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Hatano R, Lee E, Sato H, Kiuchi M, Hirahara K, Nakagawa Y, Shimano H, Nakayama T, Tanaka T, Miki T. Hepatic ketone body regulation of renal gluconeogenesis. Mol Metab 2024; 84:101934. [PMID: 38604598 PMCID: PMC11039402 DOI: 10.1016/j.molmet.2024.101934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/20/2024] [Accepted: 04/02/2024] [Indexed: 04/13/2024] Open
Abstract
OBJECTIVES During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis. Gluconeogenic genes are transactivated by fasting, but their expression patterns are chronologically different between the two organs. We find that renal gluconeogenic gene expressions are positively correlated with the blood β-hydroxybutyrate concentration. Thus, we herein aim to investigate the regulatory mechanism and its physiological implications. METHODS Gluconeogenic gene expressions in liver and kidney were examined in hyperketogenic mice such as high-fat diet (HFD)-fed and ketogenic diet-fed mice, and in hypoketogenic PPARα knockout (PPARα-/-) mice. Renal gluconeogenesis was evaluated by rise in glycemia after glutamine loading in vivo. Functional roles of β-hydroxybutyrate in the regulation of renal gluconeogenesis were investigated by metabolome analysis and RNA-seq analysis of proximal tubule cells. RESULTS Renal gluconeogenic genes were transactivated concurrently with blood β-hydroxybutyrate uprise under ketogenic states, but the increase was blunted in hypoketogenic PPARα-/- mice. Administration of 1,3-butandiol, a ketone diester, transactivated renal gluconeogenic gene expression in fasted PPARα-/- mice. In addition, HFD-fed mice showed fasting hyperglycemia along with upregulated renal gluconeogenic gene expression, which was blunted in HFD-fed PPARα-/- mice. In vitro experiments and metabolome analysis in renal tubular cells showed that β-hydroxybutyrate directly promotes glucose and NH3 production through transactivating gluconeogenic genes. In addition, RNA-seq analysis revealed that β-hydroxybutyrate-induced transactivation of Pck1 was mediated by C/EBPβ. CONCLUSIONS Our findings demonstrate that β-hydroxybutyrate mediates hepato-renal interaction to maintain homeostatic regulation of blood glucose and systemic acid-base balance through renal gluconeogenesis regulation.
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Affiliation(s)
- Ryo Hatano
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Eunyoung Lee
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiromi Sato
- Laboratory of Clinical Pharmacology and Pharmacometrics, Chiba University, Graduate School of Pharmaceutical Sciences, Chiba 260-8670, Japan
| | - Masahiro Kiuchi
- Department of Immunology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kiyoshi Hirahara
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Department of Immunology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yoshimi Nakagawa
- Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
| | - Toshinori Nakayama
- Department of Immunology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tomoaki Tanaka
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Department of Molecular Diagnosis, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takashi Miki
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.
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Nistor M, Schmidt M, Klingner C, Klingner C, Matziolis G, Shayganfar S, Schiffner R. Effect of Low-Frequency Renal Nerve Stimulation on Renal Glucose Release during Normoglycemia and a Hypoglycemic Clamp in Pigs. Int J Mol Sci 2024; 25:2041. [PMID: 38396718 PMCID: PMC10888375 DOI: 10.3390/ijms25042041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/22/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Previously, we demonstrated that renal denervation in pigs reduces renal glucose release during a hypoglycemic episode. In this study we set out to examine changes in side-dependent renal net glucose release (SGN) through unilateral low-frequency stimulation (LFS) of the renal plexus with a pulse generator (2-5 Hz) during normoglycemia (60 min) and insulin-induced hypoglycemia ≤3.5 mmol/L (75 min) in seven pigs. The jugular vein, carotid artery, renal artery and vein, and both ureters were catheterized for measurement purposes, blood pressure management, and drug and fluid infusions. Para-aminohippurate (PAH) and inulin infusions were used to determine side-dependent renal plasma flow (SRP) and glomerular filtration rate (GFR). In a linear mixed model, LFS caused no change in SRP but decreased sodium excretion (p < 0.0001), as well as decreasing GFR during hypoglycemia (p = 0.0176). In a linear mixed model, only hypoglycemic conditions exerted significant effects on SGN (p = 0.001), whereas LFS did not. In a Wilcoxon signed rank exact test, LFS significantly increased SGN (p = 0.03125) and decreased sodium excretion (p = 0.0017) and urinary flow rate (p = 0.0129) when only considering the first instance LFS followed a preceding period of non-stimulation during normoglycemia. To conclude, this study represents, to our knowledge, the first description of an induction of renal gluconeogenesis by LFS.
