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Lucidi P, Perriello G, Porcellati F, Pampanelli S, De Fano M, Tura A, Bolli GB, Fanelli CG. Diurnal Cycling of Insulin Sensitivity in Type 2 Diabetes: Evidence for Deviation From Physiology at an Early Stage. Diabetes 2023; 72:1364-1373. [PMID: 37440717 PMCID: PMC10866740 DOI: 10.2337/db22-0721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 07/03/2023] [Indexed: 07/15/2023]
Abstract
The aim of this study was to establish the contribution of insulin resistance to the morning (a.m.) versus afternoon (p.m.) lower glucose tolerance of people with type 2 diabetes (T2D). Eleven subjects with T2D (mean [SD] diabetes duration 0.79 [0.23] years, BMI 28.3 [1.8] kg/m2, A1C 6.6% [0.26%] [48.9 (2.9) mmol/mol]), treatment lifestyle modification only) and 11 matched control subjects without diabetes were monitored between 5:00 and 8:00 a.m. and p.m. (in random order) on one occasion (study 1), and on a subsequent occasion, they underwent an isoglycemic clamp (a.m. and p.m., both between 5:00 and 8:00, insulin infusion rate 10 mU/m2/min) (study 2). In study 1, plasma glucose, insulin, C-peptide, and glucagon were higher and insulin clearance lower in subjects with T2D a.m. versus p.m. and versus control subjects (P < 0.05), whereas free fatty acid, glycerol, and β-hydroxybutyrate were lower a.m. versus p.m. However, in study 2 at identical hyperinsulinemia a.m. and p.m. (∼150 pmol/L), glucose Ra and glycerol Ra were both less suppressed a.m. versus p.m. (P < 0.05) in subjects with T2D. In contrast, in control subjects, glucose Ra was more suppressed a.m. versus p.m. Leucine turnover was no different a.m. versus p.m. In conclusion, in subjects with T2D, insulin sensitivity for glucose (liver) and lipid metabolism has diurnal cycles (nadir a.m.) opposite that of control subjects without diabetes already at an early stage, suggesting a marker of T2D. ARTICLE HIGHLIGHTS In people with type 2 diabetes (T2D), fasting hyperglycemia is greater in the morning (a.m.) versus the afternoon (p.m.), and insulin sensitivity for glucose and lipid metabolism is lower a.m. versus p.m. This pattern is the reverse of the physiological diurnal cycle of people without diabetes who are more insulin sensitive a.m. versus p.m. These new findings have been observed in the present study in people without obesity but with recent-onset T2D, with good glycemic control, and in the absence of confounding pharmacological treatment. It is likely that the findings represent a specific marker of T2D, possibly present even in prediabetes before biochemical and clinical manifestations.
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Affiliation(s)
- Paola Lucidi
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
| | - Gabriele Perriello
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
| | - Francesca Porcellati
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
| | - Simone Pampanelli
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
| | - Michelantonio De Fano
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
| | - Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
| | - Geremia B. Bolli
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
| | - Carmine G. Fanelli
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, University of Perugia Medical School, Perugia, Italy
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Rittig N, Aagaard NK, Sundelin E, Villadsen GE, Sandahl TD, Holst JJ, Hartmann B, Brøsen K, Grønbaek H, Jessen N. Metformin Stimulates Intestinal Glycolysis and Lactate Release: A single-Dose Study of Metformin in Patients With Intrahepatic Portosystemic Stent. Clin Pharmacol Ther 2021; 110:1329-1336. [PMID: 34331316 DOI: 10.1002/cpt.2382] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/21/2021] [Indexed: 11/06/2022]
Abstract
The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1,000 mg metformin. Metformin increased lactate concentrations by 23% (95% confidence interval (CI): 6-40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C-peptide was higher in the portal vein compared with arterialized blood (P < 0.05, all) and was lowered at both sampling sites following metformin ingestion (P < 0.01, all). Plasma concentration of GLP-1 was 20% (95% CI: 2-38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pM, P = 0.05). The median concentration of growth differentiation factor 15 was 10% (95% CI: 1-19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3,000 ng/mL with a mean portal/arterial ratio of 1.5 (95% CI: 1.2-1.8). Non-targeted metabolomics showed that metformin acutely affected benzoate-hippurate metabolism. A single-dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of nonoxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.
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Affiliation(s)
- Nikolaj Rittig
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.,Department and Laboratories of Diabetes and Hormone diseases, Aarhus University Hospital, Aarhus N, Denmark
| | - Niels K Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Elias Sundelin
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.,Department and Laboratories of Diabetes and Hormone diseases, Aarhus University Hospital, Aarhus N, Denmark
| | - Gerda E Villadsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Thomas D Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Kim Brøsen
- Department of Public Health, Clinical Pharmacology, Pharmacy and Environmental Health, University of Southern Denmark, Odense, Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.,Department of Biomedicine, Aarhus University, Aarhus C, Denmark.,Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus N, Denmark
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El Massry M, Alaeddine LM, Ali L, Saad C, Eid AA. Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer's Disease and Depression. Curr Med Chem 2021; 28:2328-2345. [PMID: 32900343 DOI: 10.2174/0929867327666200908114902] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 11/22/2022]
Abstract
Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer's disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.
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Affiliation(s)
- Mohamed El Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Lynn M Alaeddine
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Leen Ali
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Celine Saad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
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Sundelin E, Jensen JB, Jakobsen S, Gormsen LC, Jessen N. Metformin Biodistribution: A Key to Mechanisms of Action? J Clin Endocrinol Metab 2020; 105:5850036. [PMID: 32480406 DOI: 10.1210/clinem/dgaa332] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/26/2020] [Indexed: 02/08/2023]
Abstract
Metformin has undisputed glucose-lowering effects in diabetes and an impressive safety record. It has also shown promising effects beyond diabetes, and several hundred clinical trials involving metformin are currently planned or active. Metformin targets intracellular effectors, but exactly which remain to be established, and in an era of precision medicine, an incomplete understanding of mechanisms of action may limit the use of metformin. Distribution of metformin depends on specific organic cation transporter proteins that are organ- and species-specific. Therefore, target tissues of metformin can be identified by cellular uptake of the drug, and exploring the biodistribution of the drug in humans becomes an attractive strategy to assist the many investigations into the mechanisms of action of metformin performed in animals. In this review, we combine the emerging evidence from the use of 11C-labeled metformin in humans to discuss metformin action in liver, intestines, and kidney, which are the organs with the most avid uptake of the drug.
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Affiliation(s)
- Elias Sundelin
- Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jonas Brorson Jensen
- Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Steen Jakobsen
- Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark
| | - Lars C Gormsen
- Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Jessen
- Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Pusceddu S, Vernieri C, Prinzi N, Torchio M, Coppa J, Antista M, Niger M, Milione M, Giacomelli L, Corti F, Prisciandaro M, Monteleone M, Colombo E, Di Bartolomeo M, de Braud F. The potential role of metformin in the treatment of patients with pancreatic neuroendocrine tumors: a review of preclinical to clinical evidence. Therap Adv Gastroenterol 2020; 13:1756284820927271. [PMID: 32821286 PMCID: PMC7406937 DOI: 10.1177/1756284820927271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/15/2020] [Indexed: 02/04/2023] Open
Abstract
The incidence of pancreatic neuroendocrine tumors (panNETs) has increased worldwide in the last two decades. Given the indolent nature of these tumors, several patients are diagnosed with metastatic disease, which partially impairs the long-term efficacy of currently available treatments and reduces survival rates. The search for new therapeutic strategies for cancer patients has pushed towards the retrospective analysis of studies involving patients who concomitantly received other drugs together with standard anticancer agents. In this light, several retrospective analyses have shown that metformin use is associated with improved prognosis in patients with different tumor types treated with standard antitumor agents. Metformin, the cornerstone oral agent for the treatment of type 2 diabetes, plays a role in modulating glucose cell metabolism. Its potential ability to interfere with tumors may derive from the tight relationship between metabolic reprogramming in cancer cells and tumor progression. Indications for metformin use as an anticancer drug result from pre-clinical and clinical observations. In particular, metformin use in diabetic patients with advanced panNETs has been associated with better progression-free survival in patients treated with somatostatin analogues with or without metformin.
