Increase In Hepatic Glucose Production Research Articles

Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2D and NGT Subjects.

Acute and chronic SGLT-2 inhibition increase endogenous glucose production (EGP). However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. 20 T2DM and 12 NGT subjects received [3-3H]-glucose infusion (to measure total EGP) in combination with arterial and renal vein catheterization and PAH infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 hours after dapagliflozin and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 minutes, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in either NGT and T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P<0.05 vs placebo). The increase in RGU was entirely explained by the increase in glucosuria. Single dose of dapagliflozin significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis.

Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol

Background Poor synthesis of insulin by beta cells present in the pancreas combined with resistance of insulin in peripheral organs is referred to as type 2 diabetes mellitus. Insulin resistance leads to an increase in plasma fatty acids, which reduces transfer of glucose within the cells of muscles and increases breakage of lipids, resulting in an increase in hepatic glucose production. Nishamalaki (a formulation of turmeric and Indian gooseberry) is suggested in the therapy of all kinds of Madhumeha (diabetes mellitus) in Ayurveda classics. Turmeric and Indian gooseberry are the two main ingredients. Both are considered as effective medicines in the management of Madhumeha individually as well as in combined form. Aim To compare the efficacy of Nishaamalaki and metformin in obese patients of type2 diabetes mellitus. Methods The study will include 60 obese type 2 diabetes mellitus patients who were distributed into two distinct categories, each with 30 patients. Nishamalaki Churna 3gm two times a day before food with warm water for 60 days in Group N (Experimental Group) and 500 mg metformin tablets twice daily before meals for 60 days in Group M (Control Group). Every 15th day, an assessment was made (15th, 30th, 45th and 60th day). Results Objective outcomes will be assessed. Conclusion: From this study protocol, it can be depicted that the trial formulation of turmeric and Indian gooseberry (Nisha-amalaki) is as effective in obese patients suffering from type- 2 diabetes mellitus as compared to metformin tablets.

Hepatocyte Rap1a contributes to obesity- and statin-associated hyperglycemia.

SUMMARYExcessive hepatic glucose production contributes to the development of hyperglycemia and is a key feature of type 2 diabetes. Here, we report that activation of hepatocyte Rap1a suppresses gluconeogenic gene expression and glucose production, whereas Rap1a silencing stimulates them. Rap1a activation is suppressed in obese mouse liver, and restoring its activity improves glucose intolerance. As Rap1a′s membrane localization and activation depends on its geranylgeranylation, which is inhibited by statins, we show that statin-treated hepatocytes and the human liver have lower active-Rap1a levels. Similar to Rap1a inhibition, statins stimulate hepatic gluconeogenesis and increase fasting blood glucose in obese mice. Geranylgeraniol treatment, which acts as the precursor for geranylgeranyl isoprenoids, restores Rap1a activity and improves statin-mediated glucose intolerance. Mechanistically, Rap1a activation induces actin polymerization, which suppresses gluconeogenesis by Akt-mediated FoxO1 inhibition. Thus, Rap1a regulates hepatic glucose homeostasis, and blocking its activity, via lowering geranylgeranyl isoprenoids, contributes to statin-induced glucose intolerance.

IPMK modulates hepatic glucose production and insulin signaling.

Hepatic glucose production (HGP) is crucial for the maintenance of normal glucose homeostasis. Although hepatic insulin resistance contributes to excessive glucose production, its mechanism is not well understood. Here, we show that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. IPMK-deficient hepatocytes exhibit decreased insulin-induced activation of Akt-FoxO1 signaling. The expression of messenger RNA levels of phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose 6-phosphatase (G6pc), key enzymes mediating gluconeogenesis, are increased in IPMK-deficient hepatocytes compared to wild type hepatocytes. Importantly, re-expressing IPMK restores insulin sensitivity and alleviates glucose production in IPMK-deficient hepatocytes. Moreover, hepatocyte-specific IPMK deletion exacerbates hyperglycemia and insulin sensitivity in mice fed a high-fat diet, accompanied by an increase in HGP during pyruvate tolerance test and reduction in Akt phosphorylation in IPMK deficient liver. Our results demonstrate that IPMK mediates insulin signaling and gluconeogenesis and may be potentially targeted for treatment of diabetes.

