute kidney injury (AKI) regarding the oxidative stress (OS). MATERIALS AND METHODS: Thirty Sprague Dawley male rats were divided into three groups - control group: rats treated with distilled water (orally) for 10 days (n = 10); AKI group: rats treated with distilled water and diclofenac (intraperitoneal) for 10 days (n = 10); treated group: rats treated with LPN (orally) and diclofenac for 10 days (n = 10). Body mass index (BMI) and estimated glomerular filtration rate (eGFR) were measured. Blood urea, serum creatinine (CreSerum), serum malondialdehyde (MDA), superoxide dismutase (SOD), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecules (KIM-1) were measured in the all groups on the 11th day of the experiment. RESULTS: Diclofenac-induced AKI led to significant elevations of BMI, CreSerum, and blood urea compared with control (P < 0.05). In AKI model, eGFR was reduced to 11.69 ± 2.64 ml/min/1.73 compared with control group (15.88 ± 3.75 ml/min/1.73, P = 0.03). NGAL, MDA, and KIM-1 were elevated in AKI compared with control (P < 0.001). Pretreatment with LPN led to the reduction of blood urea and CreSerum as compared with AKI (P < 0.001). Similarly, eGFR was increased significantly to 14.81 ± 3.21 ml/min/1.73 compared with 11.69 ± 2.64 ml/min/1.73 in AKI (P = 0.02). Serum levels of NGAL, KIM-1, and MDA were reduced significantly in the LPN group as compared with AKI (P = 0.001), while the SOD serum level was increased to 33. 86 ± 8.61 pg/ml as compared to 22.78 ± 7.56 pg/ml in AKI (P = 0.006). As well, LPN reduced MDA/SOD ratio as compared with AKI (P = 0.00001). CONCLUSION: The finding of this study illustrated that LPN is an effective natural antioxidant that attenuates and prevents AKI through modulation of OS and lipid peroxidation. As well, LPN might be of great value in the prevention of nephrotoxicity that induced by nephrotoxic agents like diclofenac.

Renoprotective effect of irbesartan in a rat model of gentamicin-induced nephrotoxicity: Role of oxidative stress.

BACKGROUND: The renin-angiotensin system (RAS) is essential in renal physiology; however, disturbance of the RAS is one of the chief pathways involved in renal injury. Dysregulation of RAS may result in both glomerular and tubulointerstitial injuries through direct effects of angiotensin II (Ang II) type 1 receptor. Irbesartan and other Ang II blockers have renoprotective effect through reduction of on renal inflammations. Therefore, the aim of the present study was to demonstrate the renoprotective effect of irbesartan on gentamicin-induced nephrotoxicity in rats concerning the oxidative stress. MATERIALS AND METHODS: Thirty Sprague-Dawley Male rats divided into three groups, Group I (10 rats) treated with distilled water, Group II (10 rats) treated with gentamicin, and Group III (10 rats) treated with gentamicin plus irbesartan for 12 days. Blood urea, serum creatinine, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GSH), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecules (KIM-1), and cystatin-c were measured in each group. RESULTS: Irbesartan significantly reduced blood urea, serum creatinine, serum MDA, NGAL, KIM-1, and cystatin-c P < 0.05. Irbesartan significantly increases SOD P < 0.05 without significant effect in elevation of GSH serum levels. CONCLUSION: Irbesartan has renoprotective effect in attenuation of acute nephrotoxicity through modulation of oxidative stress and antioxidant capacity in rats.

Nephrotoxicity: Role and significance of renal biomarkers in the early detection of acute renal injury.

Nephrotoxicity is defining as rapid deterioration in the kidney function due to toxic effect of medications and chemicals. There are various forms, and some drugs may affect renal function in more than one way. Nephrotoxins are substances displaying nephrotoxicity. Different mechanisms lead to nephrotoxicity, including renal tubular toxicity, inflammation, glomerular damage, crystal nephropathy, and thrombotic microangiopathy. The traditional markers of nephrotoxicity and renal dysfunction are blood urea and serum creatinine which are regarded as low sensitive in the detection of early renal damage. Thus, the detection of the initial renal injures required new biomarkers which are more sensitive and highly specific that gives an insight into the site of underlying renal damage. Kidney injury molecule-1, Cystatin C, and neutrophil gelatinase-associated lipocalin sera levels are more sensitive than blood urea and serum creatinine in the detection of acute kidney injury during nephrotoxicity.

Sulfonylurea and neuroprotection: The bright side of the moon.

Sulfonylurea (SUR) agents are the second and most used oral hypoglycemic drugs after metformin and they still as an imperative tool for most favorable of glucose control. SURs are used mainly in the management of Type 2 diabetes mellitus since; they are effective in the glycemic control and reduction of microvascular complications. First-generation SUR represents 3% of used oral hypoglycemic agents while second and third generations are used in about 25% in patients with Type 2 diabetes mellitus. Upregulation of SUR1 receptor has been observed after stroke and traumatic brain injury, therefore, SUR such as glibenclamide inhibits brain edema and astrocyte swelling following brain insults. SUR drugs mainly glibenclamide is effective at a low dose in the management of cerebral stroke and could be a contestant with corticosteroid in controlling brain edema.

Levothyroxine improves Paraoxonase (PON-1) serum levels in patients with primary hypothyroidism: Case-control study.

Primary hypothyroidism is associated with oxidative stress and insufficient antioxidant capacity. This study was conducted to evaluate the effects of levothyroxine replacement therapy on paraoxonase 1 (PON-1) serum levels in a patients with primary hypothyroidism. Thirty-one patients with primary hypothyroidism compared to 20 healthy controls were recruited from. A venous blood sample were taken after an overnight fasting for biochemical parameters, before and after starting levothyroxine therapy (100 µ g/day) for 3 months duration. The biochemical variables were PON-1 serum levels, lipid profiles, triiodothyronine (T3), thyroxin (T4), and thyroid stimulating hormone (TSH) serum levels. Levothyroxine replacement therapy leads to a significant amelioration of thyroid functions, lipid profile, cardiometabolic measures P < 0.05 in patients with primary hypothyroidism. Levothyroxine leads to significant elevation in PON-1 serum levels from 188.42 ± 19.81 (U/mL) to 361.23 ± 33.62 (U/mL) P < 0.0001. This study concluded that levothyroxine replacement therapy significantly increases PON-1 serum levels in patients with primary hypothyroidism and attenuating hypothyroidism-induced oxidative stress.