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Affiliation(s)
| | - Claudio Vernieri
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy The FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
| | - Natalie Prinzi
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Martina Torchio
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Jorgelina Coppa
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Maria Antista
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Monica Niger
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Massimo Milione
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Luca Giacomelli
- Polistudium SRL (Milan, Italy) and Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
| | - Francesca Corti
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Michele Prisciandaro
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Michela Monteleone
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Elena Colombo
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Maria Di Bartolomeo
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Filppo de Braud
- Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy University of Milan, Milan, Italy
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Nishimura R, Tanaka Y, Koiwai K, Ishida K, Salsali A, Kaspers S, Kohler S, Lund SS. Effect of Empagliflozin on Free Fatty Acids and Ketone Bodies in Japanese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial. Adv Ther 2019; 36:2769-2782. [PMID: 31444706 DOI: 10.1007/s12325-019-01045-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Indexed: 01/21/2023]
Abstract
INTRODUCTION We report a randomized, double-blind, placebo-controlled, 4-week study to investigate the effect of empagliflozin on free fatty acids and blood ketone bodies in Japanese patients with type 2 diabetes mellitus. METHODS Patients (baseline mean [standard deviation] glycated hemoglobin 7.91% [0.80%]; body mass index 24.3 [3.2] kg/m2) were randomized to empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19), or placebo (n = 21) daily as monotherapy for 28 days. Meal tolerance tests (MTTs; breakfast, lunch, dinner) were performed on day - 1, day 1 (first day of treatment), and day 28. On day 1 and day 28, study drug was administered 1 h before breakfast. Free fatty acids and blood ketone bodies were measured before and 1, 2, and 3 h after each MTT, and the next morning (overnight fast). RESULTS Empagliflozin significantly reduced plasma glucose and insulin and reduced body weight vs. placebo. Empagliflozin increased free fatty acids and total ketones bodies at day 1 and day 28. At day 28, the adjusted mean (95% confidence interval) difference vs. placebo in the time-corrected area under curve over 24 h for total ketone bodies was 67.1 (12.3, 121.8) µmol·h/L·h (P = 0.017) with empagliflozin 10 mg and 178.1 (123.9, 232.2) µmol·h/L·h (P < 0.001) with empagliflozin 25 mg. Increases in ketones with empagliflozin vs. placebo peaked just before and declined after meals, with the highest peak before breakfast. Changes in total ketone bodies appeared to be associated with changes in plasma glucose, insulin, and free fatty acids. CONCLUSION Empagliflozin modestly increased free fatty acids and blood ketone bodies after a single dose and 28 days' treatment. Increases in ketones appeared to be related to the duration of fasting and were most pronounced before breakfast. Increases in ketones appeared to be associated with changes in well-known metabolic determinants of ketone production. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT01947855. FUNDING Boehringer Ingelheim & Eli Lilly and Company.
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Affiliation(s)
| | - Yuko Tanaka
- Nippon Boehringer Ingelheim Co. Ltd., Tokyo, Japan.
| | | | | | - Afshin Salsali
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Stefan Kaspers
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Sven Kohler
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Søren S Lund
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
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7
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Gormsen LC, Søndergaard E, Christensen NL, Brøsen K, Jessen N, Nielsen S. Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia 2019; 62:1251-1256. [PMID: 30976851 DOI: 10.1007/s00125-019-4872-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 03/08/2019] [Indexed: 11/24/2022]
Abstract
AIMS/HYPOTHESIS Metformin is the endorsed first-line glucose-lowering drug for treating patients with type 2 diabetes but despite more than 50 years of use, no consensus has been reached on its mechanisms of action. In this study, we investigated the glucose-lowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals. METHODS We performed a randomised, placebo-controlled trial in 24 individuals with recent-onset type 2 diabetes (diabetes duration 50 [48] months) who had good glycaemic control (HbA1c 48 mmol/mmol [6.5%]). The studies were conducted at Aarhus University Hospital between 2013 and 2016. Participants were randomised to receive either metformin (2000 mg/day, n = 12, MET group) or placebo (n = 12, PLA group) for 90 days, using block randomisation set up by an unblinded pharmacist. Two participants withdrew from the study prior to completion and were replaced with two new participants receiving the same treatment. In addition, we recruited a group of non-diabetic individuals with similar age and BMI (n = 12, CONT group), who were all treated with 2000 mg metformin daily. Before and after treatment all individuals underwent studies of whole-body glucose metabolism by non-steady-state [3-3H]glucose kinetics, hyperinsulinaemic-euglycaemic clamping, indirect calorimetry, metabolomics, dual x-ray absorptiometry and muscle biopsies. The primary study endpoint was the effect of metformin treatment on lipid kinetics as well as glucose rate of disappearance (Rd) and endogenous glucose production (EGP). RESULTS One participant from the CONT group withdrew due to intolerable gastrointestinal side-effects and was excluded from analysis. As expected, metformin treatment lowered fasting plasma glucose (FPG) in the MET group (~1.5 mmol/l, p < 0.01), whereas no effect was observed in the PLA and CONT groups. Body weight and composition did not change in any of the groups. In both of the metformin-treated groups (MET and CONT), basal glucose Rd, EGP and glucagon levels increased by ~30% (p < 0.05) whereas this was not the case in the PLA group. CONCLUSIONS/INTERPRETATION Ninety days of metformin treatment resulted in similar increases in EGP and glucose Rd in individuals with recent-onset type 2 diabetes and in non-diabetic control individuals. These results challenge the existing paradigm that metformin primarily acts in the liver by inhibiting EGP, at least in individuals with type 2 diabetes of short duration and who have discretely affected glycaemic status. Whether metformin increases basal glucose Rd by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified. TRIAL REGISTRATION ClinicalTrials.gov NCT01729156 FUNDING: This study was supported by grants from The Danish Council for Independent Research | Medical Sciences, Aase Danielsen Fund, the Novo Nordisk Foundation, the Danish Diabetes Association and the Danish Diabetes Academy supported by the Novo Nordisk Foundation.
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Affiliation(s)
- Lars C Gormsen
- Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Esben Søndergaard
- Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark
- Danish Diabetes Academy, Odense University Hospital, Odense, Denmark
| | - Nana L Christensen
- Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Kim Brøsen
- Department of Pharmacology, Odense University Hospital, Odense, Denmark
| | - Niels Jessen
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
- Steno Diabetes Center Aarhus, Aarhus University Hospital, DK 8200, Aarhus, Denmark.
| | - Søren Nielsen
- Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, DK 8200, Aarhus, Denmark
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Green CJ, Marjot T, Tomlinson JW, Hodson L. Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis? Diabetes Obes Metab 2019; 21:749-760. [PMID: 30456918 DOI: 10.1111/dom.13592] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licensed pharmacological agent to treat it. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain; thus, there is great interest in pharmacological treatments for NAFLD. Metformin is the first-line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent specifically to reduce liver fat accumulation; data from human studies are less convincing. In the present review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies, as well as the underlying proposed mechanisms, to try and understand and reconcile the difference in findings between rodent and human work in this area.
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Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Thomas Marjot
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
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9
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Adeva-Andany MM, Rañal-Muíño E, Fernández-Fernández C, Pazos-García C, Vila-Altesor M. Metabolic Effects of Metformin in Humans. Curr Diabetes Rev 2019; 15:328-339. [PMID: 30306875 DOI: 10.2174/1573399814666181009125348] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 09/26/2018] [Accepted: 10/02/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes. INTRODUCTION Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. RESULTS Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from "de novo" synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves β-cell function in patients with type 2 diabetes. CONCLUSION Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.
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Affiliation(s)
- María M Adeva-Andany
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazan s/n, 15406 Ferrol, Spain
| | - Eva Rañal-Muíño
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazan s/n, 15406 Ferrol, Spain
| | | | - Cristina Pazos-García
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazan s/n, 15406 Ferrol, Spain
| | - Matilde Vila-Altesor
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazan s/n, 15406 Ferrol, Spain
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10
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Pandya K, Lau-Cam CA. Taurine Improves the Actions of Metformin and Lovastatin on Plasma Markers of Carbohydrate and Lipid Dysfunction of Diabetic Rats. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1155:87-99. [DOI: 10.1007/978-981-13-8023-5_8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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11
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Breining P, Jensen JB, Sundelin EI, Gormsen LC, Jakobsen S, Busk M, Rolighed L, Bross P, Fernandez-Guerra P, Markussen LK, Rasmussen NE, Hansen JB, Pedersen SB, Richelsen B, Jessen N. Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes Obes Metab 2018; 20:2264-2273. [PMID: 29752759 DOI: 10.1111/dom.13362] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 05/01/2018] [Accepted: 05/09/2018] [Indexed: 01/11/2023]
Abstract
AIMS To test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [11 C]-metformin tracer in mice and studying in vitro effects of metformin on cultured human brown adipocytes. MATERIALS AND METHODS Tissue-specific uptake of metformin was assessed in mice by PET/CT imaging after injection of [11 C]-metformin. Human brown adipose tissue was obtained from elective neck surgery and metformin transporter expression levels in human and murine BAT were determined by qPCR. Oxygen consumption in metformin-treated human brown adipocyte cell models was assessed by Seahorse XF technology. RESULTS Injected [11 C]-metformin showed avid uptake in the murine interscapular BAT depot. Metformin exposure in BAT was similar to hepatic exposure. Non-specific inhibition of the organic cation transporter (OCT) protein by cimetidine administration eliminated BAT exposure to metformin, demonstrating OCT-mediated uptake. Gene expression profiles of OCTs in BAT revealed ample OCT3 expression in both human and mouse BAT. Incubation of a human brown adipocyte cell models with metformin reduced cellular oxygen consumption in a dose-dependent manner. CONCLUSION These results support BAT as a putative metformin target.
