Litchi (Litchi sinensis), a fruit with a sweet and white aril, cultivated mainly in Southeast Asia and possesses anticancer, antibacterial, antioxidant, and other therapeutic properties. It is a delicacy among children. However, an outbreak of acute encephalopathy syndrome (AES) in litchi growing regions during the seasons of litchi ripening and harvesting (May-June) resulted in symptoms of lethargy, weakness, fever, vomiting, seizures, and coma that was most common among malnourished children below 15 years. Upon successful epidemiological studies, it was confirmed that the non-protein amino acids such as hypoglycine A (HGA) and methylenecyclopropylglycine (MCPG) are responsible for the AES outbreak. Most of the underprivileged and malnourished kids with an empty stomach venture into the litchi orchards to savor the fruit during the litchi harvesting season. Their fasting condition results in decreased glucose levels in the blood. The decreased glucose levels trigger glycogenolysis. However, gluconeogenesis takes over glycogenolysis to replenish the glucose levels due to fewer glycogen stores in malnourished children. The toxins are involved in fatty acid oxidation and gluconeogenesis pathways, by blocking several steps in the former process. Depleted glycogen stores and suppression of gluconeogenesis synergistically cause hypoglycemia and accumulation of toxic intermediates from the metabolic pathway leading to metabolic failure. The incidence of AES can be prevented by creating proper awareness among the farmers, vendors and consumers on the importance of adverse effects of litchi fruit when consumed on empty stomach or fasting state. Further, elucidating detailed biochemical pathway of HGA and MCPG toxicity, improving agricultural and public health practices, keeping glucose stores and glucose banks in the areas which are highly prone to litchi induced toxicity are some of the therapeutic measures. This review highlights and discusses the AES incidences, mechanistic pathways involved in litchi fruit toxicity, and corresponding risk factors involved and possible treatment and preventive approaches.

Hypoglycemia is an uncommon clinical problem among non-diabetic patients. It requires systematic evaluation to determine the etiology. It may be related to critical illness, hepatic insufficiency, renal insufficiency, cardiac insufficiency, drugs, alcohol, cortisol insufficiency, growth hormone insufficiency, insulinoma, gastric bypass surgery, and paraneoplastic (insulin-like growth factor-2-related) immune-mediated or inherited metabolic disorders. We aimed to summarize the literature and present a case who suffered from hypoglycemia throughout his life and was diagnosed with fructose-1, 6 bisphosphatase deficiency in adulthood to attract attention to the rare causes of hypoglycemia in adulthood.

Energy is continuously expended in the body, and gluconeogenesis maintains glucose homeostasis during starvation. Gluconeogenesis occurs in the liver and kidneys. The proximal tubule is the primary location for renal gluconeogenesis, accounting for up to 25% and 60% of endogenous glucose production during fasting and after a meal, respectively. The mechanistic target of rapamycin (mTOR), which exists downstream of the insulin pathway, plays an important role in regulating proximal tubular gluconeogenesis. mTOR is an atypical serine/threonine kinase present in two complexes. mTORC1 phosphorylates substrates that enhance anabolic processes such as mRNA translation and lipid synthesis and catabolic processes such as autophagy. mTORC2 regulates cytoskeletal dynamics and controls ion transport and proliferation via phosphorylation of SGK1. Therefore, mTOR signaling defects have been implicated in various pathological conditions, including cancer, cardiovascular disease, and diabetes. However, concrete elucidations of the associated mechanisms are still unclear. This review provides an overview of mTOR and describes the relationship between mTOR and renal.

The incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) has been rapidly increasing during the last decade. It is a relevant health problem that affects 25% of the general population. NAFLD involves an extensive array of clinical conditions. So far, no approved pharmacological therapy for NAFLD has been developed. Multiple bioactive compounds have been proposed to treat NAFLD. One of the most promising is Berberine (BBR). Its pleiotropic effect positively impacts various cardiometabolic aspects. In this review, we summarize NAFLD, its metabolic and cardiovascular complications, the hepatoprotective effects of BBR due to its broad spectrum of pharmacological effects, and the potential role of BBR in NAFLD therapy. BBR ameliorates NAFLD by affecting numerous abnormalities. It inhibits lipogenesis and gluconeogenesis, improves insulin resistance and lipid profile, and modulates gut microbiota. The exact mechanism underlying these effects is not yet entirely explained. A growing amount of evidence confirming the positive effects of BBR on multiple metabolic pathways, such as lipids and glucose metabolism, energy homeostasis, or gut microbiota modulation, allows us to speculate about the importance of this natural bioactive substance for NAFLD therapy.

Stroke is one of the most prevalent causes of death around the world. When a stroke occurs, many cellular signaling cascades and regulators are activated, which results in severe cellular dysfunction and debilitating long-term disability. One crucial regulator of cell fate and function is mammalian Forkhead box protein O1 (FoxO1). Many studies have found FoxO1 to be implicated in many cellular processes, including regulating gluconeogenesis and glycogenolysis. During a stroke, modifications of FoxO1 have been linked to a variety of functions, such as inducing cell death and inflammation, inhibiting oxidative injury, affecting the blood brain barrier (BBB), and regulating hepatic gluconeogenesis. For these functions of FoxO1, different measures and treatments were applied to FoxO1 after ischemia. However, the subtle mechanisms of post-transcriptional modification and the role of FoxO1 are still elusive and even contradictory in the development of stroke. The determination of these mechanisms will lead to further enlightenment for FoxO1 signal transduction and the identification of targeted drugs. The regulation and function of FoxO1 may provide an important way for the prevention and treatment of diseases. Overall, the functions of FoxO1 are multifactorial, and this paper will summarize all of the significant pathways in which FoxO1 plays an important role during stroke damage and recovery.

Yes-associated protein (YAP) is one of the Hippo pathway\'s two effectors, a pathway associated with organ size control. Research on YAP has focused on its oncogenic potential. However, in cancer cells, aside from inducing growth, YAP was also found to regulate glucose metabolism. The present review explores YAP\'s control of glucose metabolism and whether these findings are translatable to physiological conditions. According to current literature, YAP induces the transcriptional activity of most genes associated with glucose metabolism from enzymes to transport proteins. In glycolysis and gluconeogenesis, YAP upregulates all enzymes except for enolase and pyruvate kinase. Multiple research has also shown YAP\'s ability to regulate the expression of glucose transporter of the GLUT family. Additionally, glucose concentration, hypoxia, and hormones such as insulin and glucagon regulate YAP activity and depend on YAP to exert their biological activity. YAP is thus a central regulator of glucose metabolism, controlling both enzymes and proteins involved in glucose transport. YAP is also situated strategically in several pathways controlling glucose and was found to mediate their effects. If these results were consistent in physiological conditions and across glucose-associated metabolic disturbances, then YAP may become a prospective therapeutic target.

This study provides a critical overview of experimental studies in vitro, in humans, and in animals that evaluated the efficacy of Berberine and its effect on management of obesity and the related metabolic consequences. As a result of this review, we summarized the effects of Berberine in different models and the related mechanism of actions. In preclinical models, Berberine demonstrates that it affects gut microbiota by reducing diversity of microbes starting at a dosage of 100 mg/kg/day. Moreover, in animal models, Berberine explicates an action on glucose through the inhibition of α-glycosidase at a dose of 200 mh/kg/day. Berberine is also known to be effective against differentiation of adipocytes through a decrease in LXRs, PPARs, and SREBPs expression at 150 mg/kg/day. Other mechanism ascribed to Berberine are related to its inhibition of hepatic gluconeogenesis through the Phospheoenolpyruvate carboxykinase (PEPCK), Glucose-6-phosphate (G6Pase) and AMP-activated protein kinase (AMPK). Furthermore, Berberine (associated to Red Yeast Rice) is effective in decreasing lipid levels in rats, which consequently lowers the change of weight gain at dosage of 40 mg/kg to 380 mg/kg/day. All the above preclinical data are confirmed in human studies where Berberine can modulate the diversity of gut microbes at the dose of 500 mg/day. In addition, Berberine is found to have a beneficial impact on gene regulation for the absorption of cholesterol at a daily dose of 300 mg in humans, an amelioration on glucose accumulation at 1.0 g daily dose was also observed. For all these reasons, this review gives an important good account of the impact of Berberine in obesity treatment and prevention.

