Suppression Of Glucose Production Research Articles

GPAT1 Activity and Abundant Palmitic Acid Impair Insulin Suppression of Hepatic Glucose Production in Primary Mouse Hepatocytes

BackgroundGlycerol-3-phosphate acyltransferase (GPAT) activity is correlated with obesity and insulin resistance in mice and humans. However, insulin resistance exists in people with normal body weight, and individuals with obesity may be metabolically healthy, implying the presence of complex pathophysiologic mechanisms underpinning insulin resistance. ObjectiveWe asked what conditions related to GPAT1 must be met concurrently for hepatic insulin resistance to occur. MethodsMouse hepatocytes were overexpressed with GPATs via adenoviral infection or exposed to high or low concentrations of glucose. Glucose production by the cells and phosphatidic acid (PA) content in the cells were assayed, GPAT activity was measured, relative messenger RNA expressions of sterol-regulatory element-binding protein 1c (SREBP1c), carbohydrate response element-binding protein (ChREBP), and GPAT1 were analyzed, and insulin signaling transduction was examined. ResultsOverexpressing GPAT1 in mouse hepatocytes impaired insulin’s suppression of glucose production, together with an increase in both N-ethylmaleimide-resistant GPAT activity and the content of di-16:0 PA. Akt-mediated insulin signaling was inhibited in hepatocytes that overexpressed GPAT1. When the cells were exposed to high-glucose concentrations, insulin suppression of glucose production was impaired, and adding palmitic acid exacerbated this impairment. High-glucose exposure increased the expression of SREBP1c, ChREBP, and GPAT1 by ∼2-, 5-, and 5.7-fold, respectively. The addition of 200 mM palmitic acid or linoleic acid to the culture media did not change the upregulation of expression of these genes by high glucose. High-glucose exposure increased di-16:0 PA content in the cells, and adding palmitic acid further increased di-16:0 PA content. The effect was specific to palmitic acid because linoleic acid did not show these effects. ConclusionThese data demonstrate that high-GPAT1 activity, whether induced by glucose exposure or acquired by transfection, and abundant palmitic acid can impair insulin’s ability to suppress hepatic glucose production in primary mouse hepatocytes.

Antioxidant and Hypoglycemic Potential of Essential Oils in Diabetes Mellitus and Its Complications.

Since the earliest times, essential oils (EOs) have been utilized for medicinal and traditional purposes. However, in recent decades, an increasing interest has developed due to the need to rediscover herbal remedies and adjuvant therapies for the management of various diseases, particularly chronic ones. The present narrative review examines the potential for EOs to exert hypoglycemic and antioxidant effects in diabetes mellitus, analyzing the main publications having evaluated plant species with potentially beneficial effects through their phytocompounds in diabetes mellitus and its complications. Numerous species have shown promising characteristics that can be used in diabetes management. The hypoglycemic effects of these EOs are attributed to their capacity to stimulate glucose uptake, suppress glucose production, and increase insulin sensitivity. Moreover, EOs can alleviate the oxidative stress by manifesting their antioxidant effects via a variety of mechanisms, including the scavenging of free radicals, the regulation of antioxidant enzymes, and the decreasing of lipid peroxidation, due to their diverse chemical composition. These findings demonstrate the possible benefits of EOs as adjuvant therapeutic agents in the management of diabetes and its complications. The use of EOs in the treatment of diabetes shows good potential for the development of natural and effective strategies to enhance the health outcomes of people with this chronic condition, but additional experimental endorsements are required.

