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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes.

ABSTRACT: Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycaemia. Although current diabetes treatments have exhibited some success in lowering blood glucose levels, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycaemia. Novel antidiabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

SUBMITTER: Rines AK

PROVIDER: S-EPMC5751421 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes.

Rines Amy K AK Sharabi Kfir K Tavares Clint D J CD Puigserver Pere P

Nature reviews. Drug discovery 20160812 11

Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycaemia. Although current diabetes treatments have exhibited some success in lowering blood glucose levels, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycaemia. Novel antidiabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver to nor ...[more]

PMID: 27516169

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Project description:De novo hepatic glucose production or hepatic gluconeogenesis is the main contributor to hyperglycemia in the fasting state in patients with type 2 diabetes (T2D) owing to insulin resistance, which leads to at least twice as much glucose synthesis compared to healthy subjects. Therefore, control of this pathway is a promising target to avoid the chronic complications associated with elevated glucose levels. Patients with T2D in the rural communities of Mexico use medicinal plants prepared as infusions that are consumed over the day between meals, thus following this rationale (consumption of the infusions in the fasting state), one approach to understanding the possible mechanism of action of medicinal plants is to assess their capacity to inhibit hepatic glucose production. Furthermore, in several of these plants, the presence of phenolic acids able to block the enzyme glucose-6-phosphatase (G6Pase) is reported. In the present work, extracts of Ageratina petiolaris, Bromelia karatas, Equisetum myriochaetum, Rhizophora mangle, and Smilax moranensis, which are Mexican plants that have been traditionally used to treat T2D, were assayed to evaluate their possible hepatic glucose output (HGO) inhibitory activity with a pyruvate tolerance test in 18-h fasted STZ-NA Wistar rats after oral administration of the extracts. In addition, the in vitro effects of the extracts on the last HGO rate-limiting enzyme G6Pase was analyzed. Our results showed that four of these plants had an effect on hepatic glucose production in the in vivo or in vitro assays. A. petiolaris and R. mangle extracts decreased glucose output, preventing an increase in the blood glucose levels and sustaining this prevented increase after pyruvate administration. Moreover, both extracts inhibited the catalytic activity of the G6Pase complex. On the other hand, even though S. moranensis and B. karatas did not exhibit a significant in vivo effect, S. moranensis had the most potent inhibitory effect on this enzymatic system, while the E. myriochaetum extract only inhibited hepatic glucose production in the pyruvate tolerance test. Because of the traditional method in which diabetic patients use plants, hepatic glucose production inhibition seems to be a mechanism that partially explains the common hypoglycemic effect. However, further studies must be carried out to characterize other mechanisms whereby these plants can decrease HGO.

Project description:Glycolipid metabolic disorder is an important cause for the development of type 2 diabetes mellitus (T2DM). Clarification of the molecular mechanism of metabolic disorder and exploration of drug targets are crucial for the treatment of T2DM. Methods: We examined miR-125a-5p levels in palmitic acid-induced AML12 cells and the livers of type 2 diabetic rats and mice, and then validated its target gene. Through gain- and loss-of-function studies, the effects of miR-125a-5p via targeting of STAT3 on regulating glycolipid metabolism were further illustrated in vitro and in vivo. Results: We found that miR-125a-5p was significantly decreased in the livers of diabetic mice and rats, and STAT3 was identified as the target gene of miR-125a-5p. Overexpression of miR-125a-5p in C57BL/6 mice decreased STAT3 level and downregulated the expression levels of p-STAT3 and SOCS3. Consequently, SREBP-1c-mediated lipogenesis pathway was inhibited, and PI3K/AKT pathway was activated. Moreover, silencing of miR-125a-5p significantly increased the expression levels of STAT3, p-STAT3 and SOCS3, thus activating SREBP-1c pathway and suppressing PI3K/AKT pathway. Therefore, hyperglycemia, hyperlipidemia and decreased liver glycogen appeared in C57BL/6 mice. In palmitic acid-induced AML12 cells, miR-125a-5p mimic markedly increased glucose consumption and uptake and decreased the accumulation of lipid droplets by regulating STAT3 signaling pathway. Consistently, miR-125a-5p overexpression obviously inhibited STAT3 expression in diabetic KK-Ay mice, thereby decreasing blood glucose and lipid levels, increasing hepatic glycogen content, and decreasing accumulation of hepatic lipid droplets in diabetic mice. Furthermore, inhibition of miR-125a-5p in KK-Ay mice aggravated glycolipid metabolism dysfunction through regulating STAT3. Conclusions: Our results confirmed that miR-125a-5p should be considered as a regulator of glycolipid metabolism in T2DM, which can inhibit hepatic lipogenesis and gluconeogenesis and elevate glycogen synthesis by targeting STAT3.