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Affiliation(s)
- Marius Nistor
- Orthopaedic Department, Jena University Hospital, 07747 Jena, Germany (G.M.)
| | - Martin Schmidt
- Institute for Biochemistry II, Jena University Hospital, 07747 Jena, Germany;
| | - Carsten Klingner
- Department of Neurology, Jena University Hospital, 07747 Jena, Germany; (C.K.); (C.K.)
| | - Caroline Klingner
- Department of Neurology, Jena University Hospital, 07747 Jena, Germany; (C.K.); (C.K.)
| | - Georg Matziolis
- Orthopaedic Department, Jena University Hospital, 07747 Jena, Germany (G.M.)
| | - Sascha Shayganfar
- Emergency Department, Helios University Clinic Wuppertal, 42283 Wuppertal, Germany;
- Faculty of Health/School of Medicine, Lehrstuhl für Klinische Akut- und Notfallmedizin, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany
| | - René Schiffner
- Orthopaedic Department, Jena University Hospital, 07747 Jena, Germany (G.M.)
- Emergency Department, Helios University Clinic Wuppertal, 42283 Wuppertal, Germany;
- Faculty of Health/School of Medicine, Lehrstuhl für Klinische Akut- und Notfallmedizin, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany
- Emergency Department, Otto-von-Guericke University, 39120 Magdeburg, Germany
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Sahoo B, Srivastava M, Katiyar A, Ecelbarger C, Tiwari S. Liver or kidney: Who has the oar in the gluconeogenesis boat and when? World J Diabetes 2023; 14:1049-1056. [PMID: 37547592 PMCID: PMC10401452 DOI: 10.4239/wjd.v14.i7.1049] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/20/2023] [Accepted: 04/11/2023] [Indexed: 07/12/2023] Open
Abstract
Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation. We would be remiss to add that more recently gluconeogenesis has been described in the small intestine, especially under high-protein, low-carbohydrate diets. The contribution of the liver glucose release, the net glucose flux, towards systemic glucose is already well known. The liver is, in most instances, the primary bulk contributor due to the sheer size of the organ (on average, over 1 kg). The contribution of the kidney (at just over 100 g each) to endogenous glucose production is often under-appreciated, especially on a weight basis. Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis. Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in only a fraction of the cells in that organ (proximal tubule cells). Thus, the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level. In both these tissues, gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates. Liver and renal gluconeogenesis are differentially regulated under various pathological conditions. The impact of one source vs the other changes, based on post-prandial state, acid-base balance, hormonal status, and other less understood factors. Which organ has the oar (is more influential) in driving systemic glucose homeostasis is still in-conclusive and likely changes with the daily rhythms of life. We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.
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Affiliation(s)
- Biswajit Sahoo
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Medha Srivastava
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Arpit Katiyar
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University, Washington, DC 20057, United States
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". J Nephrol 2020; 33:9-35. [PMID: 31576500 PMCID: PMC7007429 DOI: 10.1007/s40620-019-00650-x] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
- Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Hypoglycemia. Endocrinology 2020. [PMID: 31968189 DOI: 10.1007/978-3-030-36694-0_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: New clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". Nutr Metab Cardiovasc Dis 2019; 29:1127-1150. [PMID: 31586514 DOI: 10.1016/j.numecd.2019.07.017] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Huang R, Zhu J, Zhang L, Hua X, Ye W, Chen C, Sun K, Wang W, Feng L, Zhang J. Is ELABELA a reliable biomarker for hypertensive disorders of pregnancy? Pregnancy Hypertens 2019; 17:226-232. [PMID: 31487645 PMCID: PMC7001771 DOI: 10.1016/j.preghy.2019.06.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 05/26/2019] [Accepted: 06/25/2019] [Indexed: 11/15/2022]
Abstract
OBJECTIVE We aimed to examine the ELABELA levels at different stages of pregnancy among normotensive controls and women with hypertensive disorders of pregnancy (HDP). STUDY DESIGN A total of 336 blood samples of 169 women were collected from pre-pregnancy, the first, second, and third trimesters. Women were divided into the following six groups: 1) non-pregnant healthy women; 2) healthy pregnant controls; 3) chronic hypertension; 4) gestational hypertension; 5) preeclampsia; and 6) preeclampsia superimposed on chronic hypertension. ELABELA plasma concentrations were measured by human ELA Elisa Kit (Peninsula Laboratories International, Inc. USA). Kruskal-Wallis test was used to test whether ELABELA level in each type of HDP differed from that in gestational week-matched normotensive controls. MAIN OUTCOME MEASURES Hypertensive disorders of pregnancy. RESULTS In the first trimester, patients with gestational hypertension had higher ELABELA level than gestational week-matched normotensive controls [median (ng/ml): 31.9, (IQR (ng/ml): 16.3, 47.6) vs. 19.7 (13.7, 23.2), p = 0.03]. In the second trimester, the levels were 49.2 (32.2, 69.1) vs 24.0 (13.0, 32.6) (p = 0.002), respectively. The level for gestational hypertensive women in the third trimester did not differ significantly from that of normotensive women [43.8 (30.8, 62.7) vs 25.0 (12.3, 74.0), p = 0.82]. The ELABELA levels were similar between preeclamptic women and normotensive controls throughout pregnancy. CONCLUSIONS Maternal blood ELABELA levels in the first and second trimesters were elevated in women who developed gestational hypertension late in pregnancy, but the ELABELA level bears no significant relationship with preeclampsia during any stage of pregnancy.
