GLP-1 mimetics and diabetic ketoacidosis: possible interactions and clinical consequences.

Diabetic ketoacidosis is a serious diabetes-related consequence that occurs in type 1 diabetes and less commonly in type 2 diabetes and is a major cause of death. It results from the metabolic consequences due to a lack of insulin secretion or impaired insulin activity in diabetes leading to dysregulated pathophysiologic pathways resulting in excessive ketone body formation. While ketone bodies are physiologic molecules, their high levels reduce the physiological pH of the blood and induce ketoacidosis, leading to increasing metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) mimetics are a class of recently developed diabetes therapy that do not lead to hypoglycemic, but some reports have suggested a relationship between GLP-1 mimetics and ketogenesis. To clarify the possible interactions between GLP-1 mimetics and ketogenesis in diabetes, this review was undertaken to collate and interpret the literature.

Sodium-glucose cotransporter 2 inhibitors and renin-angiotensin-aldosterone system, possible cellular interactions and benefits.

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a newly developed class of anti-diabetics which exert potent hypoglycemic effects in the diabetic milieu. However, the evidence suggests that they also have extra-glycemic effects. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system widely distributed in the body that is important for water and electrolyte homeostasis as well as renal and cardiovascular function. Therefore, modulating RAAS activity is a main goal in patients, notably diabetic patients, which are at higher risk of complications involving these organ systems. Some studies have suggested that SGLT2is have modulatory effects on RAAS activity in addition to their hypoglycemic effects and, thus, these drugs can be considered as promising therapeutic agents for renal and cardiovascular disorders. However, the exact molecular interactions between SGLT2 inhibition and RAAS activity are not clearly understood. Therefore, in the current study we surveyed the literature for possible molecular mechanisms by which SGLT2is modulate RAAS activity.

Anti-inflammatory benefits of semaglutide: State of the art.

Individuals with diabetes often have chronic inflammation and high levels of inflammatory cytokines, leading to insulin resistance and complications. Anti-inflammatory agents are proposed to prevent these issues, including using antidiabetic medications with anti-inflammatory properties like semaglutide, a GLP-1 analogue. Semaglutide not only lowers glucose but also shows potential anti-inflammatory effects. Studies suggest it can modulate inflammatory responses and benefit those with diabetes. However, the exact mechanisms of its anti-inflammatory effects are not fully understood. This review aims to discuss the latest findings on semaglutide's anti-inflammatory effects and the potential pathways involved.

Modulating effects of crocin on lipids and lipoproteins: Mechanisms and potential benefits.

Dyslipidemia poses a significant risk to cardiovascular health in both diabetic and non-diabetic individuals. Therefore, it is crucial to normalize lipid homeostasis in order to prevent or minimize complications associated with dyslipidemia. However, pharmacological interventions for controlling lipid metabolism often come with adverse effects. As an alternative, utilizing herbal-based agents, which typically have fewer side effects, holds promise. Crocin, a naturally occurring nutraceutical, has been shown to impact various intracellular pathways, reduce oxidative stress, and alleviate inflammatory processes. Recent evidence suggests that crocin may also confer lipid-related benefits and potentially contribute to the normalization of lipid homeostasis. However, the specific advantages and the cellular pathways involved are not yet well understood. In this review, we present the latest findings regarding the lipid benefits of crocin, which could be instrumental in preventing or reducing disorders associated with dyslipidemia. Additionally, we explore the potential cellular mechanisms and pathways that mediate these lipid benefits.

Glp-1 Mimetics and Autophagy in Diabetic Milieu: State-of-the-Art.

The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways.

Empagliflozin alleviates diabetes-induced cognitive impairments by lowering nicotinamide adenine dinucleotide phosphate oxidase-4 expression and potentiating the antioxidant defense system in brain tissue of diabetic rats.

