Gault V A, McClean P L, Cassidy R S, Irwin N, Flatt P R
School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, Northern Ireland, UK.
Diabetologia. 2007 Aug;50(8):1752-62. doi: 10.1007/s00125-007-0710-4. Epub 2007 Jun 9.
AIMS/HYPOTHESIS: Gastric inhibitory polypeptide (GIP) receptor antagonism with (Pro(3))GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure/function in ob/ob mice. This study examined the ability of (Pro(3))GIP to counter the development of obesity, insulin resistance and diabetes in mice fed high-fat and cafeteria diets.
Young Swiss TO mice on standard chow or high-fat, cafeteria or high-carbohydrate diets received daily injections of either saline or (Pro(3))GIP (25 nmol kg(-1)day(-1)) over 16 weeks. Food intake, body weight, and circulating glucose and insulin were measured frequently. At 16 weeks, glucose tolerance, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Adipose tissue, liver and muscle were excised and weighed, and their histology and triacylglycerol content were further examined.
(Pro(3))GIP significantly reduced body weight, enhanced locomotor activity, and improved HbA(1c), glucose tolerance, beta cell responsiveness and insulin sensitivity in mice fed high-fat and cafeteria diets (p < 0.05 to p < 0.01). Similarly, (Pro(3))GIP significantly reduced plasma corticosterone and triacylglycerols (p < 0.05 to p < 0.001), while glucagon, resistin and adiponectin were unchanged. (Pro(3))GIP decreased adipose tissue mass (p < 0.01) and the triacylglycerol content of liver, muscle and adipose tissue (p < 0.01 to p < 0.001). Adipocyte size and liver morphology were partially normalised. (Pro(3))GIP did not significantly affect any of these parameters in mice fed a high-carbohydrate diet.
CONCLUSIONS/INTERPRETATION: (Pro(3))GIP protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets. This highlights chemical GIP receptor antagonism as a new possibility for the treatment of obesity and associated metabolic disturbances.
目的/假设：用（脯氨酸³）胃抑肽（GIP）拮抗GIP受体可改善ob/ob小鼠的糖耐量，减轻胰岛素抵抗以及胰岛结构/功能异常。本研究检测了（脯氨酸³）GIP对抗高脂饮食和自助餐饮食小鼠肥胖、胰岛素抵抗及糖尿病发生发展的能力。
将处于标准饲料、高脂、自助餐或高碳水化合物饮食条件下的年轻瑞士TO小鼠，在16周内每日注射生理盐水或（脯氨酸³）GIP（25 nmol·kg⁻¹·天⁻¹）。频繁测量食物摄入量、体重以及循环血糖和胰岛素水平。在第16周时，评估糖耐量、胰岛素敏感性、糖化血红蛋白（HbA₁c）、循环激素和血浆脂质。切除脂肪组织、肝脏和肌肉并称重，进一步检查其组织学和三酰甘油含量。
（脯氨酸³）GIP显著降低了高脂饮食和自助餐饮食小鼠的体重，增强了运动活性，并改善了HbA₁c、糖耐量、β细胞反应性和胰岛素敏感性（p < 0.05至p < 0.01）。同样，（脯氨酸³）GIP显著降低了血浆皮质酮和三酰甘油水平（p < 0.05至p < 0.001），而胰高血糖素、抵抗素和脂联素水平未改变。（脯氨酸³）GIP减少了脂肪组织质量（p < 0.01）以及肝脏、肌肉和脂肪组织的三酰甘油含量（p < 0.01至p < 0.001）。脂肪细胞大小和肝脏形态部分恢复正常。（脯氨酸³）GIP对高碳水化合物饮食小鼠的这些参数均无显著影响。
结论/解读：（脯氨酸³）GIP可预防高脂饮食和自助餐饮食小鼠的肥胖、胰岛素抵抗、糖耐量异常及相关紊乱。这凸显了化学性GIP受体拮抗作用作为治疗肥胖及相关代谢紊乱的一种新可能性。
