NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Approaches to Decrease Hyperglycemia by Targeting Impaired Hepatic Glucose Homeostasis Using Medicinal Plants

Liver plays a pivotal role in maintaining blood glucose levels through complex processes which involve the disposal, storage, and endogenous production of this carbohydrate. Insulin is the hormone responsible for regulating hepatic glucose production and glucose storage as glycogen, thus abnormalities in its function lead to hyperglycemia in obese or diabetic patients because of higher production rates and lower capacity to store glucose. In this context, two different but complementary therapeutic approaches can be highlighted to avoid the hyperglycemia generated by the hepatic insulin resistance: 1) enhancing insulin function by inhibiting the protein tyrosine phosphatase 1B, one of the main enzymes that disrupt the insulin signal, and 2) direct regulation of key enzymes involved in hepatic glucose production and glycogen synthesis/breakdown. It is recognized that medicinal plants are a valuable source of molecules with special properties and a wide range of scaffolds that can improve hepatic glucose metabolism. Some molecules, especially phenolic compounds and terpenoids, exhibit a powerful inhibitory capacity on protein tyrosine phosphatase 1B and decrease the expression or activity of the key enzymes involved in the gluconeogenic pathway, such as phosphoenolpyruvate carboxykinase or glucose 6-phosphatase. This review shed light on the progress made in the past 7 years in medicinal plants capable of improving hepatic glucose homeostasis through the two proposed approaches. We suggest that Coreopsis tinctoria, Lithocarpus polystachyus, and Panax ginseng can be good candidates for developing herbal medicines or phytomedicines that target inhibition of hepatic glucose output as they can modulate the activity of PTP-1B, the expression of gluconeogenic enzymes, and the glycogen content.

Humulane-Type Macrocyclic Sesquiterpenoids From the Endophytic Fungus Penicillium sp. of Carica papaya

Three new humulane-type sesquiterpenoids, penirolide A (1), penirolide B (2), and 10-acetyl-phomanoxide (3), together with three known compounds aurasperone A (4), pughiinin A (5), and cyclo(l-Leu-l-Phe) (6) were isolated from the endophytic fungus Penicillium sp. derived from the leaves of Carica papaya L. Their structures including their absolute configurations were determined based on the analysis of NMR and HRESIMS spectra, NMR chemical shifts, and ECD calculations. Compounds 2, 3, 5, and 6 significantly inhibited glucagon-induced hepatic glucose production, with EC50 values of 33.3, 36.1, 18.8, and 32.1 μM, respectively. Further study revealed that compounds 2, 3, 5, and 6 inhibited hepatic glucose production by suppression of glucagon-induced cAMP accumulation.

In Vivo Metabolic Roles of G Proteins of the Gi Family Studied with Novel Mouse Models

G protein-coupled receptors (GPCRs) are the target of ~30-35% of all FDA-approved drugs. The individual members of the GPCR superfamily couple to one or more functional classes of heterotrimeric G proteins. The physiological outcome of activating a particular GPCR in vivo depends on the pattern of receptor distribution and the type of G proteins activated by the receptor. Based on the structural and functional properties of their α-subunits, heterotrimeric G proteins are subclassified into four major families: Gs, Gi/o, Gq/11, and G12/13. Recent studies with genetically engineered mice have yielded important novel insights into the metabolic roles of Gi/o-type G proteins. For example, recent data indicate that Gi signaling in pancreatic α-cells plays a key role in regulating glucagon release and whole body glucose homeostasis. Receptor-mediated activation of hepatic Gi signaling stimulates hepatic glucose production, suggesting that inhibition of hepatic Gi signaling could prove clinically useful to reduce pathologically elevated blood glucose levels. Activation of adipocyte Gi signaling reduces plasma free fatty acid levels, thus leading to improved insulin sensitivity in obese, glucose-intolerant mice. These new data suggest that Gi-coupled receptors that are enriched in metabolically important cell types represent potential targets for the development of novel drugs useful for the treatment of type 2 diabetes and related metabolic disorders.

Metformin: an old drug with potential therapeutic function in antitumor

Metformin is one of the first-line and widely-used drugs in patients with T2DM due to its safety profile, clinical efficacy and cheap cost. It is clearly that metformin has benefits on lowering hyperglycemia and diabetes-related complications in clinical use. The classic effect of metformin is to reduce hepatic glucose production by inhibiting gluconeogenesis in liver and increase glucose utilization in peripheral tissues. Metformin targets mitochondrial respiratory chain complex I to specifically reduce reactive oxygen species generation to protect cells against oxidative stress-induced cell apoptosis. AMPK complex is a key factor in the action of metformin; however it is inconclusive that whether metformin activate AMPK directly or indirectly. In addition, more and more studies showed that metformin act on gut microbiota to exert anti-hyperglycemia effect. Emerging evidence showed that metformin has off-label function on antitumor therapy; however the underlying mechanism of this property of metformin still remains elusive. Taken together, in this review we provide a new perspective on metformin and repurpose its novel and promising application in antitumor therapy.

Chronic AT1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade increases glucose uptake in skeletal muscle, decreases the abundance of large adipocytes, and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80 and CD11c positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60), and 120 (T120) minutes after an acute glucose challenge in the following groups of male rats: LETO (lean control; n = 5/time point), (2) obese OLETF (n = 7-8/time point) and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d; n = 7-8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80 and CD11c positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased GLUT4 protein expression in ARB compared to OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic PCK1 and G6PC1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia

Background: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. Methods: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. Results: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). Conclusions: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

Prevention of Hyperglycemia

Hyperglycemia is the elevation of blood glucose concentrations above the normal range. Prolonged uncontrolled hyperglycemia is associated with serious life-threatening complications. Hyperglycemia arises from an imbalance between glucose production and glucose uptake and utilization by peripheral tissues. Disorders that compromise pancreatic function or affect the glucose counter-regulatory hormones cause hyperglycemia. Acute or serious illness or injury may also bring about hyperglycemia, as can many classes of drugs. Metformin lowers blood glucose levels by inhibiting the production of glucose by the liver whilst enhancing uptake of circulating glucose and its utilization in peripheral tissues such as muscle and adipose tissue. Metformin suppresses hepatic gluconeogenesis by inhibiting mitochondrial respiration and causing a reduction of cellular ATP levels. Metformin may also modulate the gut-brain-liver axis, resulting in suppression of hepatic glucose production. Metformin also opposes the hyperglycemic action of glucagon and may ameliorate pancreatic cell dysfunction associated with hyperglycemia. Metformin is therefore recommended for use in the prevention of hyperglycemia, including drug-induced hyperglycemia, in at risk patients. The benefits of metformin in the prevention of hyperglycemia are unmatched despite its contraindications.