BACKGROUND: Diabetes-induced cognitive impairment is a major challenge in patients with uncontrolled diabetes mellitus. It has a complicated pathophysiology, but the role of oxidative stress is central. Therefore, the use of antidiabetic drugs with extra-glycemic effects that reduce oxidative damage may be a promising treatment option. METHODS: Male Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated (n = 8 per group). Type 1 diabetes was induced by a single intraperitoneal dose of streptozotocin (STZ) (40 mg/kg). Two treatment groups received empagliflozin for 5 weeks (20 mg/kg/po). Cognitive ability was evaluated using open field, Elevated Plus Maze (EPM) and the Morris Water Maze (MWM) tests at study completion. Blood and brain tissue samples were collected - and analysis for malondialdehyde (MDA) and glutathione (GLT) content and catalase (CAT) and superoxide dismutase (SOD) enzyme activity were performed. Additionally, expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox-4) enzyme in brain tissue was analyzed using RT-PCR. RESULTS: STZ increased blood glucose and induced diabetes with oxidative stress by lowering the antioxidant system potency and increasing Nox-4 expression after 5-weeks in brain tissue accompanied by reduction in cognitive performance. Also, diabetes induced anxiety-like behavior and impaired spatial memory in MWM, EPM and open field tests. However, empagliflozin reversed these changes, improving SOD and CAT activity, GLT content and reducing Nox-4 expression and MDA concentration in brain tissue while improving cognitive ability. It reduced anxiety and depression-related activities. It also improved spatial memory in MWM test. CONCLUSION: Uncontrolled diabetes negatively impacts mental function and impairs learning and cognitive performance via oxidative stress induction, the Nox-4 enzyme playing a central role. Empagliflozin reverses these effects, improving cognitive ability via promoting the anti-oxidative system and damping Nox-4 free radical generator enzyme expression. Therefore, empagliflozin is a promising treatment, providing both antidiabetic and extra-glycemic benefits for improving brain function in the diabetic milieu.

Nanoparticles with SGLT2 inhibitory activity: Possible benefits and future.

AIM: Nano-drug delivery is a rapidly growing approach in medicine that helps design and develop newer forms of drugs with more efficacy and lower adverse effects. Sodium-glucose cotransporter-2 inhibitors are an emerging class of antidiabetic agents that reduce the blood glucose levels by damping glucose reabsorption in renal proximal tubules. METHODS AND RESULTS: This mechanism might be followed by some adverse effects that could be prevented by nano-drug delivery. Although we have still limited evidence about nanoforms of sodium-glucose cotransporter-2 inhibitors, current knowledge strongly suggests that nanotechnology can help us design more effective drugs with lower side effects. In recent years, several studies have explored the possible benefits of nanoforms of sodium-glucose cotransporter-2 inhibitors. However, clinical trials are yet to be conducted. CONCLUSION: In the current review, we present the latest findings on the development and benefits of nanoforms of sodium-glucose cotransporter-2 inhibitors.

Saffron and crocin ameliorate prenatal valproic acid-induced autistic-like behaviors and brain oxidative stress in the male offspring rats.

Autism is a neurobehavioral disease that induces cognitive and behavioral alterations, usually accompanied by oxidative stress in the brain. Crocus sativus (saffron) and its active ingredient, crocin, have potent antioxidative effects that may benefit autistic behaviors. This study aimed to determine the effects of saffron extract and crocin against brain oxidative stress and behavioral, motor, and cognitive deficits in an animal model of autism in male offspring rats. 14 female rats were randomly divided into the saline and valproic acid (VPA) groups. Then, they were placed with mature male rats to mate and produce offspring. VPA (500 mg/kg, i.p.) was injected on day 12.5 of pregnancy (gestational day, GD 12.5) to induce an experimental model of autism. 48 male pups were left undisturbed for 29 days. First-round behavioral tests (before treatments) were performed on 30-33 post-natal days (PND), followed by 28 days of treatment (PND 34-61) with saffron (30 mg/kg, IP), crocin (15 or 30 mg/kg, i.p.), or saline (2 ml/kg, i.p.). The second round of behavioral tests (after treatments) was performed on PND 62-65 to assess the effects of the treatments on behavioral and cognitive features. In the end, animals were sacrificed under deep anesthesia, and their brains were dissected to evaluate the brain oxidative stress parameters, including malondialdehyde (MDA), glutathione (GSH), and catalase (CAT). VPA injection into female rats increased anxiety-like behaviors, enhanced pain threshold, impaired motor functions, disturbed balance power, increased MDA, and decreased GSH and CAT in their male offspring. 28 days of treatment with saffron or crocin significantly ameliorated behavioral abnormalities, reduced MDA, and increased GSH and CAT levels. Brain oxidative stress has been implicated in the pathophysiology of autistic-like behaviors. Saffron and crocin ameliorate anxiety-like behaviors, pain responses, motor functions, and brain oxidative stress parameters in an experimental model of autism. Saffron and crocin may hold promise as herbal-based pharmacological treatments for individuals with autism. However, further histological evidence is needed to confirm their efficacy.

The Beneficial Effects of Curcumin on Lipids: Possible Effects on Dyslipidemia-Induced Cardiovascular Complications.

