Diabetes and Obesity Center of Excellence, University of Washington, 850 Republican Street, Seattle, WA 98109-8055, USA.
Diabetologia. 2013 Apr;56(4):803-13. doi: 10.1007/s00125-012-2808-6. Epub 2013 Feb 13.
AIMS/HYPOTHESIS: Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca(2+)) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca(2+)/metabolic coupling process [CMCP]) by Ca(2+) mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes.
Glucose- and Ca(2+)-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia.
Glucose stimulation of cytosolic Ca(2+) and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca(2+) channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia.
CONCLUSIONS/INTERPRETATION: These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca(2+) influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.
目的/假设：先前的孤立胰岛研究表明，钙（Ca(2+)）内流与耗氧率（OCR）之间存在紧密偶联，这与胰岛素分泌率（ISR）相关。为了解释这些观察结果，我们提出了一种机制，即 Ca(2+)激活的高能过程（Ca(2+)/代谢偶联过程[CMCP]）介导 ISR 的刺激。本研究的目的是检验 CMCP 的损伤是否在 2 型糖尿病的发生发展中起作用。
比较了 2 型糖尿病大鼠模型（加利福尼亚大学戴维斯分校 2 型糖尿病[UCD-T2DM]大鼠）中血糖和 Ca(2+)介导的 OCR 和 ISR 变化与高血糖进展过程中血浆胰岛素浓度变化的时间过程，比较了分离的胰岛中葡萄糖和 Ca(2+)介导的 OCR 和 ISR 的变化。从 UCD-T2DM 大鼠高血糖发作前、1 周和 3 周时分离胰岛。
高血糖发作前和 1 周时收获的胰岛，葡萄糖刺激细胞溶质 Ca(2+)和 OCR 的作用相似。相比之下，Ca(2+)通道阻断后胰岛 OCR 和 ISR 的递减丧失与高血糖发作 3 周时大鼠空腹血浆胰岛素浓度的降低一致。
结论/解释：这些结果表明，UCD-T2DM 大鼠糖尿病胰岛的表型损伤发生在 Ca(2+)内流之后，涉及 CMCP 的不受调节的刺激。这些胰岛中慢性高血糖持续诱导的 CMCP 水平升高可能介导胰岛功能丧失。