Effect of C-reactive protein deficiency on insulin resistance reversal in rats with polycystic ovary syndrome through augmented leptin action

BackgroundC-reactive protein(CRP), is an inflammatory marker that weaken leptin bioavailability and insulin sensitivity to disturb energy and glucose metabolism. Polycystic ovary syndrome (PCOS) exhibit a metabolic component consisting of higher plasma CRP levels, hyperinsulinemic and hyperleptinemia. The ability of leptin to regulation of hepatic glucose production (HGP) in the absence of CRP in PCOS remain unknown.MethodsDehydroepiandrosterone (DHEA) was used to induce PCOS in rats. We assessed the effects of CRP gene knockout in PCOS model rats on body weight, energy expenditure glucose metabolism and insulin sensitivity. We conducted experiments involving the administration of leptin to both the peripheral and central systems in PCOS model rats with CRP knockout, and studied the effects on changes in glucose kinetics during hyperinsulinemic-euglycemic clamps.ResultsIn female PCOS rats, the lack of CRP resulted in decreased leptin resistance and weight gain, increased energy expenditure, and improved insulin sensitivity. Additionally, the deletion of the CRP gene strengthened the HGP-lowering effects of leptin when administered peripherally or centrally. This effect was accompanied by a decrease in the expression of hepatic gluconeogenic enzymes and an increase in hepatic insulin signaling. Finally, inhibition of glucose production was also enhanced for central leptin administration during lipid infusion in PCOS rats.ConclusionsOur findings highlight the therapeutic potential of targeting CRP to restore glucose homeostasis and insulin sensitivity for leptin in PCOS.

In Silico Screening and Identification of Antidiabetic Inhibitors Sourced from Phytochemicals of Philippine Plants against Four Protein Targets of Diabetes (PTP1B, DPP-4, SGLT-2, and FBPase).

Current oral medications for type 2 diabetes target a single main physiological mechanism. They either activate or inhibit receptors to enhance insulin sensitivity, increase insulin secretion, inhibit glucose absorption, or inhibit glucose production. In advanced stages, combination therapy may be required because of the limited efficacy of single-target drugs; however, medications are becoming more costly, and there is also the risk of developing the combined side effects of each drug. Thus, identifying a multi-target drug may be the best strategy to improve treatment efficacy. This study sees the potential of 2657 Filipino phytochemicals as a source of natural inhibitors against four targets of diabetes: PTP1B, DPP-4, SGLT-2, and FBPase. Different computer-aided drug discovery techniques, including ADMET profiling, DFT optimization, molecular docking, MD simulations, and MM/PBSA energy calculations, were employed to elucidate the stability and determine the binding affinity of the candidate ligands. Through in silico methods, we have identified seven potential natural inhibitors against PTP1B, DPP-4, and FBPase, and ten against SGLT-2. Eight plants containing at least one natural inhibitor of each protein target were also identified. It is recommended to further investigate the plants' potential to be transformed into a safe and scientifically validated multi-target drug for diabetes therapies.

Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, apositive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.

Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism.

The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.

A glucose-sensing mechanism with glucose transporter 1 and pyruvate kinase in the area postrema regulates hepatic glucose production in rats

The area postrema (AP) of the brain is exposed to circulating metabolites and hormones. However, whether AP detects glucose changes to exert biological responses remains unknown. Its neighboring nuclei, the nucleus tractus solitarius (NTS), responds to acute glucose infusion by inhibiting hepatic glucose production, but the mechanism also remains elusive. Herein, we characterized AP and NTS glucose-sensing mechanisms. Infusion of glucose into the AP, like the NTS, of chow rats suppressed glucose production during the pancreatic (basal insulin)-euglycemic clamps. Glucose transporter 1 or pyruvate kinase lentiviral-mediated knockdown in the AP negated AP glucose infusion to lower glucose production, while the glucoregulatory effect of NTS glucose infusion was also negated by knocking down glucose transporter 1 or pyruvate kinase in the NTS. Furthermore, we determined that high-fat (HF) feeding disrupts glucose infusion to lower glucose production in association with a modest reduction in the expression of glucose transporter 1, but not pyruvate kinase, in the AP and NTS. However, pyruvate dehydrogenase activator dichloroacetate infusion into the AP or NTS that enhanced downstream pyruvate metabolism and recapitulated the glucoregulatory effect of glucose in chow rats still failed to lower glucose production in HF rats. We discovered that a glucose transporter 1- and pyruvate kinase-dependent glucose-sensing mechanism in the AP (as well as the NTS) lowers glucose production in chow rats and that HF disrupts the glucose-sensing mechanism that is downstream of pyruvate metabolism in the AP and NTS. These findings highlight the role of AP and NTS in mediating glucose to regulate hepatic glucose production.