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Affiliation(s)
- Peter Breining
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
| | - Jonas B Jensen
- Department of Clinical Medicine, Research Laboratory for Biochemical Pathology, Aarhus University, Aarhus, Denmark
| | - Elias I Sundelin
- Department of Clinical Medicine, Research Laboratory for Biochemical Pathology, Aarhus University, Aarhus, Denmark
| | - Lars C Gormsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Steen Jakobsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Morten Busk
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Lars Rolighed
- Department of Otorhinolaryngology and Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Bross
- Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Paula Fernandez-Guerra
- Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Lasse K Markussen
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Nanna E Rasmussen
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Jacob B Hansen
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Steen B Pedersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Bjørn Richelsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Jessen
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Research Laboratory for Biochemical Pathology, Aarhus University, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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12
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Abstract
In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.
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Affiliation(s)
- George Sam Wang
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Children's Hospital Colorado, Aurora, CO, USA
| | - Christopher Hoyte
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,University of Colorado Hospital, Aurora, CO, USA
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13
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Dodd JM, Grivell RM, Deussen AR, Hague WM. Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes. Cochrane Database Syst Rev 2018; 7:CD010564. [PMID: 30039871 PMCID: PMC6513233 DOI: 10.1002/14651858.cd010564.pub2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND There has been considerable interest in providing antenatal dietary and lifestyle advice for women with obesity or who are overweight during pregnancy, as a strategy to limit gestational weight gain and improve maternal and infant health. However, such antenatal interventions appear to have a modest effect on gestational weight gain and other clinical pregnancy and birth outcomes and additional strategies are required.Metformin is an oral insulin-sensitising medication that acts to decrease blood glucose concentrations. Metformin is commonly used in the treatment of type 2 diabetes mellitus and polycystic ovarian syndrome, and is being used increasingly in the treatment of gestational diabetes, having been shown to result in decreased rates of caesarean birth and neonatal hypoglycaemia. Metformin may be an adjuvant therapy to current antenatal strategies in pregnant women with obesity or who are overweight, acting to reduce glucose production in the liver and improve glucose uptake in smooth muscle cells, and therefore improve the overall metabolic health of women in pregnancy and reduce the risk of known adverse pregnancy outcomes. OBJECTIVES To evaluate the role of metformin in pregnant women with obesity or who are overweight, on maternal and infant outcomes, including adverse effects of treatment and costs. SEARCH METHODS We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (11 October 2017), and reference lists of retrieved studies. SELECTION CRITERIA All published and unpublished randomised controlled trials evaluating metformin use (compared with placebo or no metformin) in women with obesity or who are overweight in pregnancy for improving outcomes, alone or in combination with other interventions were eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2 studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2and 29.9 kg/m2, therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin in combination with another treatment. Two other studies are ongoing.All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women attending hospitals for antenatal care.Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low risk of attrition bias and other bias; we felt it was at a high risk of reporting bias.The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex). Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence).Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10; 3 studies, 899 women; low-quality evidence).Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence).One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage.In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2 studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission between women receiving metformin or placebo; no other admission data were reported to assess differences in costs. AUTHORS' CONCLUSIONS There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency.There were only a small number of studies included in this review. Furthermore, none of the included studies included women categorised as 'overweight' and no trials looked at metformin in combination with another treatment.Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.
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Affiliation(s)
- Jodie M Dodd
- The University of Adelaide, Women's and Children's HospitalSchool of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology72 King William RoadAdelaideSouth AustraliaAustralia5006
| | - Rosalie M Grivell
- Flinders University and Flinders Medical CentreDepartment of Obstetrics and GynaecologyBedford ParkSouth AustraliaAustraliaSA 5042
| | - Andrea R Deussen
- The University of Adelaide, Women's and Children's HospitalSchool of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology72 King William RoadAdelaideSouth AustraliaAustralia5006
| | - William M Hague
- Women's and Children's HospitalKing William RoadAdelaideSouth AustraliaAustraliaSA 5006
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The effect of high fat diet and metformin treatment on liver lipids accumulation and their impact on insulin action. Sci Rep 2018; 8:7249. [PMID: 29739997 PMCID: PMC5940807 DOI: 10.1038/s41598-018-25397-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 04/18/2018] [Indexed: 12/27/2022] Open
Abstract
We sought to determine whether metformin treatment reverses a high-fat diet (HFD)-induced hepatic insulin resistance (IRes) and to identify lipid intermediates involved in induction of liver IRes. The experiments were conducted on male Wistar rats divided into three groups: 1. Control, 2. fed HFD and 3. fed HFD and treated with metformin. The animals were infused with a [U-13C]palmitate to measure fractional lipid synthesis rate. This allowed for the calculation of fractional synthesis rate of signaling lipids (FSR) through the estimation of their isotopic enrichment. Liver ceramide (Cer), diacylglycerol (DAG) and acyl-carnitine concentration and enrichment were analyzed by LC/MS/MS. The content of proteins involved in lipid metabolism and insulin signaling were analyzed by Western Blot. HFD treatment increased the content and FSR of DAG and Cer in the liver which was accompanied by systemic insulin resistance and inhibition of hepatic insulin signaling pathway under insulin stimulation. Metformin treatment ameliorated systemic insulin resistance and augmented the hepatic insulin signaling cascade. It reduced both the concentration and FSR of Cer, DAG, and increased acyl-carnitine content and the expression of mitochondrial markers. We postulate, that in liver, the insulin sensitizing effect of metformin depends on augmentation of mitochondrial β-oxidation, which protects from hepatic accumulation of both the Cer and DAG and preserves insulin sensitivity under HFD consumption. Moreover, we showed that hepatic content of Cer and DAG corresponds with their respective FSR.
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15
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Calza G, Nyberg E, Mäkinen M, Soliymani R, Cascone A, Lindholm D, Barborini E, Baumann M, Lalowski M, Eriksson O. Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver. Front Pharmacol 2018. [PMID: 29520235 PMCID: PMC5827415 DOI: 10.3389/fphar.2018.00141] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition. MALDI mass spectra of thin-sections of freeze-clamped rat liver perfused with metformin showed a peak at 130.16 m/z which was unambiguously assigned to metformin. The mass spectrometric detection limit was at a tissue concentration of about 250 nM, and uptake of metformin from the perfusion medium to the liver occurred with a Km of 0.44 mM. Metformin was evenly distributed in the liver irrespective of its concentration in the perfusion medium and the duration of a perfusion. At a parenchymal concentration of 30 μM, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that matrix-assisted laser desorption/ionization mass spectrometry imaging can be applied to estimate the tissue concentration and distribution of metformin in a therapeutically relevant micromolar concentration range. Our findings challenge the view that metformin causes an inhibition of glucose release from the liver by an acute inhibition of mitochondrial glycerol 3-phosphate dehydrogenase (EC 1.1.5.3).
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Affiliation(s)
- Giulio Calza
- Meilahti Clinical Proteomics Core Facility, Helsinki Institute of Life Science, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Elisabeth Nyberg
- Meilahti Clinical Proteomics Core Facility, Helsinki Institute of Life Science, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Matias Mäkinen
- Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Rabah Soliymani
- Meilahti Clinical Proteomics Core Facility, Helsinki Institute of Life Science, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Annunziata Cascone
- Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Dan Lindholm
- Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | | | - Marc Baumann
- Meilahti Clinical Proteomics Core Facility, Helsinki Institute of Life Science, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Maciej Lalowski
- Meilahti Clinical Proteomics Core Facility, Helsinki Institute of Life Science, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Ove Eriksson
- Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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16
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Kadoda K, Moriwaki T, Tsuda M, Sasanuma H, Ishiai M, Takata M, Ide H, Masunaga SI, Takeda S, Tano K. Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. PLoS One 2017; 12:e0185141. [PMID: 28926637 PMCID: PMC5605006 DOI: 10.1371/journal.pone.0185141] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 09/05/2017] [Indexed: 12/14/2022] Open
Abstract
Metformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear. We hypothesized that metformin is cytotoxic in a tumor-specific environment such as glucose deprivation and/or low oxygen (O2) tension. We herein demonstrated that metformin was highly cytotoxic under glucose-depleted, but not hypoxic (2% O2) conditions. In order to elucidate the underlying mechanisms of this selective cytotoxicity, we treated exposed DNA repair-deficient chicken DT40 cells with metformin under glucose-depleted conditions and measured cellular sensitivity. Under glucose-depleted conditions, metformin specifically killed fancc and fancl cells that were deficient in FANCC and FANCL proteins, respectively, which are involved in DNA interstrand cross-link repair. An analysis of chromosomal aberrations in mitotic chromosome spreads revealed that a clinically relevant concentration of metformin induced DNA double-strand breaks (DSBs) in fancc and fancl cells under glucose-depleted conditions. In summary, metformin induced DNA damage under glucose-depleted conditions and selectively killed cells. This metformin-mediated selective toxicity may suppress the growth of malignant tumors that are intrinsically deprived of glucose.
