Supplementary Material for: Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans

<b><i>Background:</i></b> Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. <b><i>Methods:</i></b> Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20–30 kg/m²) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. <b><i>Results:</i></b> Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (<i>p</i> = 10^–6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (<i>p</i> &lt; 0.0001, β = 6.00 ± 1.24) and lower in the brain insulin-resistant group (<i>p</i> = 0.005, β = –2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. <b><i>Conclusions:</i></b> In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.

<b><i>研究背景：</i></b> 动物实验与人体初步相关研究数据均表明，大脑内的胰岛素信号作用可能会影响胰腺的胰岛素分泌。介导这一过程的关键脑区为下丘脑，该区域可出现胰岛素抵抗现象。<b><i>研究方法：</i></b> 本研究纳入15名年龄27±3岁的健康青年男性，其体质量指数（Body Mass Index, BMI）分布范围较广（20~30 kg/m²），所有受试者均接受2次高血糖钳夹试验（目标血糖设定为10 mmol/L）。本研究为双盲试验，受试者在随机分配的2个试验日分别经鼻腔喷雾给予160 U胰岛素或安慰剂。另有1个试验日通过功能磁共振成像（functional magnetic resonance imaging, fMRI）检测受试者的下丘脑胰岛素敏感性。<b><i>研究结果：</i></b> 两次试验日的血糖水平无显著差异。在全部受试者中，两种干预方式下的C肽水平无显著差异。但下丘脑胰岛素敏感性、鼻腔喷雾干预类型与时间三者对C肽水平存在显著交互效应（p=10⁻⁶）。因此本研究按照下丘脑胰岛素敏感性的中位数将受试者分为两组。在下丘脑胰岛素应答较强的组别中，经鼻腔给予胰岛素后的C肽浓度显著高于安慰剂喷雾组（p<0.0001，β=6.00±1.24）；而在脑胰岛素抵抗组别中，该结果则相反（p=0.005，β=-2.68±0.95）。鼻腔喷雾干预未改变生长抑素与胰高血糖素的代谢动力学特征。<b><i>研究结论：</i></b> 在下丘脑胰岛素敏感性较高的受试者中，大脑内的胰岛素信号作用可增强胰腺β细胞的第二时相胰岛素分泌。该效应可通过门静脉胰岛素抑制肝脏葡萄糖生成，从而参与餐后晚期血糖调控。