Dyslipidemia and altered lipid metabolism are closely involved in the pathogenesis and clinical manifestation of many metabolic and non-metabolic diseases. Therefore, mitigation of pharmacological and nutritional factors together with lifestyle modifications is paramount. One potential nutraceutical exhibiting cell signaling and lipid-modulating properties implicated in dyslipidemias is curcumin. Specifically, recent evidence suggest that curcumin may improve lipid metabolism and prevent dyslipidemia-induced cardiovascular complications via several pathways. Although the exact molecular mechanisms involved are not well understood, the evidence presented in this review suggests that curcumin can provide significant lipid benefits via modulation of adipogenesis and lipolysis, and prevention or reduction of lipid peroxidation and lipotoxicity via different molecular pathways. Curcumin can also improve the lipid profile and reduce dyslipidemia-dependent cardiovascular problems by impacting important mechanisms of fatty acid oxidation, lipid absorption, and cholesterol metabolism. Although only limited direct supporting evidence is available, in this review we assess the available knowledge regarding the possible nutraceutical effects of curcumin on lipid homeostasis and its possible impacts on dyslipidemic cardiovascular events from a mechanistic viewpoint.

Sodium Glucose Cotransporter-2 Inhibitor Empagliflozin Increases Antioxidative Capacity and Improves Renal Function in Diabetic Rats.

INTRODUCTION: There are several pathologic mechanisms involved in diabetic nephropathy, but the role of oxidative stress seems to be one of the most important. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs that might also have some other effects in addition to lowering glucose. The aim of this study was to evaluate the possible effects of the SGLT2 inhibitor empagliflozin on oxidative stress and renal function in diabetes. METHODS: Male Wistar rats were randomly divided into four groups: control, control-treated, diabetic, and diabetic-treated (n = 8 per group). Diabetes was induced by a single intraperitoneal dose of streptozotocin (50 mg/kg). The treated animals received empagliflozin for 5 weeks (20 mg/kg/day/po). All groups were sacrificed on the 36th day, and blood and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose levels were determined. The level of malondialdehyde (MDA) and glutathione (GLT), as well as the activity of catalase (CAT) and superoxide dismutase (SOD), was measured in all groups. Data were analyzed using one-way Anova and paired T-tests, and p ≤ 0.05 was considered significant. RESULTS: Diabetes significantly increased urea (p < 0.001), uric acid (p < 0.001), and creatinine (p < 0.001) in the serum, while the activities of CAT (p < 0.001) and SOD (p < 0.001) were reduced. GLT was also reduced (p < 0.001), and MDA was increased (p < 0.001) in non-treated animals. Treatment with empagliflozin improved renal function, as shown by a reduction in the serum levels of urea (p = 0.03), uric acid (p = 0.03), and creatinine (p < 0.001). Empagliflozin also increased the antioxidant capacity by increasing CAT (p = 0.035) and SOD (p = 0.02) activities and GLT content (p = 0.01) and reduced oxidative damage by lowering MDA (p < 0.001). CONCLUSIONS: It seems that uncontrolled diabetes induces renal insufficiency by decreasing antioxidant defense mechanisms and inducing oxidative stress. Empagliflozin might have additional benefits in addition to lowering glucose--reversing these processes, improving antioxidative capacity, and improving renal function.

Hepatic benefits of sodium-glucose cotransporter 2 inhibitors in liver disorders.

Diabetic patients are at higher risk of liver dysfunction compared with the normal population. Thus, using hypoglycemic agents to improve liver efficiency is important in these patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are newly developed antidiabetic drugs with potent glucose-lowering effects. However, recent limited evidence suggests that they have extra-glycemic benefits and may be able to exert protective effects on the liver. Hence, these drugs could serve as promising pharmacological agents with multiple benefits against different hepatic disorders. In this review, the current knowledge about the possible effects of SGLT2 inhibitors on different forms of liver complications and possible underlying mechanisms are discussed.

SGLT2 inhibitors and autophagy in diabetes.

Autophagy is a physiological event in mammalian cells to promote cell survival and efficiency in tissues, but it may turn to be a pathological process in disease conditions such as in diabetes. Chronic hyperglycemia induces aberrant autophagy and promotes cellular death as a main underlying cause of diabetes-related complications. Therefore, autophagy-modifying therapy may be of value to prevent the development of complications. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs that achieve normoglycemia through causing overt glycosuria. There is evidence that these drugs may have pleiotropic extra-glycemic benefits, but their effect on the autophagy process is unclear; therefore, this review was undertaken to clarify the possible effects of SGLT2is on autophagy.

Anti-inflammatory effects of sodium-glucose cotransporter-2 inhibitors in COVID-19.

The ongoing pandemic of COVID-19 is intrinsically a systemic inflammatory disorder; hence, those patients suffering an underlying chronic inflammatory disease such as diabetes mellitus are at high risk of severe complications. Preventing or suppressing the inflammatory responses are of importance in diabetic patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are a newly introduced anti-diabetic drugs that have hypoglycemic effects through the urinary excretion of glucose. They also have an anti-inflammatory potential in diabetes patients, in addition to improving glycemic control, and while there is no direct data available in diabetic patients with COVID-19 disease, there is evidence that suggests that SGLT2i can reduce systemic inflammation and diminish the cytokine storm effect via several cellular mechanisms. In the current review, our aim was to classify and describe the molecular and cellular pathways by which SGLT2i have anti-inflammatory effects in diabetic patients with COVID-19 disease.