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Affiliation(s)
- Kei Kadoda
- Division of Radiation Life Science, Research Reactor Institute, Kyoto University, Kumatori, Osaka, Japan
| | - Takahito Moriwaki
- Division of Radiation Life Science, Research Reactor Institute, Kyoto University, Kumatori, Osaka, Japan
| | - Masataka Tsuda
- Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Sasanuma
- Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masamichi Ishiai
- Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan
| | - Minoru Takata
- Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan
| | - Hiroshi Ide
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Japan
| | - Shin-ichiro Masunaga
- Division of Radiation Life Science, Research Reactor Institute, Kyoto University, Kumatori, Osaka, Japan
| | - Shunichi Takeda
- Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keizo Tano
- Division of Radiation Life Science, Research Reactor Institute, Kyoto University, Kumatori, Osaka, Japan
- * E-mail:
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17
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Wang H, Zhu C, Ying Y, Luo L, Huang D, Luo Z. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget 2017. [PMID: 29515798 PMCID: PMC5839379 DOI: 10.18632/oncotarget.20807] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea. Ongoing experimental and clinical studies have illuminated great potential of berberine in regulation of glucose and lipid homeostasis, cancer growth and inflammation. Furthermore, the lipid lowering effect of berberine is comparable to those conventional lipid drugs but with low toxicity. Therefore, it is right time to transform beneficial effects of berberine into therapeutic practice. Metformin and berberine share many features in actions despite different structure and both could be excellent drugs in treating T2DM, obesity, cardiac diseases, tumour, as well as inflammation. Since these disorders are often connected and comprise common pathogenic factors that could be targeted by the two drugs, understanding their actions can give us rationale for expansion of their clinical uses.
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Affiliation(s)
- Haoran Wang
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Hospital of Nanchang University, Nanchang, China
| | - Chen Zhu
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Hospital of Nanchang University, Nanchang, China
| | - Ying Ying
- Jiangxi Provincial Key Laboratory of Tumour Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Lingyu Luo
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Hospital of Nanchang University, Nanchang, China
| | - Deqiang Huang
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Hospital of Nanchang University, Nanchang, China
| | - Zhijun Luo
- Jiangxi Provincial Key Laboratory of Tumour Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China.,Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
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18
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Krentz AJ. Metformin: new insights into an archetypal cardiometabolic drug. Cardiovasc Endocrinol 2017; 6:92-94. [PMID: 31646125 PMCID: PMC6768509 DOI: 10.1097/xce.0000000000000129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 07/05/2017] [Indexed: 11/25/2022] Open
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19
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Qi T, Chen Y, Li H, Pei Y, Woo SL, Guo X, Zhao J, Qian X, Awika J, Huo Y, Wu C. A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. J Mol Endocrinol 2017; 59:49-59. [PMID: 28559290 PMCID: PMC5512603 DOI: 10.1530/jme-17-0066] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 04/20/2017] [Indexed: 12/16/2022]
Abstract
Metformin improves obesity-associated metabolic dysregulation, but has controversial effects on adipose tissue inflammation. The objective of the study is to examine the direct effect of metformin on adipocyte inflammatory responses and elucidate the underlying mechanisms. Adipocytes were differentiated from 3T3-L1 cells and treated with metformin at various doses and for different time periods. The treated cells were examined for the proinflammatory responses, as well as the phosphorylation states of AMPK and the expression of PFKFB3/iPFK2. In addition, PFKFB3/iPFK2-knockdown adipocytes were treated with metformin and examined for changes in the proinflammatory responses. The following results were obtained from the study. Treatment of adipocytes with metformin decreased the effects of lipopolysaccharide on inducing the phosphorylation states of JNK p46 and on increasing the mRNA levels of IL-1β and TNFα. In addition, treatment with metformin increased the expression of PFKFB3/iPFK2, but failed to significantly alter the phosphorylation states of AMPK. In PFKFB3/iPFK2-knockdown adipocytes, treatment with metformin did not suppress the proinflammatory responses as did it in control adipocytes. In conclusion, metformin has a direct effect on suppressing adipocyte proinflammatory responses in an AMPK-independent manner. Also, metformin increases adipocyte expression of PFKFB3/iPFK2, which is involved in the anti-inflammatory effect of metformin.
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Affiliation(s)
- Ting Qi
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Yanming Chen
- Department of Endocrinologythe Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Honggui Li
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Ya Pei
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Shih-Lung Woo
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Xin Guo
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Jiajia Zhao
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Xiaoxian Qian
- Department of Cardiologythe Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Joseph Awika
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
| | - Yuqing Huo
- Vascular Biology CenterDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, USA
- Drug Discovery CenterKey Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Chaodong Wu
- Department of Nutrition and Food ScienceTexas A&M University, College Station, USA
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20
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Abstract
OBJECTIVE Metformin is the most commonly prescribed drug for the treatment of type 2 diabetes because of its apparent robust effects in reducing cardiovascular risk. This review examines the current literature regarding the nonglycemic effects and potential novel indications for metformin. METHODS Review of the literature, with a focus on metformin use in Stage 3 chronic kidney disease (CKD-3) and heart failure (HF). RESULTS The United Kingdom Prospective Diabetes Study suggests that metformin reduces the risk of myocardial infarction, and more recent retrospective studies have shown an association between metformin use and a reduction in stroke, atrial fibrillation and all-cause mortality. The mechanism(s) explaining these putative benefits are not clear but may involve decreased energy intake (with attendant weight loss), improvement in lipids, and lowering of blood pressure; a literature review suggests that metformin lowers blood pressure when it is elevated, but not when it is normal. Metformin appears to be safe when given to patients with CKD-3. In addition, there is evidence that individuals with CKD-3, who are at increased cardiovascular risk, stand to benefit from metformin therapy. Lactic acidosis is an extremely remote and probably avoidable risk; measurement of plasma metformin levels and more frequent monitoring of renal function may be useful in selected patients with CKD-3 who are treated with metformin. Finally, there is evidence that metformin is safe in patients with HF; metformin therapy is associated with a reduction in newly incident HF and in HF mortality. CONCLUSION Metformin has a dominant position in the treatment of type 2 diabetes that is deserved due to its favorable and robust effects on cardiovascular risk. ABBREVIATIONS AMP = adenosine monophosphate BP = blood pressure CKD = chronic kidney disease CKD-3 = Stage 3 CKD eGFR = estimated glomerular filtration rate HDL = high-density lipoprotein HF = heart failure MAP = mean arterial pressure mVO2 = myocardial oxygen consumption T2DM = type 2 diabetes mellitus UKPDS = United Kingdom Prospective Diabetes Study.
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21
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Cokorinos EC, Delmore J, Reyes AR, Albuquerque B, Kjøbsted R, Jørgensen NO, Tran JL, Jatkar A, Cialdea K, Esquejo RM, Meissen J, Calabrese MF, Cordes J, Moccia R, Tess D, Salatto CT, Coskran TM, Opsahl AC, Flynn D, Blatnik M, Li W, Kindt E, Foretz M, Viollet B, Ward J, Kurumbail RG, Kalgutkar AS, Wojtaszewski JFP, Cameron KO, Miller RA. Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice. Cell Metab 2017; 25:1147-1159.e10. [PMID: 28467931 DOI: 10.1016/j.cmet.2017.04.010] [Citation(s) in RCA: 192] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/26/2017] [Accepted: 04/12/2017] [Indexed: 12/12/2022]
Abstract
The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK β1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.