A review on potential anti-diabetic herbs and polyherbal formulations concept

Multifactorial diseases, for diabetes develop various complication like hepatic toxicity, retinopathy, neuropathy, nephropathy and immunodeficiency etc. Numerous medicinal herbs have been used for the diabetes mellitus in traditional systems of medicine worldwide as they are a great source of phytochemical constituents and many of them are known to be effective against diabetes. Medicinal herbs with antidiabetic activities are being more desired, to lesser side effect and low cost. The efficacy of antihyperglycemic herbs is achieved by increasing insulin secretion, enhancing glucose uptake, activate GLP and inhibiting glucose production. The antidiabetic herbs contains many phytochemical constituents they single herb use produce mild effect when the combining of two — three herbs which having different chemical constituent and pharmacological action and produce synergistic effect and avoid repeated dose and achieve the efficacies therapeutic effec.

A review: Herbal antidiabetic drugs

Diabetes mellitus is a systematic metabolic disease characterized by hyper-glycemia, hyper- aminoacidemia and hypoinsulinemia. It occurs when there are elevated levels of glucose in a person's blood because their body is unable to produce part or sufficient amount of the insulin hormone. Herbal medications are effective at preventing diabetes and its associated complications. Consequently, the research progresses for a maximum of explorations of the hypoglycemic potential of herbs. The anti-diabetic activity of herbal remedies is mainly due to increased pancreatic secretion of insulin, inhibition of glucose production in the liver. In this study, many authors have collected more information on the plant-based plant compounds that have been studied for diabetes. A few medicinal plants traditionally used for diabetic treatment containing chemical constituents like polyphenols, alkaloids, glycosides, flavonoids, polysaccharides and terpenoids.

Study of Basil (Ocimum basilicum L) and its Mechanism of Action on Type 2 Diabetes

Introduction: Diabetes mellitus is a chronic metabolic disease with life threatening complications such as diabetic retinopathy, renal failure and cardiovascular disease. Metformin, Glibenclamide, Acarbose, Empagliflozin, Sitagliptin and Repaglinide are the most common drugs for reducing the blood glucose. The blood glucose-lowering drugs have side effects such as severe hypoglycemia, liver cell damage, lactic acidosis, permanent neurological defects, gastrointestinal disorders, headache, and dizziness. Hence, it is necessary to use safe and effective strategies for reducing blood glucose in the management of diabetes and related diseases. Therefore, in the recent years, medicinal plants have been used all over the world due to their wide therapeutic effects. Basil (O. basilicum) is one of the medicinal plants with anti-diabetic property. This article aimed to review of the Basil effects on the type 2 diabetes.
 Conclusion: O. basilicum has significant role in the control of diabetes through different mechanisms. These include: inhibition of glucose production in the liver, increasing glycogen synthesis, decreasing gluconeogenesis and glycogenolysis, stimulation of insulin secretion by the pancreas, and inhibition of α-glucosidase and α-amylase enzymes. Therefore, Basil and its biologically active compounds such as flavonoids, alkaloids and polyphenols act as potent anti-diabetic agents.

Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy

BackgroundPartial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL). ObjectiveWe hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL. MethodsFive adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension. ResultsWithin-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25th, 75th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects’ serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets. ConclusionsIn PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.

Pea Protein-Derived Peptides Inhibit Hepatic Glucose Production via the Gluconeogenic Signaling in the AML-12 Cells.