SGLT2 Inhibition with Empagliflozin as a Possible Therapeutic Option for Postprandial Hypoglycemia After Bariatric Surgery

Since SGLT2 inhibitors may reduce postprandial hyperglycemia, this study aimed to evaluated whether empagliflozin might be useful in the treatment of postprandial hypoglycemia (PPH) postbariatric surgery (BS). Fourteen patients who underwent BS, nine without type 2 diabetes and five with diabetes before surgery and in remission after surgery, were included. Seven of them presented symptoms of PPH (hypoglycemic group; HG) and seven were asymptomatic (nonhypoglycemic group (NHG)). A meal tolerance test was performed before and after administration of a daily dose of empagliflozin (EMPA) 25mg for 3days. Plasma glucose and serum insulin levels were measured. In HG, compared with NHG, in the basal test, the area under the curve (AUC) of plasma glucose levels (AUCgly) was smaller (158.3 ± 25.3 vs 276.6 ± 79.2mgh dL-1; p = 0.001) while the AUC of insulin levels (AUCins) did not differ, leading to a higher AUCins/AUCgly ratio (0.79 ± 0.46 vs 0.38 ± 0.20; p = 0.055) and a lower HOMA-IR (0.92 ± 0.22 vs 1.75 ± 0.77; p = 0.030). The HG after EMPA, but not the NHG, showed significant increases in glycemia leading to greater AUCgly (158.0 ± 25.3 to 197.2 ± 51.6mgh dL-1; p = 0.043) without significant changes in AUCins. HOMA-IR increased only in the HG (0.92 ± 0.20 vs 1.61 ± 0.30; p = 0.025) and, when both groups were analyzed together, both before and post EMPA, a significant correlation was found between HOMA-IR and AUCgly values (r = 0.594; p = 0.002). Our results suggest that empagliflozin increased glycemic levels in patients with PPH possibly through increases in hepatic glucose production.

55-LB: Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2DM and NGT Subjects

We previously have shown that both acute and chronic SGLT-2 inhibition increases endogenous glucose production (EGP) . However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. We assessed the effect of a single dose of Dapagliflozin or Placebo on renal glucose production in 13 T2DM (age=57.5±1.8 yrs, BMI = 30±1.4 kg/m2) and 9 NGT (age 42±2 3 yrs, BMI = 30±1.1 kg/m2) subjects. Renal glucose production was measured using arteriovenous balance technique across the kidney combined with [3-3H] glucose infusion and PAH infusion (for determination of renal blood flow) before and 4 hours after administration of Dapagliflozin (10 mg) and Placebo; thus, each subject served as their own control. EGP increased following DAPA in both T2DM (2.00±0.11 to 2.43±0.15, P&amp;lt;0.05) and NGT (1.72±0.11 to 2.1±0.16, p&amp;lt;0.05) , while it decreased after placebo in T2DM (2.02±0.12 vs. 1.15±0.06) and NGT (2.10±0.2 vs. 2.05±0.1) (both p&amp;lt;0.01, DAPA vs. placebo) . The fractional renal extraction of glucose (0.02± 0.004 vs. 2.99 ± 1.0, p=0.001 in T2DM, and 0.02± 0.004 vs. 1.62± 1.4 in NGT, p=NS) and renal glucose uptake (0.067 ± 0.02 vs. 0.347 ± 0.06 in T2DM and 0.08 ± 0.02 vs. 0.27 ± 0.08 mg/kg.min in NGT) were higher following DAPA vs. placebo (p&amp;lt;0.05) and were entirely explained by the increase in glucosuria. There was a small, non-significant increase (0.065 &amp; 0.032 mg/kg.min, respectively) in renal glucose production (RGP) following dapagliflozin in T2DM and NGT compared to the 0.45 mg/kg.min increase in total body EGP. Conclusion: A single dose of Dapagliflozin significantly increases EGP which primarily is explained by an increase in hepatic glucose production. Disclosure X. Chen: None. C. Solis-herrera: Speaker’s Bureau; Novo Nordisk. D. Tripathy: None. A. A. Hansis-diarte: None. R. Chilton: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Nova Biomedical. E. Cersosimo: Research Support; AstraZeneca. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc., Speaker’s Bureau; AstraZeneca. Funding Astra Zeneca

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis.