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Affiliation(s)
- Emily C Cokorinos
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Jake Delmore
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Allan R Reyes
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Bina Albuquerque
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Rasmus Kjøbsted
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen 1017, Denmark
| | - Nicolas O Jørgensen
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen 1017, Denmark
| | - Jean-Luc Tran
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Aditi Jatkar
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Katherine Cialdea
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Ryan M Esquejo
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - John Meissen
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, CT 06340, USA
| | - Matthew F Calabrese
- Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT 06340, USA
| | - Jason Cordes
- Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA
| | - Robert Moccia
- Computational Sciences, Pfizer Inc., Cambridge, MA 02139, USA
| | - David Tess
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA 02139, USA
| | - Christopher T Salatto
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Timothy M Coskran
- Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA
| | - Alan C Opsahl
- Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA
| | - Declan Flynn
- Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA
| | - Matthew Blatnik
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, CT 06340, USA
| | - Wenlin Li
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., San Diego, CA 92121, USA
| | - Erick Kindt
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., San Diego, CA 92121, USA
| | - Marc Foretz
- INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75016, France; Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France
| | - Benoit Viollet
- INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75016, France; Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France
| | - Jessica Ward
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Ravi G Kurumbail
- Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT 06340, USA
| | - Amit S Kalgutkar
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA 02139, USA
| | - Jørgen F P Wojtaszewski
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen 1017, Denmark
| | - Kimberly O Cameron
- Cardiovascular, Metabolic, and Endocrine Diseases Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA
| | - Russell A Miller
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Inc., Cambridge, MA 02139, USA.
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Aghaalikhani N, Goodarzi MT, Latifi Z, Farimani AR, Fattahi A. Effects of Different Doses of Metformin on Serum Fatty Acid Composition in Type 2 Diabetic Rats. AVICENNA JOURNAL OF MEDICAL BIOCHEMISTRY 2017. [DOI: 10.15171/ajmb.2017.04] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: Several studies have shown association of fatty acids with type 2 diabetes (T2D), as well as metformin effects on blood glucose concentrations through affecting lipid metabolism. Objectives: Since the exact therapeutic mechanism of metformin is not clear, in this study we investigated effects of different doses of metformin on serum fatty acids in rats with T2D. Materials and Methods: Twenty-five adult albino male Wistar rats were divided into the following groups: Healthy, untreated T2D, and T2D rats receiving metformin for 4 weeks with doses of 100, 150, and 200 mg/kg/d. Serum insulin and triglyceride (TG) were measured using commercial kits. Serum total lipids were extracted by the Bligh-Dyer method and then compositions of fatty acids were evaluated using gas chromatograph. Results: Monounsaturated fatty acid (MUFA) levels in T2D rats were lower than those in healthy rats (P < 0.05). We also observed that diabetic rats treated with 100 or 150 mg/kg/d of metformin had higher levels of arachidonic acid and polyunsaturated fatty acids (PUFA) in comparison with the healthy group (P < 0.05). Moreover, the T2D+Met (150 mg/kg) group showed increased levels of MUFA compared with the T2D group. Such a difference was seen in levels of arachidonic acid between the T2D+Met 100 mg/ kg group and untreated T2D group. In the group treated with high doses of metformin (200 mg/kg/d), levels of palmitic acid, palmitoleic acid, and saturated fatty acid (SFA) were higher and levels of oleic acid, linoleic acid, arachidonic acid, MUFA, PUFA, and also SFA/UFA ratio were lower compared with other metformin treated and untreated groups (P < .05). In untreated T2D group, there were positive correlations between glucose levels and linoleic acid and PUFA levels (r = 0.707, P = .049 and r = 0.726, P = .041 respectively). Arachidonic acid levels were positively correlated with glucose levels in T2D rats treated with 100 mg/kg/d of metformin (r = 0.969, P = .031). Conclusions: Our study showed that different doses of metformin could have different effects on serum levels of saturated and unsaturated fatty acids, as 200 mg/kg/d of metformin could increase and decrease saturated and unsaturated fatty acids respectively, while lower doses increased unsaturated fatty acids, particularly arachidonic acid.
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Affiliation(s)
- Nazi Aghaalikhani
- Department of Nursing, Dezful Branch, Islamic Azad University, Dezful, Iran
| | - Mohammad Taghi Goodarzi
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Zeinab Latifi
- Department of Biochemistry and Clinical Laboratories, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azam Rezaei Farimani
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Fattahi
- Department of Biochemistry and Clinical Laboratories, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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23
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Howell JJ, Hellberg K, Turner M, Talbott G, Kolar MJ, Ross DS, Hoxhaj G, Saghatelian A, Shaw RJ, Manning BD. Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. Cell Metab 2017; 25:463-471. [PMID: 28089566 PMCID: PMC5299044 DOI: 10.1016/j.cmet.2016.12.009] [Citation(s) in RCA: 301] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/02/2016] [Accepted: 12/10/2016] [Indexed: 02/08/2023]
Abstract
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.
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Affiliation(s)
- Jessica J Howell
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Kristina Hellberg
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Marc Turner
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - George Talbott
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Matthew J Kolar
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Debbie S Ross
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Gerta Hoxhaj
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Alan Saghatelian
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Reuben J Shaw
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
| | - Brendan D Manning
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
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24
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Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes 2017; 18:10-16. [PMID: 28052534 DOI: 10.1111/pedi.12473] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 10/16/2016] [Accepted: 10/20/2016] [Indexed: 12/25/2022] Open
Abstract
Metformin is a widely prescribed medication that has been used to treat children with type 2 diabetes in the United States for the past 15 years. Metformin now has a variety of clinical applications in pediatrics, and its potential clinical uses continue to expand. In addition to reviewing the current understanding of its mechanisms of action including the newly discovered effects on the gastrointestinal tract, we will also discuss current clinical uses in pediatrics, including in type 1 diabetes. Finally, we examine the existing state of monitoring for metformin efficacy and side effects and discuss prospective future clinical uses.
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Affiliation(s)
- Inas Thomas
- Division of Pediatric Endocrinology, Diabetes and Metabolism, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
| | - Brigid Gregg
- Division of Pediatric Endocrinology, Diabetes and Metabolism, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
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25
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Chen C, Huang Q, Li C, Fu X. Hypoglycemic effects of a Fructus Mori polysaccharide in vitro and in vivo. Food Funct 2017. [DOI: 10.1039/c7fo00417f] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Mulberry fruit polysaccharide (MFP), one of the major active ingredients isolated from the mulberry fruit, possesses numerous bioactivities.
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Affiliation(s)
- Chun Chen
- College of Light Industry and Food Sciences
- South China University of Technology
- Guangzhou 510640
- China
| | - Qiang Huang
- College of Light Industry and Food Sciences
- South China University of Technology
- Guangzhou 510640
- China
| | - Chao Li
- College of Light Industry and Food Sciences
- South China University of Technology
- Guangzhou 510640
- China
| | - Xiong Fu
- College of Light Industry and Food Sciences
- South China University of Technology
- Guangzhou 510640
- China
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26
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Bosley JR, Maurer TS, Musante CJ. Systems Pharmacology Modeling in Type 2 Diabetes Mellitus. SYSTEMS PHARMACOLOGY AND PHARMACODYNAMICS 2016. [DOI: 10.1007/978-3-319-44534-2_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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27
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Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, Viollet B, DeBerardinis RJ, Jones RG. Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis. PLoS Biol 2015; 13:e1002309. [PMID: 26625127 PMCID: PMC4666657 DOI: 10.1371/journal.pbio.1002309] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 10/27/2015] [Indexed: 12/17/2022] Open
Abstract
Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC). However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK) and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA) cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity. How does the antidiabetic drug metformin inhibit cancer? This metabolomic study shows that metformin blocks tumor cell proliferation independently of the classic metabolic checkpoints by suppressing mitochondrial-dependent biosynthesis. Cancer is a disease characterized by unregulated proliferation of transformed cells. To meet the increased biosynthetic demands of proliferation, biosynthetic building blocks required for cellular growth must be generated in large quantities. As cancer cells increase their anabolic metabolism to promote cell growth, there is significant interest in targeting these processes for cancer therapy. Metformin is a drug prescribed to treat Type II diabetes that has gained interest as an anti-tumor agent due to its suppressive effects on cancer cell proliferation. However, how metformin works to slow cancer cell growth has remained poorly understood. Here we show that metformin arrests cancer cell proliferation by starving mitochondria of the necessary metabolic intermediates required for anabolic metabolism in tumor cells. This results in reduced proliferation in part due to decreased synthesis of lipids used for membrane biosynthesis. We also show that some cancer cells use alternative metabolic pathways to synthesize lipids independently of mitochondrial metabolism, and that these cells are resistant to the antigrowth effects of metformin. Better understanding of mechanisms of metformin resistance will be crucial for metformin to be used as an effective anticancer agent.