Pea protein is considered to be a high quality dietary protein source, but also it is an ideal raw material for the production of bioactive peptides. Although the hypoglycemic effect of pea protein hydrolysate (PPH) has been previously reported, the underlying mechanisms, in particular its effect on the hepatic gluconeogenesis, remain to be elucidated. In the present study, we found that PPH suppressed glucose production in mouse liver cell-line AML-12 cells. Although both of the gluconeogenic and insulin signaling pathways in the AML-12 cells could be regulated by PPH, the suppression of glucose production was dependent on the inhibition of the cAMP response element-binding protein (CREB)-mediated signaling in the gluconeogenic pathway, but not the activation of insulin signaling. Findings from the present study have unveiled a novel role of PPH underlying its anti-diabetic activity, which could be helpful to accelerate the development of functional foods and nutraceuticals using PPH as a starting material.

N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction.

With a resurgence of covalent drugs, there is an urgent need for the identification of new moieties capable of cysteine bond formation. Herein, we report on the N-acylamino saccharin moieties capable of novel covalent reactions with cysteine. Their utility as alternative electrophilic warheads was demonstrated through the covalent modification of fructose-1,6-bisphosphatase (FBPase), a promising target associated with cancer and type 2 diabetes. The cocrystal structure of title compound W8 bound with FBPase unexpectedly revealed that the N-acylamino saccharin moiety worked as an electrophile warhead that covalently modified the noncatalytic C128 site in FBPase while releasing saccharin, suggesting a previously undiscovered covalent reaction mechanism of saccharin derivatives with cysteine. Treatment of title compound W8 displayed potent inhibition of glucose production in vitro and in vivo. This newly discovered reactive warhead supplements the current repertoire of cysteine covalent modifiers while avoiding some of the limitations generally associated with established moieties.

Mitochondrial GCN5L1 regulates cytosolic redox state and hepatic gluconeogenesis via glycerol phosphate shuttle GPD2

Hepatic gluconeogenesis is crucial for maintaining blood glucose during starvation, and a major contributor for hyperglycemia. Cellular redox state is related to mitochondrial biology and regulates conversion of specific metabolites to glucose. General control of amino acid synthesis 5 (GCN5) like-1 (GCN5L1) is a mitochondria-enriched protein which modulates glucose and amino acid metabolism. Here we show a new regulatory mode of GCN5L1 on gluconeogenesis using lactate and glycerol. We observed GCN5L1 deletion dramatically inhibited glucose production derived from glycerol and lactate, due to increased cytosolic redox state. The underlying mechanism is that GCN5L1 directly binds to the key component of mitochondrial shuttle glycerol phosphate dehydrogenase 2 (GPD2) and modulates its activity. These results have significant implications for understanding the physiological role and regulatory mechanism of mitochondrial shuttle in diabetes development and provide a novel therapeutic potential for diabetes.

Inhibition of basal and glucagon-induced hepatic glucose production by 991 and other pharmacological AMPK activators.

Pharmacological AMPK activation represents an attractive approach for the treatment of type 2 diabetes (T2D). AMPK activation increases skeletal muscle glucose uptake, but there is controversy as to whether AMPK activation also inhibits hepatic glucose production (HGP) and pharmacological AMPK activators can have off-target effects that contribute to their anti-diabetic properties. The main aim was to investigate the effects of 991 and other direct AMPK activators on HGP and determine whether the observed effects were AMPK-dependent. In incubated hepatocytes, 991 substantially decreased gluconeogenesis from lactate, pyruvate and glycerol, but not from other substrates. Hepatocytes from AMPKβ1-/- mice had substantially reduced liver AMPK activity, yet the inhibition of glucose production by 991 persisted. Also, the glucose-lowering effect of 991 was still seen in AMPKβ1-/- mice subjected to an intraperitoneal pyruvate tolerance test. The AMPK-independent mechanism by which 991 treatment decreased gluconeogenesis could be explained by inhibition of mitochondrial pyruvate uptake and inhibition of mitochondrial sn-glycerol-3-phosphate dehydrogenase-2. However, 991 and new-generation direct small-molecule AMPK activators antagonized glucagon-induced gluconeogenesis in an AMPK-dependent manner. Our studies support the notion that direct pharmacological activation of hepatic AMPK as well as inhibition of pyruvate uptake could be an option for the treatment of T2D-linked hyperglycemia.