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Affiliation(s)
- Rong Huang
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Jing Zhu
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Zhang
- Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolin Hua
- Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiping Ye
- Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang Chen
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Sun
- Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Weiye Wang
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Liping Feng
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA.
| | - Jun Zhang
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Plomgaard P, Hansen JS, Ingerslev B, Clemmesen JO, Secher NH, van Hall G, Fritsche A, Weigert C, Lehmann R, Häring HU, Heni M. Nasal insulin administration does not affect hepatic glucose production at systemic fasting insulin levels. Diabetes Obes Metab 2019; 21:993-1000. [PMID: 30552787 DOI: 10.1111/dom.13615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 12/11/2018] [Accepted: 12/13/2018] [Indexed: 12/27/2022]
Abstract
AIMS To evaluate the effects of brain insulin on endogenous glucose production in fasting humans, with a focus on hepatic glucose release by performing a randomized, placebo-controlled, blinded, crossover experiment. MATERIALS AND METHODS On two separate days, 2 H2 -glucose was infused to nine healthy lean men, and blood was sampled from the hepatic vein and a radial artery. On day 1, participants received 160 U human insulin through nasal spray, and on day 2 they received placebo spray, together with an intravenous insulin bolus to mimic spillover of nasal insulin to the circulation. Hepatic glucose fluxes and endogenous glucose production were calculated. RESULTS Plasma insulin concentrations were similar on the two study days, and no differences in whole-body endogenous glucose production or hepato-splanchnic glucose turnover were detected. CONCLUSIONS Nasal administration of insulin does not influence whole-body or hepatic glucose production in fasting humans. By contrast, pharmacological delivery of insulin to the brain might modulate insulin effectiveness in glucose-producing tissue when circulating insulin levels are elevated; therefore, the metabolic consequences of brain insulin action appear to be dependent on metabolic prandial status.
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Affiliation(s)
- Peter Plomgaard
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Centre of Inflammation and Metabolism, and the Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Jakob S Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Centre of Inflammation and Metabolism, and the Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Bodil Ingerslev
- Centre of Inflammation and Metabolism, and the Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jens O Clemmesen
- Department of Hepatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Niels H Secher
- Department of Anaesthesiology, Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Cora Weigert
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Rainer Lehmann
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
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Abstract
PURPOSE OF REVIEW Older adults often live with chronic disease including diabetes and its complications. In this review, we examine the complexity and heterogeneity of older adults with diabetes and chronic kidney disease, explore the nuances in their diabetes-related monitoring, and discuss their best diabetes management. RECENT FINDINGS Although there remains an overall lack of studies in older adults with diabetes and chronic kidney disease, recent reports have highlighted their vulnerabilities. These individuals face an increased risk of cognitive impairment and dementia, frailty, dysglycemia, polypharmacy, declining kidney function, and acute kidney injury. Their diabetes management should focus upon safer antihyperglycemic medications, close monitoring, and care individualization. Older adults with diabetes and chronic kidney disease are a complex population who requires careful diabetes management and monitoring. Research efforts might focus on improving the care and outcomes of these patients.
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Affiliation(s)
- Kristin K Clemens
- Department of Medicine, Division of Endocrinology, Western University, London, Ontario, Canada.
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
- St. Joseph's Health Care London, London, Ontario, Canada.
- Institute for Clinical Evaluative Sciences, Ontario, Canada.
- Lawson Health Research Institute, London, Ontario, Canada.
| | - Niamh O'Regan
- St. Joseph's Health Care London, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
- Department of Medicine, Division of Geriatric Medicine, Western University, London, Ontario, Canada
| | - Jinnie J Rhee
- Department of Medicine, Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA
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Hypoglycemia. Endocrinology 2019. [DOI: 10.1007/978-3-319-27316-7_22-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Alkhalidy H, Wang Y, Liu D. Dietary Flavonoids in the Prevention of T2D: An Overview. Nutrients 2018; 10:nu10040438. [PMID: 29614722 PMCID: PMC5946223 DOI: 10.3390/nu10040438] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 03/15/2018] [Accepted: 03/29/2018] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes (T2D) is a progressive metabolic disease that is increasing in prevalence globally. It is well established that insulin resistance (IR) and a progressive decline in functional β-cell mass are hallmarks of developing T2D. Obesity is a leading pathogenic factor for developing IR. Constant IR will progress to T2D when β-cells are unable to secret adequate amounts of insulin to compensate for decreased insulin sensitivity. Recently, a considerable amount of research has been devoted to identifying naturally occurring anti-diabetic compounds that are abundant in certain types of foods. Flavonoids are a group of polyphenols that have drawn great interest for their various health benefits. Results from many clinical and animal studies demonstrate that dietary intake of flavonoids might be helpful in preventing T2D, although cellular and molecular mechanisms underlying these effects are still not completely understood. This review discusses our current understanding of the pathophysiology of T2D and highlights the potential anti-diabetic effects of flavonoids and mechanisms of their actions.