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Affiliation(s)
- Takla Griss
- Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Emma E. Vincent
- Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Robert Egnatchik
- Children’s Medical Center Research Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
- McDermott Center for Human Growth and Development, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
- Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
| | - Jocelyn Chen
- Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Eric H. Ma
- Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Brandon Faubert
- Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Benoit Viollet
- Inserm, U1016, Institut Cochin, Paris, France
- CNRS, UMR 8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
- McDermott Center for Human Growth and Development, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
- Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
| | - Russell G. Jones
- Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
- * E-mail:
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28
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Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456-480. [PMID: 25897356 PMCID: PMC4398902 DOI: 10.4239/wjd.v6.i3.456] [Citation(s) in RCA: 738] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 11/21/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM.
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29
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Bohannon NJV. Individualized Treatment of Type 2 Diabetes Mellitus Using Noninsulin Agents: Clinical Considerations for the Primary Care Physician. Postgrad Med 2015; 124:95-108. [DOI: 10.3810/pgm.2012.07.2572] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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30
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Tan BK, Chen J, Hu J, Amar O, Mattu HS, Ramanjaneya M, Patel V, Lehnert H, Randeva HS. Circulatory changes of the novel adipokine adipolin/CTRP12 in response to metformin treatment and an oral glucose challenge in humans. Clin Endocrinol (Oxf) 2014; 81:841-6. [PMID: 24612181 DOI: 10.1111/cen.12438] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 12/27/2013] [Accepted: 02/19/2014] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Adipolin/CTRP12 is a novel adipokine with anti-inflammatory and glucose-lowering properties in rodents. We sought to investigate the effects of metformin treatment (850 mg twice daily for 6 months) and a 2 h 75 g oral glucose tolerance test (OGTT) on serum adipolin concentrations in humans. DESIGN Cross-sectional study [PCOS (n = 83) and control (n = 39) subjects]. Serum adipolin was measured by ELISA. Metformin treatment (850 mg twice daily for 6 months) was offered to all women with PCOS, 34 women participated but 21 women completed 6 months of metformin therapy. Reasons for subjects not completing the study were nausea and gastrointestinal side effects (n = 4), pregnancies (n = 5), noncompliance (n = 2) and loss of contact (n = 2). RESULTS Metformin treatment (850 mg twice daily for 6 months) substantially increased serum adipolin concentrations (P < 0·05) in women with polycystic ovary syndrome (PCOS), a pro-inflammatory state associated with obesity, diabetes, dyslipidaemia and atherosclerosis. Furthermore, changes in waist-hip ratio, glucose, triglycerides, CRP and carotid intima media thickness showed significant negative associations with changes in adipolin levels (P < 0·05, P < 0·01); in multiple regression analyses, only changes in glucose were predictive of changes in adipolin levels (β = -0·570, P = 0·009). Serum adipolin decreased significantly in response to the OGTT in PCOS and control subjects at 90 min (P < 0·05) and 120 min (P < 0·01). CONCLUSIONS Adipolin and/or novel pharmacologic agents that increase adipolin's circulating concentrations might constitute a novel approach in the treatment of insulin resistant states.
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Affiliation(s)
- Bee K Tan
- Warwick Medical School, University of Warwick, Coventry, UK; Department of Obstetrics and Gynaecology, Birmingham Heartlands and Solihull Hospitals, Heart of England NHS Foundation Trust, Birmingham, UK
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31
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Zhao Q, Hong D, Zheng D, Xiao Y, Wu B. Risk of diarrhea in patients with type 2 diabetes mellitus treated with sitagliptin: a meta-analysis of 30 randomized clinical trials. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:2283-94. [PMID: 25419118 PMCID: PMC4234286 DOI: 10.2147/dddt.s70945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Sitagliptin is an important drug used for diabetes treatment and is used as a monotherapy in diabetic patients. However, there are also reported cases of diarrhea with sitagliptin use. Unfortunately, data concerning the relationship of diarrhea with sitagliptin use in various conditions have yet to be identified. Therefore, the overall incidence and risk of diarrhea with sitagliptin use have not been well defined. METHODS We conducted searches on Embase, PubMed, and the Cochrane Library databases for relevant randomized controlled trials. Registered relevant trials at the clinical trials registration website were also searched. Statistical analyses were conducted to calculate the overall incidence, odds ratios, and 95% confidence intervals (CI) by using either random-effects or fixed-effect models according to the heterogeneity of the included studies. RESULTS A total of 8,891 subjects with diabetes from 30 randomized clinical trials were included in the meta-analysis. The overall incidence of sitagliptin-associated diarrhea was 4.48% (95% CI: 3.59%-5.58%). Compared with the controls, the use of sitagliptin was not associated with a significantly increased risk of diarrhea with an odds ratio of 1.10 (95% CI: 0.78%-1.55%; P=0.58). No evidence of publication bias was observed. CONCLUSION Our study has shown that there is no difference in diarrhea risk between sitagliptin and controlled therapies. Moreover, sitagliptin is not a medicine that potentially increases the risk of diabetic diarrhea. More studies are recommended to further investigate this association.
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Affiliation(s)
- Qingwei Zhao
- Department of Pharmacy, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Dongsheng Hong
- Department of Pharmacy, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Dongsheng Zheng
- Department of Pharmacy, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Yao Xiao
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, People's Republic of China
| | - Baohua Wu
- Department of Pharmacy, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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32
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Ermakov S, Forster P, Pagidala J, Miladinov M, Wang A, Baillie R, Bartlett D, Reed M, Leil TA. Virtual Systems Pharmacology (ViSP) software for simulation from mechanistic systems-level models. Front Pharmacol 2014; 5:232. [PMID: 25374542 PMCID: PMC4205926 DOI: 10.3389/fphar.2014.00232] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 09/30/2014] [Indexed: 12/27/2022] Open
Abstract
Multiple software programs are available for designing and running large scale system-level pharmacology models used in the drug development process. Depending on the problem, scientists may be forced to use several modeling tools that could increase model development time, IT costs and so on. Therefore, it is desirable to have a single platform that allows setting up and running large-scale simulations for the models that have been developed with different modeling tools. We developed a workflow and a software platform in which a model file is compiled into a self-contained executable that is no longer dependent on the software that was used to create the model. At the same time the full model specifics is preserved by presenting all model parameters as input parameters for the executable. This platform was implemented as a model agnostic, therapeutic area agnostic and web-based application with a database back-end that can be used to configure, manage and execute large-scale simulations for multiple models by multiple users. The user interface is designed to be easily configurable to reflect the specifics of the model and the user's particular needs and the back-end database has been implemented to store and manage all aspects of the systems, such as Models, Virtual Patients, User Interface Settings, and Results. The platform can be adapted and deployed on an existing cluster or cloud computing environment. Its use was demonstrated with a metabolic disease systems pharmacology model that simulates the effects of two antidiabetic drugs, metformin and fasiglifam, in type 2 diabetes mellitus patients.
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Affiliation(s)
- Sergey Ermakov
- Exploratory Clinical and Translational Research, Bristol-Myers Squibb Princeton, NJ, USA
| | | | - Jyotsna Pagidala
- Research IT and Automation, Bristol-Myers Squibb Princeton, NJ, USA
| | - Marko Miladinov
- Research IT and Automation, Bristol-Myers Squibb Princeton, NJ, USA
| | - Albert Wang
- Research IT and Automation, Bristol-Myers Squibb Princeton, NJ, USA
| | | | | | | | - Tarek A Leil
- Exploratory Clinical and Translational Research, Bristol-Myers Squibb Princeton, NJ, USA
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Abstract
Metformin is the most commonly prescribed medication for type 2 diabetes (T2DM) in the world. It has primacy in the treatment of this disease because of its safety record and also because of evidence for reduction in the risk of cardiovascular events. Evidence has accumulated indicating that metformin is safe in people with stage 3 chronic kidney disease (CKD-3). It is estimated that roughly one-quarter of people with CKD-3 and T2DM in the United States (well over 1 million) are ineligible for metformin treatment because of elevated serum creatinine levels. This could be overcome if a scheme, perhaps based on pharmacokinetic studies, could be developed to prescribe reduced doses of metformin in these individuals. There is also substantial evidence from epidemiologic studies to indicate that metformin may not only be safe, but may actually benefit people with heart failure (HF). Prospective, randomized trials of the use of metformin in HF are needed to investigate this possibility.
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Affiliation(s)
- John M. Miles
- To whom correspondence should be addressed. Telephone 507 284 3289; Fax 507 255 4828
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Kristensen JM, Treebak JT, Schjerling P, Goodyear L, Wojtaszewski JFP. Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle. Am J Physiol Endocrinol Metab 2014; 306:E1099-109. [PMID: 24644243 PMCID: PMC4971810 DOI: 10.1152/ajpendo.00417.2013] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Metformin-induced activation of the 5'-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr(308) and Ser(473) phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr(308)/Ser(473) and TBC1D4 Thr(642)/Ser(711) phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment.