1307-P: Leptin Action in the Nucleus of the Solitary Tract

Obesity and diabetes are characterized by a disruption in energy balance and glucose homeostasis in association with leptin resistance. Leptin action in the hypothalamus regulates glucose levels and body weight, but whether other brain regions facilitate leptin action remain unclear. Here, we investigate whether the nucleus of the solitary tract (NTS) of the brainstem is a crucial site for leptin action in regulating glucose homeostasis in 3d high-fat (HF) -fed male rats, as recent studies report leptin activates leptin receptor in the NTS to regulate feeding. In this study, we performed brain stereotaxic bilateral surgery targeting the NTS followed one week later by catheterization of the left carotid artery and right internal jugular vein for infusion/sampling purposes. Rats that attained >90% of presurgical weight received 3d of Lard oil enriched HF diet and were fasted 4-6 hr before undergoing a 2min pancreatic (basal insulin) -euglycemic clamp studies together with tracer glucose infusion to assess glucose metabolism independent of changes in plasma insulin and glucagon levels. Leptin (91.7 ng/uL at 0.33 ul/hr) or saline was infused into the NTS throughout the duration of the clamp studies. Correct placement of the NTS catheter was verified by infusion of bromophenol blue dye through the brain cannula. For the first time, we found that leptin vs. saline infusion into the NTS markedly increased the exogenous glucose infusion [lep: 4.6±0.2 vs. sal: 1.3±0.4 mg/kg/min; p<0.005; n=12, 5] required to maintain euglycemia [lep: 137.5±2.2 vs. sal: 145±3.1 mg/dl; p>0.05; n=12, 5], during the clamps. The drop in plasma glucose levels was due to an inhibition of glucose production [lep: 4.9±0.1 vs. sal: 8.4±0.7 mg/kg/min; p<0.01; n=12, 5], but not an increase in glucose uptake [lep: 10.4±0.5 vs. sal: 9.7±0.3 mg/kg/min; p>0.05; n=12, 5]. These findings demonstrate that the NTS mediates leptin action on glucose homeostasis. Future studies are needed to investigate the NTS leptin signaling cascade in glucose homeostasis in obesity and diabetes. Disclosure K.Bruce: None. R.Li: None. Y.Lim: None. J.T.Yue: None. T.K.Lam: None. Funding Canadian Institutes of Health Research Foundation Grant (FDN-143204)

Evaluation of Anti-diabetic Activity of Bambusa Bambos using Streptozocin Diabetic Model Induced

Diabetes mellitus, commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. If left untreated, diabetes can cause many health complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment. Herbal medicine is a drug or preparation made from plants or parts of plant (leaves, root, bark, seeds and flowers) valued for its medicinal, aromatic or savoury qualities to treat the symptoms of wide range of problems from depression to cold and flu. Herbal medicine has been widely used for thousands of years. One of them is Bambusa bambos which is very well known for its ethno pharmacological activities, also known as Bans in hindi andvansa in sanskrit. leaves were washed and dried was extracted with hydroalcohol. The present study represents the assessment of anti- hyperglycemic effects of the hydro alcoholic extract from bambusa bambos in streptozotocin (STZ) induced diabetic rats. The bambusa bambos hydoalcoholic extracts at the tested doses of 100, 200 and 400 mg/kg showed comparable activity with the standard. Metformin decreases hyperglycaemia primarily by suppressing glucose production by the liver. The streptozotocin induced diabetes is characterized by a severe loss in body weight. The decrease in the body weight of diabetic rats in this study was due to the loss or degradation of structural proteins. Insulin plays an important role in the regulation of protein synthesis and proteolysis in skeletal muscle. In the present study, diabetic control rats showed marked reduction in their body weight when compared to normal rats. The ability of the extract to protect body weight loss in diabetic rats seems to be the result of their ability to reduce hyperglycemia. During the study, it was found that the extract significantly (p<0.001) controlled the blood glucose level in STZ-induced diabetic rats. The bambusa bambos hydroalcoholic extracts showed reduction in blood glucose level in STZ-induced diabetic rats when compared to the diabetic control group at a dose of 400 mg/kg,
 Keywords: Bambusa bambos, Hydroalcoholic extracts, Metformin, Streptozotocin.

