TY  - JOUR
A1  - Wigger, Dominik
A1  - Schumacher, Fabian
A1  - Schneider-Schaulies, Sibylle
A1  - Kleuser, Burkhard
T1  - Sphingosine 1-phosphate metabolism and insulin signaling
JF  - Cellular signalling
N2  - Insulin is the main anabolic hormone secreted by 13-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic 13-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D.
KW  - Insulin resistance
KW  - Type 2 diabetes
KW  - Sphingolipids
KW  - Hepatocytes
KW  - Adipocytes
KW  - Skeletal muscle cells
Y1  - 2021
U6  - https://doi.org/10.1016/j.cellsig.2021.109959
SN  - 0898-6568
SN  - 1873-3913
VL  - 82
PB  - Elsevier Science
CY  - Amsterdam [u.a.]
ER  - 
TY  - JOUR
A1  - Laeger, Thomas
A1  - Castano-Martinez, Teresa
A1  - Werno, Martin W.
A1  - Japtok, Lukasz
A1  - Baumeier, Christian
A1  - Jonas, Wenke
A1  - Kleuser, Burkhard
A1  - Schürmann, Annette
T1  - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.
KW  - Energy expenditure
KW  - FGF21
KW  - Hyperglycaemia
KW  - Insulin resistance
KW  - NZO
KW  - Obesity
KW  - Protein restriction
Y1  - 2018
U6  - https://doi.org/10.1007/s00125-018-4595-1
SN  - 0012-186X
SN  - 1432-0428
VL  - 61
IS  - 6
SP  - 1459
EP  - 1469
PB  - Springer
CY  - New York
ER  -