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Affiliation(s)
- Jonas Møller Kristensen
- Molecular Physiology Group, August Krogh Centre, Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jonas T Treebak
- Molecular Physiology Group, August Krogh Centre, Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Schjerling
- Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and
| | - Laurie Goodyear
- Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Jørgen F P Wojtaszewski
- Molecular Physiology Group, August Krogh Centre, Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark;
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Woo SL, Xu H, Li H, Zhao Y, Hu X, Zhao J, Guo X, Guo T, Botchlett R, Qi T, Pei Y, Zheng J, Xu Y, An X, Chen L, Chen L, Li Q, Xiao X, Huo Y, Wu C. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS One 2014; 9:e91111. [PMID: 24638078 PMCID: PMC3956460 DOI: 10.1371/journal.pone.0091111] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 02/06/2014] [Indexed: 01/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages.
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Affiliation(s)
- Shih-Lung Woo
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Hang Xu
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Honggui Li
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Yan Zhao
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Xiang Hu
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America; Department of Endocrinology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiajia Zhao
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America; Department of Stomatology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xin Guo
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Ting Guo
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Rachel Botchlett
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Ting Qi
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Ya Pei
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
| | - Juan Zheng
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America; Department of Endocrinology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yiming Xu
- Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Xiaofei An
- Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Lulu Chen
- Department of Endocrinology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qifu Li
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqiu Xiao
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Laboratory of Lipid & Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuqing Huo
- Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Chaodong Wu
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America
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Liu W, Zheng Y, Zhang Z, Yao W, Gao X. Hypoglycemic, hypolipidemic and antioxidant effects of Sarcandra glabra polysaccharide in type 2 diabetic mice. Food Funct 2014; 5:2850-60. [DOI: 10.1039/c4fo00430b] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Sarcandra glabra(Thunb.) Nakai is a traditional Chinese herbal medicine and dietary supplement used for treating several diseases.
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Affiliation(s)
- Wei Liu
- State Key Laboratory of Natural Medicines
- China Pharmaceutical University
- Nanjing 210009, PR China
- Department of Food Quality and Safety
- China Pharmaceutical University
| | - Ying Zheng
- State Key Laboratory of Natural Medicines
- China Pharmaceutical University
- Nanjing 210009, PR China
- School of Life Science and Technology
- China Pharmaceutical University
| | - Zhenzhen Zhang
- State Key Laboratory of Natural Medicines
- China Pharmaceutical University
- Nanjing 210009, PR China
- School of Life Science and Technology
- China Pharmaceutical University
| | - Wenbing Yao
- State Key Laboratory of Natural Medicines
- China Pharmaceutical University
- Nanjing 210009, PR China
- School of Life Science and Technology
- China Pharmaceutical University
| | - Xiangdong Gao
- State Key Laboratory of Natural Medicines
- China Pharmaceutical University
- Nanjing 210009, PR China
- School of Life Science and Technology
- China Pharmaceutical University
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Tan BK, Chen J, Adya R, Ramanjaneya M, Patel V, Randeva HS. Metformin increases the novel adipokine adipolin/CTRP12: role of the AMPK pathway. J Endocrinol 2013; 219:101-8. [PMID: 23946431 DOI: 10.1530/joe-13-0277] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Adipolin is a novel adipokine with anti-inflammatory and glucose-lowering properties. Lower levels of adipolin are found in obese and diabetic mice. Polycystic ovary syndrome (PCOS) is a pro-inflammatory state associated with obesity and diabetes. To date, there are no human studies on adipolin. Therefore, we measured serum (ELISA) and adipose tissue adipolin mRNA expression (RT-PCR) and protein concentrations (western blotting) in PCOS and control subjects. We also investigated the ex vivo effect of glucose and metformin on adipolin protein production in human subcutaneous adipose tissue explants. We report novel data that serum and subcutaneous adipose tissue adipolin mRNA expression and protein concentrations were significantly lower in women with PCOS compared with control subjects. Furthermore, Spearman's rank analysis showed that serum adipolin concentrations were significantly negatively correlated with BMI, waist-to-hip ratio, and glucose (P<0.05). However, when subjected to multiple regression analysis, none of these variables were predictive of serum adipolin concentrations (P>0.05). Also, subcutaneous adipose tissue adipolin mRNA expression and protein concentrations were only significantly negatively correlated with glucose (P<0.05). No significant correlations were found with omental adipose tissue adipolin mRNA expression and protein concentrations (P>0.05). Moreover, glucose profoundly reduced and metformin significantly increased adipolin protein production in human adipose tissue explants respectively. Importantly, metformin's effects appear to be via the AMP-activated protein kinase signaling pathway.
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Affiliation(s)
- Bee K Tan
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
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Petersons CJ, Mangelsdorf BL, Jenkins AB, Poljak A, Smith MD, Greenfield JR, Thompson CH, Burt MG. Effects of low-dose prednisolone on hepatic and peripheral insulin sensitivity, insulin secretion, and abdominal adiposity in patients with inflammatory rheumatologic disease. Diabetes Care 2013; 36:2822-9. [PMID: 23670996 PMCID: PMC3747874 DOI: 10.2337/dc12-2617] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-(2)H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.
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Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013; 56:1898-906. [PMID: 23835523 PMCID: PMC3737434 DOI: 10.1007/s00125-013-2991-0] [Citation(s) in RCA: 326] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/13/2013] [Indexed: 12/24/2022]
Abstract
Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin's molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.
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Affiliation(s)
- Graham Rena
- Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK
| | - Ewan R. Pearson
- Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK
| | - Kei Sakamoto
- Nestlé Institute of Health Sciences SA, Campus EPFL, Quartier de l’innovation, bâtiment G, 1015 Lausanne, Switzerland
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Eames AJ, Grivell RM, Deussen AR, Hague W, Dodd JM. Metformin for women who are obese during pregnancy for improving maternal and infant outcomes. Hippokratia 2013. [DOI: 10.1002/14651858.cd010564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Amanda J Eames
- The University of Adelaide, Women's and Children's Hospital; Discipline of Obstetrics and Gynaecology; 72 King William Road Adelaide Australia 5006
| | - Rosalie M Grivell
- The University of Adelaide, Women's and Children's Hospital; Discipline of Obstetrics and Gynaecology; 72 King William Road Adelaide Australia 5006
| | - Andrea R Deussen
- The University of Adelaide, Women's and Children's Hospital; Discipline of Obstetrics and Gynaecology; 72 King William Road Adelaide Australia 5006
| | - William Hague
- Women's and Children's Hospital; King William Road Adelaide South Australia Australia SA 5006
| | - Jodie M Dodd
- The University of Adelaide; School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology; Women's and Children's Hospital 72 King William Road Adelaide South Australia Australia 5006
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Moser EG, Morris AA, Garg SK. Emerging diabetes therapies and technologies. Diabetes Res Clin Pract 2012; 97:16-26. [PMID: 22381908 DOI: 10.1016/j.diabres.2012.01.027] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Accepted: 01/23/2012] [Indexed: 11/20/2022]
Abstract
The prevalence of diabetes is increasing globally and is expected to increase to 439 million people by the year 2030. Several studies have shown that improved glycemic control measured by glycosylated hemoglobin (A1c) in patients with type 1 and type 2 diabetes results in a reduction of both the micro- and macrovascular complications associated with the disease. The recent introduction of new oral medications, insulin analogs (long and rapid acting), insulin pens and pumps, better SMBG meters and continuous glucose monitoring (CGM) have all resulted in improvement of glycemic control. Closed-loop devices currently in development aim to integrate the CGM and pump system in order to more closely mimic the human pancreas. The other upcoming new basal insulin (Degludec), prandial insulin, other new technologies and improved oral therapies will significantly improve patient acceptance of intensive therapy, glycemic control and quality of life in patients with diabetes.
