Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin.
Bile acid-binding resins, such as cholestyramine and colestimide, have been clinically used as cholesterol-lowering agents. These agents bind bile acids in the intestine and reduce enterohepatic circulation of bile acids, leading to accelerated conversion of cholesterol to bile acids. A significant improvement in glycemic control was reported in patients with type 2 diabetes whose hyperlipidemia was treated with bile acid-binding resins. To confirm the effect of such drugs on glucose metabolism and to investigate the underlying mechanisms, an animal model of type 2 diabetes was given a high-fat diet with and without colestimide. Diet-induced obesity and fatty liver were markedly ameliorated by colestimide without decreasing the food intake. Hyperglycemia, insulin resistance, and insulin response to glucose, as well as dyslipidemia, were markedly and significantly ameliorated by the treatment. Gene expression of the liver indicated reduced expression of small heterodimer partner, a pleiotropic regulator of diverse metabolic pathways, as well as genes for both fatty acid synthesis and gluconeogenesis, by treatment with colestimide. This study provides a molecular basis for a link between bile acids and glucose metabolism and suggests the bile acid metabolism pathway as a novel therapeutic target for the treatment of obesity, insulin resistance, and type 2 diabetes.
Kobayashi
Misato
M
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Ikegami
Hiroshi
H
Fujisawa
Tomomi
T
Nojima
Koji
K
Kawabata
Yumiko
Y
Noso
Shinsuke
S
Babaya
Naru
N
Itoi-Babaya
Michiko
M
Yamaji
Kaori
K
Hiromine
Yoshihisa
Y
Shibata
Masao
M
Ogihara
Toshio
T
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000627:therapeutic use*; D002792:Cholestyramine Resin / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D004811:Epichlorohydrin / Q000627:therapeutic use*; D005215:Fasting; D005234:Fatty Liver / Q000517:prevention & control; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D007093:Imidazoles / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D051379:Mice; D009765:Obesity / Q000517:prevention & control*; D012117:Resins, Synthetic / Q000627:therapeutic use*; D015430:Weight Gain
D000924:Anticholesteremic Agents; D001786:Blood Glucose; D002352:Carrier Proteins; D007093:Imidazoles; D008562:Membrane Glycoproteins; D012117:Resins, Synthetic; C037643:bile acid binding proteins; C417427:colestimide; D004811:Epichlorohydrin; D002792:Cholestyramine Resin