Rickels Michael R, Fuller Carissa, Dalton-Bakes Cornelia, Markmann Eileen, Palanjian Maral, Cullison Kevin, Tiao Janice, Kapoor Shiv, Liu Chengyang, Naji Ali, Teff Karen L
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Diabetes. 2015 May;64(5):1713-8. doi: 10.2337/db14-1620. Epub 2014 Dec 18.
Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ∼30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-(2)H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.
长期患1型糖尿病（T1D）的患者可能会出现葡萄糖反向调节功能缺陷和低血糖症状识别受损，这大大增加了他们发生严重低血糖的风险。本研究的目的是确定肝内胰岛移植是否能改善严重低血糖的T1D患者对低血糖的内源性葡萄糖生成（EGP）。我们对12名病程约30年的受试者进行了纵向研究，在肝内胰岛移植前和移植后6个月，使用逐步高胰岛素-低血糖钳夹法和配对高胰岛素-正常血糖钳夹法，并输注6,6-(2)H2-葡萄糖，同时将结果与非糖尿病对照组（8名）进行比较。胰岛移植后，糖化血红蛋白（HbA1c）恢复正常，连续血糖监测显示低血糖（<70mg/dL）持续时间几乎消失。对胰岛素诱导的低血糖反应中，移植前不存在的C肽得到适当抑制，移植后胰高血糖素分泌恢复，肾上腺素分泌改善。与这些激素变化相对应，移植前不存在的对胰岛素诱导低血糖的EGP反应在移植后恢复正常，自主神经症状也有类似效果。由于最终需要增加EGP的能力来避免低血糖的发生，这些结果提供了证据，证明肝内胰岛移植可以恢复长期T1D患者的葡萄糖反向调节功能，并支持将其作为治疗严重低血糖且无低血糖意识患者的治疗方法。