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Affiliation(s)
- Emily G Moser
- School of Medicine, University of Colorado Denver, Aurora, CO 80045, United States
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Gómez-Sámano MÁ, Gulias-Herrero A, Cuevas-Ramos D, Brau-Figueroa H, Mehta R, Vargas-Gutiérrez D, Meza-Arana CE, Nieves-Niebla JM, Vázquez-Hernández MO. Metformin and improvement of the hepatic insulin resistance index independent of anthropometric changes. Endocr Pract 2012; 18:8-16. [PMID: 21742607 DOI: 10.4158/ep11072.or] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To determine the change in the hepatic insulin resistance index (HIRI) after metformin treatment. METHODS In this retrospective cohort study, Mexican mestizo patients with a body mass index (BMI) of 25 kg/m(2) or greater were evaluated. Participants were classified into 2 groups: patients who received metformin and patients who did not. Both groups were followed up for a median of 6 months (range, 4-10 months). The HIRI was calculated at baseline and at follow-up in both groups. We evaluated the independent effect of metformin on HIRI after adjustment for the difference in basal and final values (DELTA) of BMI, waist circumference, glucose, and insulin. RESULTS A total of 71 patients were enrolled (51 [72%] female). Forty-one patients received metformin and 30 patients did not. Mean age was 36.3 ± 12.2 years and mean BMI was 42.2 ± 10.7 kg/m(2). After metformin treatment, HIRI significantly decreased from 38 ± 10.7 to 34.7 ± 9.5 (P = .03). In contrast, the control group had a nonsignificant increase in HIRI (37.6 ± 11.7 to 40.0 ± 14.0, P = .22). Weight significantly decreased in both groups (group 1: 114.6 ± 33.8 kg to 107.6 ± 28.9 kg, P<.01; group 2: 104.8 ± 28.5 kg to 98.9 ± 26.0 kg, P<.01). After BMI adjustment, the total metformin dosage correlated negatively with HIRI (r = -0.36, P = .03). Using a linear regression model (F = 6.0, r2 = 0.37, P = .002) adjusted for DELTA BMI and DELTA waist circumference, the administration of metformin resulted in independent improvement in the HIRI level (standardized β = -0.29, t = -2.0, P = .04). CONCLUSIONS Metformin improves HIRI independently of anthropometric changes. In persons with elevated HIRI levels, metformin may be considered among the treatment options.
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Affiliation(s)
- Miguel Ángel Gómez-Sámano
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact. Trends Pharmacol Sci 2011; 32:607-16. [PMID: 21824668 DOI: 10.1016/j.tips.2011.06.006] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 06/16/2011] [Accepted: 06/21/2011] [Indexed: 12/25/2022]
Abstract
Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM.
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Forst T, Hanefeld M, Pfützner A. Review of approved pioglitazone combinations for type 2 diabetes. Expert Opin Pharmacother 2011; 12:1571-84. [DOI: 10.1517/14656566.2011.567266] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Tan BK, Chen J, Adya R, Randeva HS. Phosphoprotein enriched in diabetes gene product (Ped/pea-15) is increased in omental adipose tissue of women with the polycystic ovary syndrome: ex vivo regulation of ped/pea-15 by glucose, insulin and metformin. Diabetes Obes Metab 2011; 13:181-4. [PMID: 21199270 DOI: 10.1111/j.1463-1326.2010.01329.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Polycystic ovary syndrome (PCOS), the commonest endocrine disorder in women, is characterized by an altered steroid milieu and is associated with insulin resistance and type 2 diabetes mellitus (T2DM). Phosphoprotein enriched in diabetes gene product (Ped/pea-15) regulates glucose metabolism and is increased in T2DM. Our novel data indicate that Ped/pea-15 mRNA expression and protein levels are significantly increased in omental adipose tissue (AT) from PCOS women compared to matched controls (p < 0.01); Ped/pea-15 levels in subcutaneous AT were not significantly different. Furthermore, Ped/pea-15 mRNA expression and protein levels were higher in omental compared to subcutaneous AT in PCOS subjects (p < 0.01); however, in control subjects, this was not significant. Glucose was predictive of omental AT Ped/pea-15 mRNA expression (p = 0.045). Importantly, glucose and insulin increased whereas metformin significantly decreased Ped/pea-15 levels in human omental AT explants. Our findings should serve to promote further research on Ped/pea-15 biology.
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Koiou E, Tziomalos K, Dinas K, Katsikis I, Kalaitzakis E, Delkos D, Kandaraki EA, Panidis D. The effect of weight loss and treatment with metformin on serum vaspin levels in women with polycystic ovary syndrome. Endocr J 2011; 58:237-46. [PMID: 21325745 DOI: 10.1507/endocrj.k10e-330] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Many patients with polycystic ovary syndrome (PCOS) have insulin resistance, obesity (mostly visceral) and glucose intolerance, conditions associated with abnormalities in the production of vaspin, a novel adipokine that appears to preserve insulin sensitivity and glucose tolerance. The aim of the study was to assess serum vaspin levels in PCOS and the effects on vaspin levels of metformin or of weight loss. We studied 79 patients with PCOS and 50 healthy female volunteers. Normal weight patients with PCOS (n=25) were treated with metformin 850 mg bid for 6 months. Overweight/obese patients with PCOS (n=54) were prescribed a normal-protein, energy-restricted diet for 6 months; half of them were also given orlistat 120 mg tid and the rest were given sibutramine 10 mg qd. At baseline and after 6 months, serum vaspin levels and anthropometric, metabolic and hormonal features of PCOS were determined. Overall, patients with PCOS had higher vaspin levels than controls (p=0.021). Normal weight patients with PCOS had higher vaspin levels than normal weight controls (p=0.043). Vaspin levels were non-significantly higher in overweight/obese patients with PCOS than in overweight/obese controls. In normal weight patients with PCOS, metformin reduced vaspin levels non-significantly. In overweight/obese patients with PCOS, diet plus orlistat or sibutramine did not affect vaspin levels. Vaspin levels were independently correlated with body mass index in women with PCOS (p=0.001) and with waist circumference in controls (p=0.015). In conclusion, serum vaspin levels are elevated in PCOS but neither a small weight loss nor metformin affect vaspin levels significantly.
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Affiliation(s)
- Ekaterini Koiou
- Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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Abstract
Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein kinase, adiponectin, and the sympathetic nervous system. If ligands for these targets have obvious acute thermogenic activity, it is often because they increase sympathetic activity. This promotes fuel mobilisation, as well as fuel oxidation. When thermogenesis thermogenesis is not obvious, researchers often argue that it has occurred by using the inappropriate device of treating animals for days or weeks until there is weight (mainly fat) loss and then expressing energy expenditure energy expenditure relative to body weight. In reality, thermogenesis may have occurred, but it is too small to detect, and this device distracts us from really appreciating why insulin sensitivity has improved. This is that by increasing fatty acid oxidation fatty acid oxidation more than fatty acid supply, drugs lower the concentrations of fatty acid metabolites that cause insulin resistance. Insulin sensitivity improves long before any anti-obesity effect can be detected.
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Affiliation(s)
- Jonathan R S Arch
- Clore Laboratory, University of Buckingham, Buckingham, MK18 1EG, UK
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48
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Cha HN, Choi JH, Kim YW, Kim JY, Ahn MW, Park SY. Metformin Inhibits Isoproterenol-induced Cardiac Hypertrophy in Mice. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2010; 14:377-84. [PMID: 21311678 DOI: 10.4196/kjpp.2010.14.6.377] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2010] [Revised: 11/30/2010] [Accepted: 12/07/2010] [Indexed: 12/18/2022]
Abstract
The present study examined whether metformin treatment prevents isoporterenol-induced cardiac hypertrophy in mice. Chronic subcutaneous infusion of isoproterenol (15 mg/kg/24 h) for 1 week using an osmotic minipump induced cardiac hypertrophy measured by the heart-to-body weight ratio and left ventricular posterior wall thickness. Cardiac hypertrophy was accompanied with increased interleukin-6 (IL-6), transforming growth factor (TGF)-β, atrial natriuretic peptide (ANP), collagen I and III, and matrix metallopeptidase 2 (MMP-2). Coinfusion of metformin (150 mg/kg/24 h) with isoproterenol partially inhibited cardiac hypertrophy that was followed by reduced IL-6, TGF-β, ANP, collagen I and III, and MMP-2. Chronic subcutaneous infusion of metformin did not increase AMP-activated protein kinase (AMPK) activity in heart, although acute intraperitoneal injection of metformin (10 mg/kg) increased AMPK activity. Isoproterenol increased nitrotyrosine levels and mRNA expression of antioxidant enzyme glutathione peroxidase and metformin treatment normalized these changes. These results suggest that metformin inhibits cardiac hypertrophy through attenuating oxidative stress.
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Affiliation(s)
- Hye-Na Cha
- Department of Physiology, College of Medicine, Yeungnam University, Daegu 705-717, Korea
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49
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Ito H, Ohno Y, Yamauchi T, Kawabata Y, Ikegami H. Efficacy and safety of metformin for treatment of type 2 diabetes in elderly Japanese patients. Geriatr Gerontol Int 2010; 11:55-62. [DOI: 10.1111/j.1447-0594.2010.00635.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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50
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Ratziu V, Caldwell S, Neuschwander-Tetri BA. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology 2010; 52:2206-15. [PMID: 21105109 DOI: 10.1002/hep.24042] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials.
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Affiliation(s)
- Vlad Ratziu
- Université Pierre et Marie Curie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpêtrière, INSERM UMRS 893 Paris, France.
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