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Affiliation(s)
- Hana Alkhalidy
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA.
- Department of Nutrition and Food Technology, Faculty of Agriculture, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Yao Wang
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA.
| | - Dongmin Liu
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA.
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13
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Hypoglycemia. Endocrinology 2018. [DOI: 10.1007/978-3-319-27316-7_22-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Hodge M, McArthur E, Garg AX, Tangri N, Clemens KK. Hypoglycemia Incidence in Older Adults by Estimated GFR. Am J Kidney Dis 2017; 70:59-68. [PMID: 28139395 DOI: 10.1053/j.ajkd.2016.11.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 11/07/2016] [Indexed: 11/11/2022]
Abstract
BACKGROUND Bedside estimates of the risk for hypoglycemia by estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (ACR), and use of antihyperglycemic medications would be helpful. STUDY DESIGN Population-based cohort study. SETTING & PARTICIPANTS Older adults (mean age, 75 years) in Ontario, Canada, from April 2002 through March 2013. FACTORS eGFR stage, ACR stage, and use of antihyperglycemic medications. OUTCOME 3-year incidence rate of a hospital encounter with hypoglycemia (emergency department or inpatient encounter). RESULTS In users and nonusers of antihyperglycemic medications, there was a graded increase in risk for hypoglycemia by eGFR stage. Incidence rates in antihyperglycemic medication users were 82 (95% CI, 71-94), 122 (95% CI, 115-130), 235 (95% CI, 218-254), 379 (95% CI, 349-413), 596 (95% CI, 524-678), and 785 (95% CI, 689-894) encounters per 10,000 person-years when eGFR was ≥90, 60 to <90, 45 to <60, 30 to <45, 15 to <30, and <15mL/min/1.73m2 or the patient was receiving dialysis, respectively (P<0.001). Corresponding values in nonusers were 2 (95% CI, 2-4), 3 (95% CI, 3-4), 3 (95% CI, 2-4), 7 (95% CI, 5-9), 14 (95% CI, 9-22), and 55 (95% CI, 43-71) encounters/10,000 person-years, respectively (P<0.001). A similar relationship was evident by eGFR and ACR risk category. LIMITATIONS Only hypoglycemia episodes that were associated with a hospital encounter were assessed. Results cannot be generalized to younger patients. CONCLUSIONS In older adults, the risk for hypoglycemia is higher in those with lower kidney function. Our results may aid the patient-provider dialogue and inform future studies to prevent hypoglycemia in an at-risk population.
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Affiliation(s)
- Meryl Hodge
- School of Health Studies, Western University, London, Ontario, Canada
| | - Eric McArthur
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - Amit X Garg
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Navdeep Tangri
- Division of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Seven Oaks General Hospital, Winnipeg, Manitoba, Canada
| | - Kristin K Clemens
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, Western University, London, Ontario, Canada.
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Chandrakumar A, Dilip C, Suriyaprakash TNK, Thomas L, Surendran R. Incidence and risk factors of hypoglycemia among Type 2 diabetic patients in a South Indian hospital. Diabetes Metab Syndr 2016; 10:S22-S25. [PMID: 26806327 DOI: 10.1016/j.dsx.2016.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 01/09/2016] [Indexed: 02/03/2023]
Abstract
AIM The study was aimed at assessing the cumulative incidence of hypoglycemia and precipitating risk factors among type 2 diabetes mellitus in-patients of a tertiary care hospital in South India. METHODS The prospective cross sectional study spanning 14 months was conducted in a tertiary care hospital in Kerala. All T2DM patients who were administered any form of insulin during the length of hospital stay was monitored for assessing the hypoglycemic episodes. Any patient with a GRBS value less than 70mg/dL was defined to be hypoglycemic as per the ADA guidelines. The statistical analysis of collected data was performed using SPSS 18 for windows version. RESULTS Of the 1650 subjects enrolled in the study, 204 subjects developed hypoglycemia. The sample composed of 60.8% females and 39.2% males and the difference was significant with p=0.02. A significant positive correlation was observed between HbA1c values and GRBS value, with a 2 tailed Pearson correlation coefficient of 0.027. On stratifying as per the modality of insulin dose prescribed, 72.5% of the hypoglycemic patients were found to have been administered fixed dose insulin. CONCLUSION The cumulative incidence of institutional hypoglycemia among type 2 diabetic inpatients was gauged as 12.36%; among which, 26.96% had asymptomatic episodes.