Brain insulin signaling and cognition: Possible links.

Poor cognitive ability is a consequence of a wide variety of neurobehavioral disorders and is a growing health problem, especially among the elderly and patients with diabetes. The precise underlying cause of this complication is not well-defined. However, recent studies have highlighted the possible role of insulin hormone signaling in brain tissue. Insulin is a metabolic peptide integral to whole body energy homeostasis; it does, however, have extrametabolic impacts, such as upon neuronal circuits. Therefore, it has been suggested that insulin signaling may modify cognitive ability by yet unknown pathways. In the current review, we discuss the cognitive role of brain insulin signaling and consider the possible links between brain insulin signaling and cognitive ability.

Sodium-glucose cotransporter 2 inhibitors and mitochondrial functions: state of the art.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs with potent hypoglycemic effects. Recent evidence suggests that these drugs have extraglycemic impacts and are therefore able to provide additional benefits beyond glucose lowering. Mitochondrial dysfunction is a central facet of many disorders that negatively impacts many tissues and organs, especially in the setting of diabetes. Therefore, it would be hugely beneficial if an antidiabetic drug could also provide mitochondrial benefits to improve cellular function and reduce the risk of diabetic complications. In this review, we have surveyed the literature for possible mitochondrial benefits of SGLT2is and we discuss the possible mechanisms involved.

Benefits of GLP-1 Mimetics on Epicardial Adiposity.

The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.

Sodium-glucose cotransporter 2 inhibitors: A comprehensive review from cells to bedside.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years, they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice.

Sodium-glucose co-transporter-2 inhibitors and epicardial adiposity.

Epicardial adipose tissue is a layer of adipocytes that physiologically surround the myocardium and play some physiologic roles in normal heart function. However, in pathologic conditions, the epicardial adipose tissue can present a potent cardiac risk factor that is capable of impairing heart function through several pathways, increasing the risk of dysrhythmia and creating an inflammatory milieu around the heart tissues. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a relatively newly introduced class of antidiabetes drugs which effectively normalize blood glucose via overt glycosuria. Some recent reports suggest that these drugs are able to modulate epicardial adiposity and decrease the risk of cardiac complications in diabetic patients who are at higher risk of epicardial adiposity-dependent cardiac disorders. If proven to be true, these antidiabetic drugs can provide dual benefits as both hypoglycemic agents and as epicardial adiposity normalizing agents, thus providing cardiac benefits. In this study, we discuss the physiological and pathophysiological importance of epicardial adiposity and the potential positive effects of SGLT2is in the diabetic milieu.

Renal Effects of Empagliflozin in Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is one of the main causes of mortality and morbidity worldwide. It leads to various long-term complications such as diabetic nephropathy. Diabetes nephropathy is the leading cause of renal failure in patients with chronic kidney diseases undergoing hemodialysis. Hence preventing the development and progression of diabetic nephropathy is one of the main goals in the management of patients with type 2 diabetes. Sodium-glucose cotransporter 2 inhibitors of empagliflozin is a potent anti-hyperglycemic agents. In addition, it has been shown to have some pharmacologic potentials to provide renoprotective effects in patients with T2DM. In the current study, we review the available clinical data on the potential renoprotective effects of this drug from a mechanistic and molecular viewpoint.

Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu.

Chronic hyperglycemia induces pathophysiologic pathways with negative effects on the metabolism of most substrates as well as lipids and lipoproteins, and thereby induces dyslipidemia. Thus, the diabetic milieu is commonly accompanied by different levels of atherogenic dyslipidemia, which is per se a major risk factor for subsequent complications such as atherosclerosis, coronary heart disease, acute myocardial infarction, ischemic stroke, and nephropathy. Therefore, readjusting lipid metabolism in the diabetic milieu is a major goal for preventing dyslipidemia-induced complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of relatively newly introduced antidiabetes drugs (including empagliflozin, canagliflozin, dapagliflozin, etc.) with potent hypoglycemic effects and can reduce blood glucose by inducing glycosuria. However, recent evidence suggests that they could also provide extra-glycemic benefits in lipid metabolism. It seems that they can increase fat burning and lipolysis, normalizing the lipid metabolism and preventing or improving dyslipidemia. Nevertheless, the exact mechanisms involved in this process are not well-understood. In this review, we tried to explain how these drugs could regulate lipid homeostasis and we presented the possible involved cellular pathways supported by clinical evidence.