Project description:Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy* Kinetic Model of Human Hepatic Glucose Metabolism in T2DM Authors Matthias Koenig and Hermann-Georg Holzhuetter Corresponding Author Matthias Koenig matthias.koenig@charite.de Charite Berlin, Computational Systems Biochemistry, Germany Keywords hepatic glucose metabolism; kinetic model; glucose homeostasis; liver, T2DM A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM. Compartments Id Name Dimension Constant SBO GO cyto cytosol 3 Y SBO:0000290 physical compartment GO:0005829 cytosol blood blood 3 Y SBO:0000290 physical compartment GO:0005615 extracellular space mito mitochondrion 3 Y SBO:0000290 physical compartment GO:0005739 mitochondrion mm mitochondrial membrane 2 Y SBO:0000290 physical compartment GO:0031966 mitochondrial membrane pm plasma membrane 2 Y SBO:0000290 physical compartment GO:0005886 plasma membrane Species Id Name Compartment Constant Init [mM] KEGG CHEBI UNIPROT SBO atp ATP cyto Y 2.8 KEGG:C00002 CHEBI:15422 SBO:0000299 metabolite adp ADP cyto Y 0.8 KEGG:C00008 CHEBI:16761 SBO:0000299 metabolite amp AMP cyto Y 0.16 KEGG:C00020 CHEBI:16027 SBO:0000299 metabolite utp UTP cyto N 0.27 KEGG:C00075 CHEBI:15713 SBO:0000299 metabolite udp UDP cyto N 0.09 KEGG:C00015 CHEBI:17659 SBO:0000299 metabolite gtp GTP cyto N 0.29 KEGG:C00044 CHEBI:15996 SBO:0000299 metabolite gdp GDP cyto N 0.10 KEGG:C00035 CHEBI:17552 SBO:0000299 metabolite nad NAD+ cyto Y 1.22 KEGG:C00003 CHEBI:15846 SBO:0000299 metabolite nadh NADH cyto Y 5.60E-004 KEGG:C00004 CHEBI:16908 SBO:0000299 metabolite p phosphate cyto Y 5 KEGG:C00009 SBO:0000299 metabolite pp pyrophosphate cyto N 0.008 KEGG:C00013 SBO:0000299 metabolite h2o H2O cyto Y 55000 KEGG:C00001 CHEBI:15377 SBO:0000299 metabolite co2 CO2 cyto Y 5 KEGG:C00011 CHEBI:16526 SBO:0000299 metabolite h H+ cyto Y 5.00E-008 KEGG:C00080 CHEBI:24636 SBO:0000299 metabolite glc1p glucose-1-phosphate cyto N 0.012 KEGG:C00103 CHEBI:16077 SBO:0000299 metabolite udpglc UDP-glucose cyto N 0.38 KEGG:C00029 CHEBI:18066 SBO:0000299 metabolite glc glucose cyto N 5 KEGG:C00031 CHEBI:4167 SBO:0000299 metabolite glyglc glycogen cyto N 250 KEGG:C00182 CHEBI:28087 SBO:0000299 metabolite fru6p fructose-6-phosphate cyto N 0.05 KEGG:C00085 CHEBI:15946 SBO:0000299 metabolite glc6p glucose-6-phosphate cyto N 0.12 KEGG:C00092 CHEBI:4170 SBO:0000299 metabolite fru26bp fructose-2,6-bisphospate cyto N 0.004 KEGG:C00665 CHEBI:28602 SBO:0000299 metabolite fru16bp fructose-1,6-bisphospate cyto N 0.02 KEGG:C00354 CHEBI:16905 SBO:0000299 metabolite dhap dihydroxyacetone phosphate cyto N 0.03 KEGG:C00111 CHEBI:16108 SBO:0000299 metabolite grap glyceraldehyde 3-phosphate cyto N 0.1 KEGG:C00118 CHEBI:29052 SBO:0000299 metabolite pg3 3-phosphoglycerate cyto N 0.27 KEGG:C00197 CHEBI:17794 SBO:0000299 metabolite bpg13 1,3-bisphospho-glycerate cyto N 0.3 