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Affiliation(s)
- Abin Chandrakumar
- Department of Pharmacy Practice, Al Shifa College of Pharmacy, Poonthavanam, Kizhattur P.O, Perinthalmanna, Kerala, 679325.
| | - C Dilip
- Department of Pharmacy Practice, Al Shifa College of Pharmacy, Poonthavanam, Kizhattur P.O, Perinthalmanna, Kerala, 679325
| | - T N K Suriyaprakash
- Department of Pharmaceutics, Al Shifa College of Pharmacy, Poonthavanam, Kizhattur P.O, Perinthalmanna, Kerala, 679325
| | - Levin Thomas
- Department of Pharmacy Practice, Al Shifa College of Pharmacy, Poonthavanam, Kizhattur P.O, Perinthalmanna, Kerala, 679325
| | - Reshma Surendran
- Department of Pharmacy Practice, Al Shifa College of Pharmacy, Poonthavanam, Kizhattur P.O, Perinthalmanna, Kerala, 679325
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Park CS. Predictive roles of intraoperative blood glucose for post-transplant outcomes in liver transplantation. World J Gastroenterol 2015; 21:6835-6841. [PMID: 26078559 PMCID: PMC4462723 DOI: 10.3748/wjg.v21.i22.6835] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 03/25/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
Diabetogenic traits in patients undergoing liver transplantation (LT) are exacerbated intraoperatively by exogenous causes, such as surgical stress, steroids, blood transfusions, and catecholamines, which lead to intraoperative hyperglycemia. In contrast to the strict glucose control performed in the intensive care unit, no systematic protocol has been developed for glucose management during LT. Intraoperative blood glucose concentrations typically exceed 200 mg/dL in LT, and extreme hyperglycemia (> 300 mg/dL) is common during the neohepatic phase. Only a few retrospective studies have examined the relationship between intraoperative hyperglycemia and post-transplant complications, with reports of infectious complications or mortality. However, no prospective studies have been conducted regarding the influence of intraoperative hyperglycemia in LT on post-transplant outcome. In addition to absolute blood glucose values, the temporal patterns in blood glucose levels during LT may serve as prognostic features. Persistent neohepatic hyperglycemia (without a decline) throughout LT is a useful indicator of early graft dysfunction. Moreover, intraoperative variability in glucose levels may predict the need for reoperation for hemorrhage after LT. Thus, there is an urgent need for guidelines for glucose control in these patients, as well as prospective studies on the impact of glucose control on various post-transplant complications. This report highlights some of the recent studies related to perioperative blood glucose management focused on LT and liver disease.
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Alsahli M, Gerich JE. Hypoglycemia in Patients with Diabetes and Renal Disease. J Clin Med 2015; 4:948-64. [PMID: 26239457 PMCID: PMC4470208 DOI: 10.3390/jcm4050948] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 04/19/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022] Open
Abstract
This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.
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Affiliation(s)
- Mazen Alsahli
- Department of Medicine, Southlake Health Center and University of Toronto Faculty of Medicine, 531 Davis Dr, Newmarket, Ontario L3Y 6P5, Canada.
| | - John E Gerich
- Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA.
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Bokhari S, Plummer E, Emmerson P, Gupta A, Meyer C. Glucose counterregulation in advanced type 2 diabetes: effect of β-adrenergic blockade. Diabetes Care 2014; 37:3040-6. [PMID: 25092686 DOI: 10.2337/dc14-0782] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To examine counterregulatory glucose kinetics and test the hypothesis that β-adrenergic blockade impairs these in patients with type 2 diabetes mellitus (T2DM) and advanced β-failure. RESEARCH DESIGN AND METHODS Nine insulin-requiring T2DM subjects and six matched nondiabetic control subjects were studied. β-Cell function was assessed by the C-peptide response to arginine stimulation. Counterregulatory hormonal responses and glucose kinetics were assessed by hyperinsulinemic euglycemic-hypoglycemic clamps with [3-(3)H]glucose infusion. T2DM subjects underwent two clamp experiments in a randomized crossover fashion: once with infusion of the β-adrenergic antagonist propranolol and once with infusion of normal saline. RESULTS Compared with the control subjects, T2DM subjects had threefold reduced C-peptide responses to arginine stimulation. During the hypoglycemic clamp, glucagon responses were markedly diminished (16.0 ± 4.2 vs. 48.6 ± 6.0 ng/L, P < 0.05), but other hormonal responses and the decrement in the required exogenous glucose infusion rate (GIR) from the euglycemic clamp were normal (-10.4 ± 1.1 vs. -7.8 ± 1.9 µmol · kg(-1) · min(-1) in control subjects); however, endogenous glucose production (EGP) did not increase (-0.8 ± 1.0 vs. 2.2 ± 0.7 µmol · kg(-1) · min(-1) in control subjects, P < 0.05), whereas systemic glucose disposal decreased normally. β-Adrenergic blockade in the T2DM subjects increased GIR ∼20% during the euglycemic clamp (P < 0.01), but neither increased GIR during the hypoglycemic clamp or decreased its decrement from the euglycemic clamp to the hypoglycemic clamp. CONCLUSIONS Overall glucose counterregulation is preserved in advanced T2DM, but the contribution of EGP is diminished. β-Adrenergic blockade may increase insulin sensitivity at normoglycemia but does not impair glucose counterregulation in T2DM patients, even those with advanced β-cell failure.
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Alsahli M, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus. Mayo Clin Proc 2014; 89:1564-71. [PMID: 25305751 DOI: 10.1016/j.mayocp.2014.07.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 07/12/2014] [Accepted: 07/25/2014] [Indexed: 12/21/2022]
Abstract
Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.
