Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats
Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats
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DOI：
10.1016/j.npep.2018.02.001
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发表时间：
2018-04-01
期刊：
影响因子：
2.9
通讯作者：
Yada, T.
中科院分区：
文献类型：
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作者：
Ando, A.;Gantulga, D.;Yada, T.
食欲过盛会引发并加速糖尿病，并阻碍血糖的适当饮食控制。然而，高血糖对摄食过多的影响以及2型糖尿病中这两种代谢紊乱常见的可能机制原因尚不明确。本研究观察了Goto-Kakizaki（GK）2型糖尿病大鼠高血糖和高摄食的确切发展过程，并探讨了其主要摄食和代谢中心下丘脑弓状核（ARC）的变化。GK大鼠在3 ~ 4周龄中期表现为高血糖，随后出现摄食过多，ARC中促氧化原阿黑皮素原（POMC）和葡萄糖激酶mRNA表达减少。此外，在4周的GK大鼠ARC POMC神经元对高糖的[Ca 2 +]i反应受损。用抗糖尿病药物米格列醇从3周龄早期到6周龄中期治疗GK大鼠，不仅抑制了高血糖，而且改善了摄食过多，并恢复了ARC中POMC mRNA的表达。这些结果表明，早期高血糖可能导致GK大鼠POMC神经元的葡萄糖敏感性和神经元活动受损，从而导致GK大鼠的摄食过多。早期纠正高血糖可预防和/或改善2型糖尿病患者的摄食过度进展。
Hyperphagia triggers and accelerates diabetes, and prevents proper dietary control of glycemia. Inversely, the impact of hyperglycemia on hyperphagia and possible mechanistic cause common for these two metabolic disorders in type 2 diabetes are less defined. The present study examined the precise developmental process of hyperglycemia and hyperphagia and explored the alterations in the hypothalamic arcuate nucleus (ARC), the primary feeding and metabolic center, in Goto-Kakizaki (GK) rats with type 2 diabetes and nearly normal body weight. At mid 3 to 4 weeks of age, GK rats first exhibited hyperglycemia, and then hyperphagia and reduced mRNA expressions for anorexigenic pro-opiomelanocortin (POMC) and glucokinase in ARC. Furthermore, [Ca2+]i responses to high glucose in ARC POMC neurons were impaired in GK rats at 4 weeks. Treating GK rats from early 3 to mid 6 weeks of age with an anti-diabetic medicine miglitol not only suppressed hyperglycemia but ameliorated hyperphagia and restored POMC mRNA expression in ARC. These results suggest that the early hyperglycemia occurring in weaning period may lead to impaired glucose sensing and neuronal activity of POMC neurons, and thereby induce hyperphagia in GK rats. Correction of hyperglycemia in the early period may prevent and/or ameliorate the progression of hyperphagia in type 2 diabetes.