Akheruzzaman Md, Hegde Vijay, Siddik Md Abu Bakkar, Feizy Zahra, Shin Andrew C, Dhurandhar Nikhil V
Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA.
Int J Obes (Lond). 2022 May;46(5):918-925. doi: 10.1038/s41366-021-01062-3. Epub 2022 Jan 12.
Obesity is often associated with hyperinsulinemia due to insulin resistance. In mice models of hyperinsulinemia, adenovirus-derived E4orf1 protein promotes glucose disposal via insulin-independent pathway, and reduces insulin response to glucose load, described as its "Insulin Sparing Action". This is likely because less insulin is needed for disposing glucose in presence of E4orf1, however, there are other potential possibilities. This study determined if E4orf1 reduces insulin response to glucose load because it a) suppresses the ability of pancreatic β-cells to secret insulin, or b) upregulates glucagon production by the pancreas.
C57BL/6J wild type (control) and transgenic C57BL/6J (E4orf1) mice that express E4orf1 protein in adipose tissue upon doxycycline feeding, were used. Post-doxycycline feeding, insulin and glucagon secretion in response to glibenclamide or phenylephrine were compared between the two groups. The pancreases were examined for histological changes.
In response to glibenclamide, E4orf1 mice secreted more insulin and exhibited lower blood glucose compared to control (47.4 ± 4.4 vs 27.4 ± 3.7 mg/dl, p < 0.003), but showed no difference in glucagon secretion. Post-phenylephrine injection, no differences were observed between the two groups for glucagon or insulin, except E4orf1 mice had a lower blood glucose rise after 10-min of injection compared to the control (39.7 ± 4.7 vs. 58.3 ± 7.5 mg/dl, p < 0.05). E4orf1 mice had significantly larger pancreatic islets and higher number of islets per mm tissue area. Neither the size nor the number of islets met the criteria of hypertrophy or hyperplasia.
CONCLUSIONS/INTERPRETATION: E4orf1 retains and may enhance the ability of the pancreases to secret insulin in response to insulin secretagogue. Glucagon does not seem to play a role in the Insulin Sparing Action of E4orf1. Overall, the histology studies support better pancreatic islet health in presence of E4orf1, compared to that in control mice. The "insulin-independent" role of E4orf1 has potential therapeutic implications in addressing hyperinsulinemia in obesity.
肥胖常因胰岛素抵抗而与高胰岛素血症相关。在高胰岛素血症小鼠模型中，腺病毒衍生的E4orf1蛋白通过非胰岛素依赖途径促进葡萄糖代谢，并降低胰岛素对葡萄糖负荷的反应，这被称为其“胰岛素节省作用”。这可能是因为在存在E4orf1的情况下，处理葡萄糖所需的胰岛素较少，然而，还有其他潜在的可能性。本研究确定E4orf1是否通过以下原因降低胰岛素对葡萄糖负荷的反应：a）抑制胰腺β细胞分泌胰岛素的能力，或b）上调胰腺胰高血糖素的产生。
使用C57BL/6J野生型（对照）小鼠和转基因C57BL/6J（E4orf1）小鼠，后者在给予强力霉素后在脂肪组织中表达E4orf1蛋白。在给予强力霉素后，比较两组小鼠对格列本脲或去氧肾上腺素的胰岛素和胰高血糖素分泌情况。检查胰腺的组织学变化。
对格列本脲的反应中，与对照组相比，E4orf1小鼠分泌更多胰岛素且血糖更低（47.4±4.4对27.4±3.7mg/dl，p<0.003），但胰高血糖素分泌无差异。注射去氧肾上腺素后，两组的胰高血糖素或胰岛素无差异，只是与对照组相比，E4orf1小鼠在注射10分钟后的血糖升高较低（39.7±4.7对58.3±7.5mg/dl，p<0.05）。E4orf1小鼠的胰岛明显更大，每平方毫米组织面积的胰岛数量更多。胰岛的大小和数量均未达到肥大或增生的标准。
结论/解读：E4orf1保留并可能增强胰腺对胰岛素促分泌剂分泌胰岛素的能力。胰高血糖素似乎在E4orf1的胰岛素节省作用中不起作用。总体而言，组织学研究表明表明，与对照小鼠相比，存在E4orf1时胰腺胰岛健康状况更好。E4orf1的“非胰岛素依赖”作用在解决肥胖症中的高胰岛素血症方面具有潜在的治疗意义。