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MESH Headings
- Albuminuria/etiology
- Biomarkers/urine
- Databases, Bibliographic
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Glomerular Filtration Rate/physiology
- Humans
- Hypoglycemia/chemically induced
- Hypoglycemia/epidemiology
- Hypoglycemia/etiology
- Hypoglycemia/therapy
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/therapeutic use
- Insulin/adverse effects
- Insulin/therapeutic use
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/epidemiology
- Risk Factors
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Affiliation(s)
- Mazen Alsahli
- Faculty of Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - John E Gerich
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
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Avogaro A, Schernthaner G. Achieving glycemic control in patients with type 2 diabetes and renal impairment. Acta Diabetol 2013; 50:283-91. [PMID: 23212669 DOI: 10.1007/s00592-012-0442-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 11/05/2012] [Indexed: 12/31/2022]
Abstract
Defining optimal regimens for the management of diabetes among patients with renal impairment is often clinically challenging, and guidance on the optimal management of these patients in clinical practice can vary considerably. Moreover, as many anti-diabetes agents are predominantly excreted renally, treatment options to control blood glucose levels are limited for patients with type 2 diabetes and concomitant chronic kidney disease. Many of the widely used and more established anti-diabetes drugs cannot be used in this population either or must be down-titrated to reduce the increased risk of severe hypoglycemic episodes. A number of more recently available anti-diabetes drugs are indicated for use in patients with type 2 diabetes and chronic kidney disease. Newer drugs that may improve the currently very limited treatment options for patients with type 2 diabetes and renal impairment include the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors. This review paper, based on a literature search for both original and review articles (Medline), relevant clinical practice/regulatory guidelines and integrating our own knowledge of the field, provides an up-to-date examination of the current treatment options available. However, further studies with larger populations of patients with type 2 diabetes and chronic kidney disease are needed to clarify the efficacy and safety of the different treatment options, including newer drugs.
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Affiliation(s)
- Angelo Avogaro
- Department of Medicine, School of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
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Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle HJ, Dugi K. Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects. Clin Pharmacol Drug Dev 2013; 2:152-61. [DOI: 10.1002/cpdd.16] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 01/02/2013] [Indexed: 12/15/2022]
Affiliation(s)
- Leo Seman
- Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT; USA
| | - Sreeraj Macha
- Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT; USA
| | - Gerhard Nehmiz
- Boehringer Ingelheim Pharma GmbH & Co. KG; Biberach; Germany
| | - Gudrun Simons
- Boehringer Ingelheim Pharma GmbH & Co. KG; Biberach; Germany
| | - Bailuo Ren
- Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT; USA
| | - Sabine Pinnetti
- Boehringer Ingelheim Pharma GmbH & Co. KG; Biberach; Germany
| | - Hans J. Woerle
- Boehringer Ingelheim Pharma GmbH & Co. KG; Ingelheim; Germany
| | - Klaus Dugi
- Boehringer Ingelheim GmbH; Ingelheim; Germany
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Abstract
Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during exercise is much debated. In the early days skeletal muscle was mainly seen as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later it was recognized that skeletal muscle not only played an important role in lactate production but also in lactate clearance and this led to a renewed interest, not the least from the Copenhagen School in the 1930s, in the metabolic role of lactate in skeletal muscle. With the introduction of lactate isotopes muscle lactate kinetics and oxidation could be studied and a simultaneous lactate uptake and release was observed, not only in muscle but also in other tissues. Therefore, this review will discuss in vivo human: (1) skeletal muscle lactate metabolism at rest and during exercise and suggestions are put forward to explain the simultaneous lactate uptake and release; and (2) lactate metabolism in the heart, liver, kidneys, brain, adipose tissue and lungs will be discussed and its potential importance in these tissues.
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Affiliation(s)
- Gerrit van Hall
- Metabolic Mass-Spectrometry Facility, Rigshospitalet and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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Nery M. [Hypoglycemia as a limiting factor in the management of type 1 diabetes]. ACTA ACUST UNITED AC 2009; 52:288-98. [PMID: 18438539 DOI: 10.1590/s0004-27302008000200016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2007] [Accepted: 12/03/2007] [Indexed: 01/31/2023]
Abstract
Type 1 diabetic patients frequently present hypoglycemic episodes during their insulinotherapy, which, besides the discomfort and constrains does not allow the ideal glycemic control. Further, hypoglycemic events lead to the deficiency of the counter-regulation mechanisms in the subsequent episode, with a decrease in the release of epinephrine and the symptoms of warming, with great risk of severe hypoglycemia. The occurrence of hypoglycemia during some risky activities, specially driving, could result in accidents with the patient and /or third parts including property damage, stressing here the need to advise diabetics against having the necessary caution while driving. Generally the connective recovery is total after correcting a hypoglycemic coma. However when these episodes are repetitive, particularly in children, they could result in definitive cognitive disturbances. Hypoglycemic events without a warning signal (hypoglycemic unawareness) are difficult to reverse, thus it is necessary to prevent their occurrence, adjusting the treatment with glycemic targets, using continuous glucose monitoring at home and teaching them how to have an early recognition of hypoglycemia.
