Metformin causes a futile intestinal-hepatic cycle which increase energy expenditure and slows down development of a type 2 diabetes-like state
| Autor: | Martin Hrabé de Angelis, Philipp Schommers, Dirk Gründemann, Andreas R. Klatt, Jens Alber, Martin Klingenspor, Anja Sterner-Kock, Insa Bultmann-Mellin, Anna Thurau, Rudolf J. Wiesner, Maria Guschlbauer, Jan Rozman |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty lcsh:Internal medicine endocrine system diseases Type 2 diabetes Mitochondrion Biology Diet High-Fat 03 medical and health sciences chemistry.chemical_compound Mice Diabetes mellitus Internal medicine medicine Animals Hypoglycemic Agents Lactic Acid Intestinal Mucosa lcsh:RC31-1245 Molecular Biology Futile cycle Cell Biology medicine.disease Metformin 3. Good health Lactic acid Mitochondria Intestines Mice Inbred C57BL 030104 developmental biology Endocrinology Glucose Splanchnic bed Gluconeogenesis chemistry Diabetes Mellitus Type 2 Liver Original Article medicine.symptom Energy Metabolism Weight gain medicine.drug |
| Zdroj: | Mol. Metab. 6, 737-747 (2017) Molecular Metabolism, Vol 6, Iss 7, Pp 737-747 (2017) Molecular Metabolism |
| Popis: | Objective Metformin, the first line drug for treatment of type 2 diabetes, suppresses hepatic gluconeogenesis and reduces body weight in patients, the latter by an unknown mechanism. Methods Mice on a high fat diet were continuously fed metformin in a therapeutically relevant dose, mimicking a retarded formulation. Results Feeding metformin in pharmacologically relevant doses to mice on a high fat diet normalized HbA1c levels and ameliorated glucose tolerance, as expected, but also considerably slowed down weight gain. This was due to increased energy expenditure, since food intake was unchanged and locomotor activity was even decreased. Metformin caused lactate accumulation in the intestinal wall and in portal venous blood but not in peripheral blood or the liver. Increased conversion of glucose-1-13C to glucose-1,6-13C under metformin strongly supports a futile cycle of lactic acid production in the intestinal wall, and usage of the produced lactate for gluconeogenesis in liver. Conclusions The reported glucose–lactate–glucose cycle is a highly energy consuming process, explaining the beneficial effects of metformin given continuously on the development of a type 2 diabetic-like state in our mice. Highlights • Orally administered metformin slowed down weight gain on a high fat diet. • Metformin treatment led to increased energy expenditure, but decreased locomotion. • Metformin treatment caused a futile, energy consuming glucose–lactate–glucose cycle. |
| Databáze: | OpenAIRE |
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