Inflammatory cascades are a critical component of the immune response to infection or tissue damage, involving an array of signals, including water-soluble metabolites, lipid mediators and several classes of proteins. Early investigation of these signaling pathways focused largely on immune cells and acute disease models. However, more recent findings have highlighted critical roles of both immune cells and inflammatory mediators on tissue remodeling and metabolic homeostasis in healthy animals. In dairy cattle, inflammatory signals in various tissues and in circulation change rapidly and dramatically, starting just prior to and at the onset of lactation. Furthermore, several observations in healthy cows point to homeostatic control of inflammatory tone, which we define as a regulatory process to balance immune tolerance with activation to keep downstream effects under control. Recent evidence suggests that peripartum inflammatory changes influence whole-body nutrient flux of dairy cows over the course of days and months. Inflammatory mediators can suppress appetite, even at levels that do not induce acute responses (e.g. fever), thereby decreasing nutrient availability. On the other hand, inhibition of inflammatory signaling with non-steroidal anti-inflammatory drug (NSAID) treatment suppresses hepatic gluconeogenesis, leading to hypoglycemia in some cases. Over the long term, though, peripartum NSAID treatment substantially increases peak and whole-lactation milk synthesis by multiparous cows. Inflammatory regulation of nutrient flux may provide a homeorhetic mechanism to aid cows in adapting to rapid changes in metabolic demand at the onset of lactation, but excessive systemic inflammation has negative effects on metabolic homeostasis through inhibition of appetite and promotion of immune cell activity. Thus, in this review, we provide perspectives on the overlapping regulation of immune responses and metabolism by inflammatory mediators, which may provide a mechanistic underpinning for links between infectious and metabolic diseases in transition dairy cows. Moreover, we point to novel approaches to the management of this challenging phase of the production cycle.

Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide⁺ (NAD⁺) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings of SIRT6 since future research may hold the key to engendering strategies involving SIRT6 that may have significant implications for human health and expand upon possible treatment options. In this review, we are primarily concerned with exploring the latest advances in understanding SIRT6 and how it can alter the course of several life-threatening diseases such as processes related to aging, cancer, neurodegenerative diseases, heart disease, and diabetes (SIRT6 has also shown to be involved in liver disease, inflammation, and bone-related issues) and any recent promising pharmacological investigations or potential therapeutics that are of interest.

Diabetes mellitus is the most common endocrine disorder and a major cause of morbidity and mortality. Traditional medicines worldwide suggest a wide range of natural remedies for the prevention and treatment of chronic disorders, including diabetes mellitus. This mechanistic review aims to highlight the significance of medicinal plants traditionally used as dietary supplements in Persian medicine in adjunct with restricted conventional drugs for the prevention and treatment of diabetes mellitus. Mounting evidence suggests that these natural agents perform their protective and therapeutic effect on diabetes mellitus via several cellular mechanisms, including regeneration of pancreatic β cell, limitation of glycogen degradation and gluconeogenesis, anti-inflammatory, immunoregulatory, antiapoptosis, antioxidative stress, as well as modulation of intracellular signaling transduction pathways. In conclusion, traditional medicinal plants used in Persian medicine can be considered as dietary supplements with therapeutic potential for diabetes mellitus and maybe potential sources of new orally active agent(s).