KEGG:C00236 CHEBI:16001 SBO:0000299 metabolite pep phosphoenolpyruvate cyto N 0.15 KEGG:C00074 CHEBI:44897 SBO:0000299 metabolite pg2 2-phosphoglycerate cyto N 0.03 KEGG:C00631 CHEBI:17835 SBO:0000299 metabolite oaa oxaloacetate cyto N 0.01 KEGG:C00036 CHEBI:30744 SBO:0000299 metabolite pyr pyruvate cyto N 0.1 KEGG:C00022 CHEBI:32816 SBO:0000299 metabolite glc_blood glucose blood Y 5 KEGG:C00031 CHEBI:4167 SBO:0000299 metabolite lac lactate cyto N 0.5 KEGG:C00186 CHEBI:422 SBO:0000299 metabolite p_mito phosphate mito Y 5 KEGG:C00009 SBO:0000299 metabolite oaa_mito oxaloacetate mito N 0.01 KEGG:C00036 CHEBI:30744 SBO:0000299 metabolite lac_blood lactate blood Y 1.2 KEGG:C00186 CHEBI:422 SBO:0000299 metabolite co2_mito CO2 mito Y 5 KEGG:C00011 CHEBI:16526 SBO:0000299 metabolite pyr_mito pyruvate mito N 0.1 KEGG:C00022 CHEBI:32816 SBO:0000299 metabolite cit_mito citrate mito Y 0.32 KEGG:C00158 CHEBI:30769 SBO:0000299 metabolite pep_mito pep mito N 0.15 KEGG:C00074 CHEBI:44897 SBO:0000299 metabolite acoa_mito acetyl-coenzyme A mito Y 0.04 KEGG:C00024 CHEBI:15351 SBO:0000299 metabolite gtp_mito GTP mito N 0.29 KEGG:C00044 CHEBI:15996 SBO:0000299 metabolite gdp_mito GDP mito N 0.10 KEGG:C00035 CHEBI:17552 SBO:0000299 metabolite atp_mito ATP mito Y 2.8 KEGG:C00002 CHEBI:15422 SBO:0000299 metabolite adp_mito ADP mito Y 0.8 KEGG:C00008 CHEBI:16761 SBO:0000299 metabolite nad_mito NAD+ mito Y 0.98 KEGG:C00003 CHEBI:15846 SBO:0000299 metabolite h_mito H+ mito Y 1.00E-008 KEGG:C00011 CHEBI:24636 SBO:0000299 metabolite coa_mito coenzymeA mito Y 0.055 KEGG:C00010 CHEBI:15346 SBO:0000299 metabolite nadh_mito NADH mito Y 0.24 KEGG:C00004 CHEBI:16908 SBO:0000299 metabolite epinephrine_blood epinephrine blood N 206.11 KEGG:C00547 CHEBI:18357 SBO:0000299 metabolite glucagon_blood glucagon blood N 4.36E-008 KEGG:C01501 UNIPROT:P01275 SBO:0000299 metabolite insulin_blood insulin blood N 7.61E-008 KEGG:C00723 UNIPROT:P01308 SBO:0000299 metabolite h20_mito H2O mito Y 55000 KEGG:C00080 CHEBI:15377 SBO:0000299 metabolite Reactions Id Name Compartment Irreversible Vmax [µmol/kg/min] EC KEGG UNIPROT SBO GLUT2 GLUT2 glucose transporter (facilitated diffusion) pm N 420 UNIPROT:P11168 SBO:0000284 transporter GK Glucokinase, hexokinase IV cyto Y 25.2 EC:2.7.1.2 KEGG:R00299 UNIPROT:P35557 SBO:0000014 enzyme G6PASE Glucose-6-phosphatase cyto Y 18.9 EC:3.1.3.9 KEGG:R00303 UNIPROT:P35575 SBO:0000014 enzyme GPI Glucose-6-phosphate isomerase cyto N 420 EC:5.3.1.9 KEGG:R00771 UNIPROT:P06744 SBO:0000014 enzyme G16PI glucose-1-phosphate 1,6-phosphomutase cyto N 100 EC:5.4.2.2 KEGG:R00959 UNIPROT:P36871, UNIPROT:Q96G03 SBO:0000014 enzyme UPGASE UTP:Glucose-1-phosphate uridylyltransferase cyto N 80 EC:2.7.7.9 KEGG:R00289 UNIPROT:Q16851 SBO:0000014 enzyme PPASE Pyrophosphate phosphohydrolase cyto Y 2.4 EC:3.6.1.1 KEGG:R00004 UNIPROT:Q15181 SBO:0000014 enzyme GS Glycogen