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Affiliation(s)
- Márcia Nery
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
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Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev 2007; 28:253-83. [PMID: 17409288 DOI: 10.1210/er.2006-0026] [Citation(s) in RCA: 284] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The hyperglycemic activity of pancreatic extracts was encountered some 80 yr ago during efforts to optimize methods for the purification of insulin. The hyperglycemic substance was named "glucagon," and it was subsequently determined that glucagon is a 29-amino acid peptide synthesized and released from pancreatic alpha-cells. This article begins with a brief overview of the discovery of glucagon and the contributions that somatostatin and a sensitive and selective assay for pancreatic (vs. gut) glucagon made to understanding the physiological and pathophysiological roles of glucagon. Studies utilizing these tools to establish the function of glucagon in normal nutrient homeostasis and to document a relative glucagon excess in type 2 diabetes mellitus (T2DM) and precursors thereof are then discussed. The evidence that glucagon excess contributes to the development and maintenance of fasting hyperglycemia and that failure to suppress glucagon secretion contributes to postprandial hyperglycemia is then reviewed. Although key human studies are emphasized, salient animal studies highlighting the importance of glucagon in normal and defective glucoregulation are also described. The past eight decades of research in this area have led to development of new therapeutic approaches to treating T2DM that have been shown to, or are expected to, improve glycemic control in patients with T2DM in part by improving alpha-cell function or by blocking glucagon action. Accordingly, this review ends with a discussion of the status and therapeutic potential of glucagon receptor antagonists, alpha-cell selective somatostatin agonists, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-IV inhibitors. Our overall conclusions are that there is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.
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Israelian Z, Szoke E, Woerle J, Bokhari S, Schorr M, Schwenke DC, Cryer PE, Gerich JE, Meyer C. Multiple defects in counterregulation of hypoglycemia in modestly advanced type 2 diabetes mellitus. Metabolism 2006; 55:593-8. [PMID: 16631434 DOI: 10.1016/j.metabol.2005.11.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2005] [Accepted: 11/03/2005] [Indexed: 02/03/2023]
Abstract
In type 2 diabetes mellitus (T2DM), little is known about hormonal responses to hypoglycemia. In particular, beta-cell responses to hypoglycemia have not been carefully investigated and potentially because of confounding factors or insufficient power, conflicting data have been obtained regarding growth hormone responses. We therefore compared hormonal responses including rates of insulin secretion during a 2-hour hyperinsulinemic hypoglycemic clamp in a relatively large number of nondiabetic (n=21) and moderately insulin-deficient subjects with T2DM (homeostasis model assessment of beta-cell function [HOMA-%B], 751+/-160 vs 1144+/-83 [pmol/L]/[mmol/L], P<.04) (n=14) matched for age, sex, and body mass index. Subjects with T2DM were excluded for antecedent hypoglycemia, and baseline glycemia was controlled by a variable infusion of insulin overnight. Although both groups of subjects had indistinguishable plasma glucose levels at baseline and virtually identical levels of plasma insulin and glucose throughout the hypoglycemic clamp, insulin secretion decreased more slowly in the subjects with T2DM. The time required for insulin secretion to decline to half its baseline level was markedly increased (38.9+/-4.9 vs 22.3+/-1.3 minutes [SD], P<.01), and insulin secretion decreased to a lesser extent (-0.79+/-0.17 vs -1.51+/-0.09 [pmol/L]/kg per minute, P<.002). Moreover, responses of glucagon (28.3+/-7.3 vs 52.8+/-7.0 ng/L, P<.05) and growth hormone (2.9+/-0.8 vs 6.3+/-0.9 ng/mL, P<.04) were reduced in the subjects with T2DM, whereas responses of epinephrine, norepinephrine, and cortisol were similar to those in nondiabetic subjects (all P>0.6). We conclude that multiple defects exist in hormonal responses to hypoglycemia in T2DM with moderate beta-cell failure. These include delayed and reduced decreases in insulin secretion, and impaired increases of plasma glucagon and growth hormone.