Background: Established neuroendocrine signals do not sufficiently account for the exercise-induced increase in glucose production. Using an innovative, yet classical cross-circulation procedure, we studied whether contracting muscle produces a factor that directly stimulates hepatic glycogenolysis. Methods: Isolated rat hindquarters were perfused in series with isolated livers. Results: Stimulation of the sciatic nerve of one or both legs resulted in an increase in force, which rapidly waned. During one-legged contractions, hepatic glucose production increased initially (from −0.9 ± 0.5 (mean ± SE) to 3.3 ± 0.7 µmol/min, p < 0.05). The peak did not differ significantly from that seen after 20 nM of epinephrine (5.1 ± 1.2 µmol/min, p > 0.05). In response to two-legged contractions, the increase in hepatic glucose production (to 5.4 ± 1.3 µmol/min) was higher (p < 0.05) and lasted longer than that seen during one-legged contractions. During contractions, peak hepatic glucose output exceeded concomitant hepatic lactate uptake (p < 0.05), and glucose output decreased to basal levels, while lactate uptake rose to a plateau. Furthermore, in separate experiments an increase in lactate supply to isolated perfused livers increased lactate uptake, but not glucose output. In intact rats, intra-arterial injection of extract made from mixed leg muscle elicited a prolonged increase (p < 0.05) in plasma glucose concentration (from 5.2 ± 0.1 mM to 8.3 ± 1.5 mM). In perfused livers, muscle extract increased glucose output dose dependently. Fractionation by chromatography of the extract showed that the active substance had a MW below 2000. Conclusion: This study provides evidence that contracting skeletal muscle may produce a hormone with a MW below 2000, which enhances hepatic glycogenolysis according to energy needs. Further chemical characterization is warranted.

The kinetics of glucagon action on the liver during insulin-induced hypoglycemia.

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg-1·min-1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg-1·min-1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg-1·min-1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg-1·min-1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Mild sustained physiological hyperglycemia impairs hepatic insulin sensitivity in healthy individuals with normal glucose tolerance

Previous studies have shown that chronic hyperglycemia exacerbates skeletal muscle insulin resistance and worsens β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity stays unclear. This paper is the Chinese translation of Mild physiologic hyperglycemia induces hepatic insulin resistance in healthy normal glucose-tolerant participants , published on Journal of Clinical Endocrinology & Metabolism [Tripathy D, Merovci A, Basu R, et al. J Clin Endocrinol Metab, 2019, 104(7): 2842-2850] after obtaining the copyright of the original journal. This study examined the effect of sustained physiologic hyperglycemia on endogenous glucose production(EGP) in 16 healthy individuals with three-step hyperinsulinemic euglycemic clamp. The results showed that sustained physiologic hyperglycemia for only 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in healthy persons with normal glucose tolerance, indicating the role of glucotoxicity in the increase of hepatic glucose production in type 2 diabetes. Key words: Hyperglycemia; Insulin resistance; Normal glucose tolerance

Pterostilbene reverses palmitic acid mediated insulin resistance in HepG2 cells by reducing oxidative stress and triglyceride accumulation

Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we evaluated ability of pterostilbene (PTS), a methoxylated analogue of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated IR in HepG2 cells. PTS prevented reactive oxygen species (ROS) formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 (NOX3) in PA treated HepG2 cells. Hepatic glucose production was used as a measure of IR and PTS reversed PA-mediated increase in hepatic glucose production by reducing expression of genes coding for gluconeogenic enzymes namely glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC); and their transcription factors cAMP response element binding protein (CREB) and fork head class Box O (FOXO1) along with its coactivator peroxisome proliferator-activated receptor gamma co-activator-1 α (PGC1α). PTS reversed PA-mediated activation of c-Jun N-terminal kinase (JNK), which in turn altered insulin signalling pathway by phosphorylating IRS-1 at Ser 307, leading to inhibition of phosphorylation of Akt and GSK-3β. PTS also reduced PA-mediated lipid accumulation by reducing expression of transcription factors SREBP1c and PPARα. SREBP1c activates genes involved in fatty acid and triglyceride synthesis while PPARα activates CPT1, a rate limiting enzyme for controlling entry and oxidation of fatty acids into mitochondria. PTS, however, did not influence PA uptake confirmed by using BODIPY-labelled fluorescent C16 fatty acid analogue. Thus, our data provides a possible mechanistic explanation for reversal of PA-mediated IR in HepG2 cells.