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b.

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.

Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, ameliorates type 2 diabetes via reduced gluconeogenesis

AimsPyruvate dehydrogenase (PDH) catalyzes the decarboxylation of pyruvate to acetyl-CoA, which plays a key role in linking cytosolic glycolysis to mitochondria metabolism. PDH is physiologically inactivated by pyruvate dehydrogenase kinases (PDKs). Thus, activation of PDH via inhibiting PDK may lead to metabolic benefits. In the present study, we investigated the antidiabetic effect of PDK inhibition using dichloroacetate (DCA), a PDK inhibitor. Main methodsWe evaluated the effect of single dose of DCA on plasma metabolic parameters in normal rats. Next, we investigated the antidiabetic effect of DCA in diabetic ob/ob mice. In addition, we performed in vitro assays to understand the effect and mechanism of action of DCA on gluconeogenesis in mouse myoblast cell line C2C12 and rat hepatoma cell line FaO. Key findingsIn normal rats, a single dose of DCA decreased the plasma level of pyruvate, the product of glycolysis, and the plasma glucose level only in the fasting state. Meanwhile, a single dose of DCA lowered the plasma glucose level, and a three-week treatment decreased the fructosamine level in diabetic ob/ob mice. In vitro experiments demonstrated concentration-dependent suppression of lactate production in C2C12 myotubes. In addition, DCA suppressed glucose production from pyruvate and lactate in FaO hepatoma cells. Thus, DCA-mediated restricted supply of gluconeogenic substrates from the muscle to liver, and direct suppression of hepatic gluconeogenesis might have contributed to its glucose-lowering effect in the current models. SignificancePDK inhibitor may be considered as a potential antidiabetic agent harboring inhibitory effect on gluconeogenesis.

Comparative analysis of oral and intraperitoneal glucose tolerance tests in mice

ObjectiveThe glucose tolerance test (GTT) is widely used in preclinical research to investigate glucose metabolism, but there is no standardised way to administer glucose. The aim of this study was to directly compare the effect of the route of glucose administration on glucose and insulin kinetics during a GTT in mice. MethodsA GTT was performed in lean male and female mice and obese male mice and glucose was administered via the oral or intraperitoneal (I.P.) route. Samples were collected frequently during the GTT to provide a full time-course of the insulin and glucose excursions. In another cohort of lean male mice, plasma concentrations of insulin, c-peptide, and incretin hormones were measured at early time points after glucose administration. A stable-isotope labelled GTT (SiGTT) was then performed to delineate the contribution of exogenous and endogenous glucose to glycemia during the GTT, comparing both methods of glucose administration. Finally, we present a method to easily measure insulin from small volumes of blood during a GTT by directly assaying whole-blood insulin using ELISA and show a good concordance between whole-blood and plasma insulin measurements. ResultsWe report that I.P. glucose administration results in an elevated blood glucose excursion and a largely absent elevation in blood insulin and plasma incretin hormones when compared to oral administration. Utilising stable-isotope labelled glucose, we demonstrate that the difference in glucose excursion between the two routes of administration is mainly due to the lack of suppression of glucose production in I.P. injected mice. Additionally, rates of exogenous glucose appearance into circulation were different between lean and obese mice after I.P., but not after oral glucose administration. ConclusionReflecting on these data, we suggest that careful consideration be given to the route of glucose administration when planning a GTT procedure in mice and that in most circumstances the oral route of glucose administration should be preferred over the I.P. route to avoid possible artifacts originating from a non-physiological route.