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Affiliation(s)
- Zarmen Israelian
- Department of Endocrinology, Carl T. Hayden VA Medical Center, Phoenix, AZ 85012, and Department of Medicine, University of Rochester School of Medicine, NY 14642, USA
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Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care 2005; 28:2948-61. [PMID: 16306561 DOI: 10.2337/diacare.28.12.2948] [Citation(s) in RCA: 289] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Nicola N Zammitt
- Department of Diabetes, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, Scotland, U.K
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Fanelli CG, Porcellati F, Pampanelli S, Bolli GB. Insulin therapy and hypoglycaemia: the size of the problem. Diabetes Metab Res Rev 2004; 20 Suppl 2:S32-42. [PMID: 15551297 DOI: 10.1002/dmrr.514] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND METHODS Hypoglycaemia is a fact of life for people with diabetes mellitus. Mild, asymptomatic episodes occur once or twice a week in insulin-treated diabetic subjects. Asymptomatic hypoglycaemia, including nocturnal hypoglycaemia, occurs in about 25% of diabetic subjects treated with insulin therapy. Mild hypoglycaemia, if recurrent, induces unawareness of hypoglycaemia and impairs glucose counterregulation, which in turn predisposes to severe hypoglycaemia. Even brief hypoglycaemia can cause profound dysfunction of the brain. Prolonged, severe hypoglycaemia can cause permanent neurological sequels. In addition, it is possible that hypoglycaemia may accelerate the vascular complications of diabetes by increasing platelet aggregation and/or fibrinogen formation. Finally, hypoglycaemia may be fatal. Hypoglycaemia induced by insulin as treatment of type 1 diabetes mellitus (T1 DM) is not the consequence of diabetes, but invariably of the non-physiological replacement of insulin. RESULTS A number of studies have demonstrated that by moving from non-physiological to more physiological models of insulin therapy, most of the hypoglycaemia problems may be overcome, the percentage of glycated hemoglobin (A1c) decreased, and the quality of life improved. Interestingly, in T1 DM with hypoglycaemia unawareness, prevention of hypoglycaemia reverses not only unawareness but also improves glucose counterregulation, primarily the responses of adrenaline. CONCLUSIONS In order to best prevent hypoglycaemia, insulin should preferably be given as continuous subcutaneous infusion via a minipump (the 'golden standard') or multiple daily insulin administrations with insulin analogues (basal insulin glargine, meal insulin rapid-acting insulin analogues) in T1 DM.
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Battezzati A, Caumo A, Martino F, Sereni LP, Coppa J, Romito R, Ammatuna M, Regalia E, Matthews DE, Mazzaferro V, Luzi L. Nonhepatic glucose production in humans. Am J Physiol Endocrinol Metab 2004; 286:E129-35. [PMID: 12824085 DOI: 10.1152/ajpendo.00486.2002] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Extrahepatic glucose release was evaluated during the anhepatic phase of liver transplantation in 14 recipients for localized hepatocarcinoma with mild or absent cirrhosis, who received a bolus of [6,6-2H2]glucose and l-[3-13C]alanine or l-[1,2-13C2]glutamine to measure glucose kinetics and to prove whether gluconeogenesis occurred from alanine and glutamine. Twelve were studied again 7 mo thereafter along with seven healthy subjects. At the beginning of the anhepatic phase, plasma glucose was increased and then declined by 15%/h. The right kidney released glucose, with an arteriovenous gradient of -3.7 mg/dl. Arterial and portal glucose concentrations were similar. The glucose clearance was 25% reduced, but glucose uptake was similar to that of the control groups. Glucose production was 9.5 +/- 0.9 micromol.kg-1. min-1, 30% less than in controls. Glucose became enriched with 13C from alanine and especially glutamine, proving the extrahepatic gluconeogenesis. The gluconeogenic precursors alanine, glutamine, lactate, pyruvate, and glycerol, insulin, and the counterregulatory hormones epinephrine, cortisol, growth hormone, and glucagon were increased severalfold. Extrahepatic organs synthesize glucose at a rate similar to that of postabsorptive healthy subjects when hepatic production is absent, and gluconeogenic precursors and counterregulatory hormones are markedly increased. The kidney is the main, but possibly not the unique, source of extrahepatic glucose production.
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Affiliation(s)
- Alberto Battezzati
- International Center for the Assessment of Nutritional Status, DiSTAM, University of Milan, 20133 Milan, Italy.
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Weis BC, Margolis D, Burgess SC, Merritt ME, Wise H, Sherry AD, Malloy CR. Glucose production pathways by2H and13C NMR in patients with HIV-associated lipoatrophy. Magn Reson Med 2004; 51:649-54. [PMID: 15065235 DOI: 10.1002/mrm.20057] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Patients with HIV taking protease inhibitors were selected for the presence (five subjects) or absence (five subjects) of lipoatrophy. Following an overnight fast, subjects were given oral (2)H(2)O in divided doses (5 mL/kg body water), [U-(13)C(3)] propionate (10 mg/kg), and acetaminophen (1000 mg). Glucose (from plasma) or acetaminophen glucuronide (from urine) were converted to monoacetone glucose for (2)H NMR and (13)C NMR analysis. The fraction of plasma glucose derived from gluconeogenesis was not significantly different between groups. However, flux from glycerol into gluconeogenesis relative to glucose production was increased from 0.20 +/- 0.13 among subjects without lipoatrophy to 0.42 +/- 0.12 (P < 0.05) among subjects with lipoatrophy, and the TCA cycle contribution was reduced. Lipoatrophy was associated with an abnormal profile of glucose production as assessed by (13)C and (2)H NMR of plasma and urine.
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Affiliation(s)
- Brian C Weis
- The Mary Nell and Ralph B. Rogers Magnetic Resonance Center, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9085, USA
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Current literature in diabetes. Diabetes Metab Res Rev 2003; 19:421-8. [PMID: 12951651 DOI: 10.1002/dmrr.350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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