1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p&amp;lt;0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p&amp;lt;0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production. Disclosure X. Chen: None. A. Merovci: None. E. Case: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None.

Intercellular calcium waves integrate hormonal control of glucose output in the intact liver.

Key points Sympathetic outflow and circulating glucogenic hormones both regulate liver function by increasing cytosolic calcium, although how these calcium signals are integrated at the tissue level is currently unknown.We show that stimulation of hepatic nerve fibres or perfusing the liver with physiological concentrations of vasopressin only will evoke localized cytosolic calcium oscillations and modest increases in hepatic glucose production.The combination of these stimuli acted synergistically to convert localized and asynchronous calcium responses into co‐ordinated intercellular calcium waves that spread throughout the liver lobule and elicited a synergistic increase in hepatic glucose production.The results obtained in the present study demonstrate that subthreshold levels of one hormone can create an excitable medium across the liver lobule, which allows global propagation of calcium signals in response to local sympathetic innervation and integration of metabolic regulation by multiple hormones. This enables the liver lobules to respond as functional units to produce full‐strength metabolic output at physiological levels of hormone. Glucogenic hormones, including catecholamines and vasopressin, induce frequency‐modulated cytosolic Ca2+ oscillations in hepatocytes, and these propagate as intercellular Ca2+ waves via gap junctions in the intact liver. We investigated the role of co‐ordinated Ca2+ waves as a mechanism for integrating multiple endocrine and neuroendocrine inputs to control hepatic glucose production in perfused rat liver. Sympathetic nerve stimulation elicited localized Ca2+ increases that were restricted to hepatocytes in the periportal zone. During perfusion with subthreshold vasopressin, sympathetic stimulation converted asynchronous Ca2+ signals in a limited number of hepatocytes into co‐ordinated intercellular Ca2+ waves that propagated across entire lobules. A similar synergism was observed between physiological concentrations of glucagon and vasopressin, where glucagon also facilitated the recruitment of hepatocytes into a Ca2+ wave. Hepatic glucose production was significantly higher with intralobular Ca2+ waves. We propose that inositol 1,4,5‐trisphosphate (IP3)‐dependent Ca2+ signalling gives rise to an excitable medium across the functional syncytium of the hepatic lobule, co‐ordinating and amplifying the metabolic responses to multiple hormonal inputs.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.

Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear. To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals. Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion. Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study. EGP. Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects. Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

Gut ghrelin regulates hepatic glucose production and insulin signaling via a gut-brain-liver pathway

BackgroundGhrelin modulates many physiological processes. However, the effects of intestinal ghrelin on hepatic glucose production (HGP) are still unclear. The current study was to explore the roles of intestinal ghrelin on glucose homeostasis and insulin signaling in the liver.MethodsThe system of intraduodenal infusion and intracerebral microinfusion into the nucleus of the solitary tract (NTS) in the normal chow-diet rats and pancreatic-euglycemic clamp procedure (PEC) combined with [3-3H] glucose as a tracer were used to analyze the effect of intestinal ghrelin. Intraduodenal co-infusion of ghrelin, tetracaine and Activated Protein Kinase (AMPK) activator (AICAR), or pharmacologic and molecular inhibitor of N-methyl-D-aspartate receptors within the dorsal vagal complex, or hepatic vagotomy in rats were used to explore the possible mechanism of the effect of intestinal ghrelin on HGP.ResultsOur results demonstrated that gut infusion of ghrelin inhibited duodenal AMP-dependent protein kinase (AMPK) signal pathways, increased HGP and expression of gluconeogenic enzymes, and decreased insulin signaling in the liver of the rat. Intraduodenal co-infusion of ghrelin receptor antagonist [D-Lys3]-GHRP-6 and AMPK agonist with ghrelin diminished gut ghrelin-induced increase in HGP and decrease in glucose infusion rate (GIR) and hepatic insulin signaling. The effects of gut ghrelin were also negated by co-infusion with tetracaine, or MK801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, and adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shNR1) within the dorsal vagal complex, and hepatic vagotomy in rats. When ghrelin and lipids were co-infused into the duodenum, the roles of gut lipids in increasing the rate of glucose infusion (GIR) and lowering HGP were reversed.ConclusionsThe current study provided evidence that intestinal ghrelin has an effect on HGP and identified a neural glucoregulatory function of gut ghrelin signaling.