synthase cyto Y 13.2 UNIPROT:P54840 SBO:0000014 enzyme GP Glycogen phosphorylase cyto N 6.8 UNIPROT:P06737 SBO:0000014 enzyme NTKGTP Nucleosid diphosphate kinase (GTP) cyto N 0 EC:2.7.4.6 KEGG:R00330 SBO:0000014 enzyme NTKUTP Nucleosid diphosphate kinase (UTP) cyto N 2940 EC:2.7.4.6 KEGG:R00156 SBO:0000014 enzyme AK Adenylat kinase cyto N 0 EC:2.7.4.3 KEGG:R00127 SBO:0000014 enzyme PFK2 Phosphofructo kinase 2 cyto Y 0.0042 EC:2.7.1.105 KEGG:R02732 UNIPROT:P16118 SBO:0000014 enzyme FBP2 Fructose-2,6-bisphosphatase cyto Y 0.126 EC:3.1.3.46 KEGG:R02731 UNIPROT:P16118 SBO:0000014 enzyme PFK1 Phosphofructo kinase 1 cyto Y 7.182 EC:2.7.1.11 KEGG:R00756 UNIPROT:P17858 SBO:0000014 enzyme FBP1 Fructose-1,6-bisphosphatase cyto Y 4.326 EC:3.1.3.11 KEGG:R00762 UNIPROT:O00757, UNIPROT:P09467 SBO:0000014 enzyme TPI Triosephosphate isomerase cyto N 420 EC:5.3.1.1 KEGG:R01015 UNIPROT:P60174 SBO:0000014 enzyme ALD Aldolase cyto N 420 EC:4.1.2.13 KEGG:R01068 UNIPROT:P05062 SBO:0000014 enzyme PGK Phosphoglycerate kinase cyto N 420 EC:2.7.2.3 KEGG:R01512 UNIPROT:P00558 SBO:0000014 enzyme GAPDH Glyceraldehydephosphate dehydrogenase cyto N 420 EC:1.2.1.12 KEGG:R01061 UNIPROT:P04406 SBO:0000014 enzyme EN Enolase cyto N 35.994 EC:4.2.1.11 KEGG:R00658 UNIPROT:P06733, UNIPROT:P09104, UNIPROT:P13929 SBO:0000014 enzyme PGAM 3-Phosphoglycerate mutase cyto N 420 EC:5.4.2.1 KEGG:R01518 UNIPROT:P18669 SBO:0000014 enzyme PEPCK Phosphoenolpyruvate carboxykinase cyto N 0 EC:4.1.1.32 KEGG:R00431 UNIPROT:P35558 SBO:0000014 enzyme PK Pyruvate kinase cyto Y 46.2 EC:2.7.1.40 KEGG:R00200 UNIPROT:P30613 SBO:0000014 enzyme PC Pyruvate Carboxylase mito Y 168 EC:6.4.1.1 KEGG:R00344 UNIPROT:P11498 SBO:0000014 enzyme PEPCK_mito Phosphoenolpyruvate carboxykinase mito N 546 EC:4.1.1.32 KEGG:R00431 UNIPROT:Q16822 SBO:0000014 enzyme LACT Lactate transporter pm N 5.418 SBO:0000284 transporter LDH Lactate dehydrogenase cyto N 12.6 EC:1.1.1.27 -KEGG:R00703 UNIPROT:P00338, UNIPROT:P07195, UNIPROT:P07864 SBO:0000014 enzyme PEPT PEP transporter mm N 33.6 SBO:0000284 transporter PYRT Pyruvate transporter mm N 42 SBO:0000284 transporter CS Citrate synthase mito N 4.2 EC:2.3.3.1 -KEGG:R00351 UNIPROT:O75390 SBO:0000014 enzyme PDH Pyruvate dehydrogenase mito Y 13.44 EC:1.2.4.1 KEGG:R00209 UNIPROT:P08559, UNIPROT:P11177, UNIPROT:P10515, UNIPROT:P09622, O00330 SBO:0000014 enzyme ACOAFLX Acetyl-CoA flux mito N 0 SBO:0000014 enzyme VCITFLX Citrate flux mito N 0 SBO:0000014 enzyme NDK_mito Nucleosid diphosphate kinase (GTP) mito N 420 EC:2.7.4.6 KEGG:R00330 SBO:0000014 enzyme OAAFLX Oxalacetate flux mito N 0 SBO:0000014 enzyme

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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes.

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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes.

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