Abstract
ObjectiveMetformin, 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. MethodsMice on a high fat diet were continuously fed metformin in a therapeutically relevant dose, mimicking a retarded formulation. ResultsFeeding 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. ConclusionsThe 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
Type 2 Diabetes Mellitus (T2DM) is one of the most common disorders in industrialized countries, with rapidly increasing patient numbers in the last decades; its successful treatment in the setting of a metabolic syndrome gets more and more important
Since high blood glucose causes the most severe complications in T2DM, researchers interested in understanding its mode of action mostly concentrated on the suppression of glucose production in the liver, which certainly occurs in vivo in patients upon treatment [35]
In our study metformin slowed down the development of a type 2 diabetes-like phenotype with disruption of glycemic control and dyslipidemia, as expected, it significantly slowed down weight gain
Summary
Type 2 Diabetes Mellitus (T2DM) is one of the most common disorders in industrialized countries, with rapidly increasing patient numbers in the last decades; its successful treatment in the setting of a metabolic syndrome gets more and more important. According to the 2015 guidelines of the ADA (American Diabetes Association) and the EASD (European Diabetes Association), lifestyle modification, i.e. weight control and physical activity, in combination with metformin (1,1-dimethylbiguanide) is the current first-line therapeutic concept for T2DM patients [1,2]. Metformin lowers elevated blood glucose levels, and, with the successful treatment of hyperglycemia, it results in a significantly reduced diabetes-related morbidity [3]. Beyond its glucose lowering effect, metformin-treatment results in significant weight loss (summarized in recent large meta-analyses [4,5]). The mechanisms responsible for lowering body weight are unknown, even though weight loss alone improves glucose homeostasis in T2DM. It was shown in isolated hepatocytes that metformin in high
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