Potential antidiabetic activity of medicinal plants – A short review

Diabetes mellitus is a dreadful disease caused by the increase in hepatic glucose production and impaired insulin action. The usage of herbal based medicine has been increasing tremendously in both developing and developed countries over the last three decades. The present study aims to provide a comprehensive review of antidiabetic activity of following medicinal plants like Gymnema sylvestris, Rubia cardifolia, Bilberry, Green Tea, Salacia reticulate, Berberis aristata, Pterocarpus marsupium, Fenugreek, Ashwagandha, Bitter melon. The efficiency of these medicinal plants may regulate the diabetic metabolic abnormalities. This work would help researchers to choose potential herbal for diabetic treatment.

Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice

Obesity-associated insulin resistance (IR) is a major risk factor for developing type 2 diabetes and an array of other metabolic disorders. In particular, hepatic IR contributes to the increase in hepatic glucose production and consequently the development of fasting hyperglycemia. In this study, we explored whether kaempferol, a flavonoid isolated from Gink go biloba, is able to regulate hepatic gluconeogenesis and blood glucose homeostasis in high-fat diet-fed obese mice and further explored the underlying mechanism by which it elicits such effects. Oral administration of kaempferol (50 mg/kg/day), which is the human equivalent dose of 240 mg/day for an average 60 kg human, significantly improved blood glucose control in obese mice, which was associated with reduced hepatic glucose production and improved whole-body insulin sensitivity without altering body weight gain, food consumption or adiposity. In addition, kaempferol treatment increased Akt and hexokinase activity, but decreased pyruvate carboxylase (PC) and glucose-6 phosphatase activity in the liver without altering their protein expression. Consistently, kaempferol decreased PC activity and suppressed gluconeogenesis in HepG2 cells as well as primary hepatocytes isolated from the livers of obese mice. Furthermore, we found that kaempferol is a direct inhibitor of PC. These findings suggest that kaempferol may be a naturally occurring antidiabetic compound that acts by suppressing glucose production and improving insulin sensitivity. Kaempferol suppression of hepatic gluconeogenesis is due to its direct inhibitory action on the enzymatic activity of PC.

Hepatic Gi signaling regulates whole-body glucose homeostasis.

An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic Gi signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic Gi-coupled GPCRs may prove beneficial as antidiabetic drugs.

Hepatic β-arrestin 2 is essential for maintaining euglycemia.

An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.

Central chronic apelin infusion decreases energy expenditure and thermogenesis in mice

Apelin is a bioactive peptide involved in the control of energy metabolism. In the hypothalamus, chronic exposure to high levels of apelin is associated with an increase in hepatic glucose production, and then contributes to the onset of type 2 diabetes. However, the molecular mechanisms behind deleterious effects of chronic apelin in the brain and consequences on energy expenditure and thermogenesis are currently unknown. We aimed to evaluate the effects of chronic intracerebroventricular (icv) infusion of apelin in normal mice on hypothalamic inflammatory gene expression, energy expenditure, thermogenesis and brown adipose tissue functions. We have shown that chronic icv infusion of apelin increases the expression of pro-inflammatory factors in the hypothalamus associated with an increase in plasma interleukin-1 beta. In parallel, mice infused with icv apelin exhibit a significant lower energy expenditure coupled to a decrease in PGC1alpha, PRDM16 and UCP1 expression in brown adipose tissue which could explain the alteration of thermogenesis in these mice. These data provide compelling evidence that central apelin contributes to the development of type 2 diabetes by altering energy expenditure, thermogenesis and fat browning.

PP33 - H2S-induced increase in hepatic glucose production and the underlying mechanisms

PP33 - H2S-induced increase in hepatic glucose production and the underlying mechanisms