Thondam Sravan K, Daousi Christina, Wilding John P H, Holst Jens J, Ameen Gulizar I, Yang Chenjing, Whitmore Catherine, Mora Silvia, Cuthbertson Daniel J
Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom
Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom.
Am J Physiol Endocrinol Metab. 2017 Mar 1;312(3):E224-E233. doi: 10.1152/ajpendo.00347.2016. Epub 2017 Jan 10.
Glucose-dependent insulinotropic polypeptide (GIP) beyond its insulinotropic effects may regulate postprandial lipid metabolism. Whereas the insulinotropic action of GIP is known to be impaired in type 2 diabetes mellitus (T2DM), its adipogenic effect is unknown. We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance. Twenty-three subjects categorized into four groups, normoglycemic lean ( = 6), normoglycemic obese ( = 6), obese with impaired glucose regulation (IGR; = 6), and obese T2DM ( = 5), participated in a double-blind, randomized, crossover study involving a hyperglycemic clamp with a 240-min GIP infusion (2 pmol·kg·min) or normal saline. Insulin, NEFA, SAT-TAG content, and gene expression of key lipogenic enzymes were determined before and immediately after GIP/saline infusions. GIP lowered NEFA concentrations in the obese T2DM group despite diminished insulinotropic activity (mean NEFA AUC ± SE, 41,992 ± 9,843 µmol·l·min vs. 71,468 ± 13,605 with placebo, = 0.039, 95% CI: 0.31-0.95). Additionally, GIP increased SAT-TAG in obese T2DM (1.78 ± 0.4 vs 0.86 ± 0.1-fold with placebo, = 0.043, 95% CI: 0.1-1.8). Such effect with GIP was not observed in other three groups despite greater insulinotropic activity. Reduction in NEFA concentration with GIP correlated with adipose tissue insulin resistance for all subjects (Pearson, = 0.56, = 0.005). There were no significant gene expression changes in key SAT lipid metabolism enzymes. In conclusion, GIP appears to promote fat accretion and thus may exacerbate obesity and insulin resistance in T2DM.
葡萄糖依赖性促胰岛素多肽（GIP）除了具有促胰岛素作用外，还可能调节餐后脂质代谢。虽然已知GIP的促胰岛素作用在2型糖尿病（T2DM）中受损，但其促脂肪生成作用尚不清楚。我们假设GIP在人体皮下脂肪组织（SAT）中具有合成代谢作用，通过非酯化脂肪酸（NEFA）的再酯化促进三酰甘油（TAG）沉积，并且这种作用可能因肥胖状态或糖耐量不同而有所差异。23名受试者被分为四组：血糖正常的瘦人（n = 6）、血糖正常的肥胖者（n = 6）、葡萄糖调节受损的肥胖者（IGR；n = 6）和肥胖的T2DM患者（n = 5），参与了一项双盲、随机、交叉研究，该研究包括一次高血糖钳夹试验，期间输注GIP（2 pmol·kg·min）或生理盐水240分钟。在输注GIP/生理盐水之前和之后立即测定胰岛素、NEFA、SAT-TAG含量以及关键脂肪生成酶的基因表达。尽管GIP的促胰岛素活性降低，但它降低了肥胖T2DM组中的NEFA浓度（平均NEFA AUC±SE，41,992±9,843 μmol·l·min，而安慰剂组为71,468±13,605，P = 0.039，95%CI：0.31 - 0.95）。此外，GIP增加了肥胖T2DM患者的SAT-TAG含量（1.78±0.4倍，而安慰剂组为0.86±0.1倍，P = 0.043，95%CI：0.1 - 1.8）。尽管其他三组的促胰岛素活性更高，但未观察到GIP有这种作用。对于所有受试者，GIP使NEFA浓度降低与脂肪组织胰岛素抵抗相关（Pearson相关系数，r = 0.56，P = 0.005）。SAT关键脂质代谢酶的基因表达没有显著变化。总之，GIP似乎促进脂肪堆积，因此可能会加重T2DM患者的肥胖和胰岛素抵抗。
