Rastogi K S, Lickley L, Jokay M, Efendic S, Vranic M
Department of Physiology, University of Toronto, Ontario, Canada.
Endocrinology. 1990 Feb;126(2):1096-104. doi: 10.1210/endo-126-2-1096.
In alloxan-diabetic (A-D) dogs, plasma glucagon does not increase when glycemia is decreased by insulin. Therefore, as in insulin-dependent diabetes mellitus (IDDM), increased glucose utilization is not matched by an increase in hepatic production. To explore further the abnormal effects of insulin on regulation of pancreatic glucagon, we studied content and morphology of pancreatic hormones in six normal (N) dogs, five hyperglycemic A-D (HD) dogs, and in four A-D dogs where normoglycemia was maintained by insulin (ND). Morphometric measurement of islets and of immunocytochemically localized A cells (glucagon) were performed by an image analysis system. In normal pancreas, islets of tail and body were bigger in size (tail = 4850 +/- 376 microns 2, body = 3256 +/- 198 microns 2), than the head (2009 +/- 207 microns 2). Glucagon content was 331 +/- 50 micrograms with a mean concentration of 8.5 +/- 0.9 micrograms/g in N dogs, and did not change in HD dogs (422 +/- 34 micrograms, 9.3 +/- 0.4 micrograms/g). With normoglycemia, glucagon content decreased by 5-fold (p less than 0.001). Morphometry indicated that, although A cell area per islet increased (2.7-fold), islet number decreased (70%), explaining the unchanged glucagon content in HD dogs. This decrease in islet number can also justify the dramatic glucagon decrease in ND dogs. Despite the 70% decrease in islet numbers in HD dogs, pancreatic somatostatin increased 3-fold (9.93 +/- 3.3 to 30.6 +/- 7.2 micrograms), indicating that its islet content was augmented 10-fold. Somatostatin content returned to normal with normoglycemia. Pancreatic insulin content in HD dogs was negligible (55 +/- 23 micrograms) when compared with that in N dogs (5500 micrograms) and it did not increase with normoglycemia. The distinct but markedly diminished insulin and proinsulin peaks in HD dogs nearly disappeared in ND dogs. Thus, in alloxan-diabetic HD dogs, 70% of islets are destroyed. A marked increase in glucagon in residual islets can explain the unchanged islet size despite the absence of B cells; however, the percent increase of somatostatin is larger than that of glucagon. Normoglycemia 1) normalizes somatostatin content, 2) further diminishes insulin and proinsulin synthesis presumably due to lack of hyperglycemic stimulus, and 3) paradoxically decreases pancreatic glucagon content 5-fold below its normal level. We hypothesize that with normalization of plasma insulin, glucagon content in each islet normalizes, but because of destruction of most islets, pancreatic glucagon content becomes extremely low.(ABSTRACT TRUNCATED AT 400 WORDS)
在四氧嘧啶糖尿病（A-D）犬中，当通过胰岛素降低血糖时，血浆胰高血糖素不会增加。因此，与胰岛素依赖型糖尿病（IDDM）一样，葡萄糖利用增加但肝生成并未相应增加。为了进一步探究胰岛素对胰腺胰高血糖素调节的异常作用，我们研究了6只正常（N）犬、5只高血糖A-D（HD）犬以及4只通过胰岛素维持血糖正常的A-D犬（ND）的胰腺激素含量和形态。通过图像分析系统对胰岛以及免疫细胞化学定位的A细胞（胰高血糖素）进行形态计量学测量。在正常胰腺中，尾部和体部的胰岛尺寸较大（尾部=4850±376平方微米，体部=3256±198平方微米），大于头部（2009±207平方微米）。N犬的胰高血糖素含量为331±50微克，平均浓度为8.5±0.9微克/克，HD犬的胰高血糖素含量未发生变化（422±34微克，9.3±0.4微克/克）。血糖正常时，胰高血糖素含量下降了5倍（p<0.001）。形态计量学表明，尽管每个胰岛的A细胞面积增加了（2.7倍），但胰岛数量减少了（70%），这解释了HD犬胰高血糖素含量未变的原因。胰岛数量的减少也可以解释ND犬胰高血糖素的显著下降。尽管HD犬的胰岛数量减少了70%，但胰腺生长抑素增加了3倍（从9.93±3.3微克增加到30.6±7.2微克），表明其胰岛含量增加了10倍。血糖正常时，生长抑素含量恢复正常。与N犬（5500微克）相比，HD犬的胰腺胰岛素含量可忽略不计（55±23微克），且血糖正常时并未增加。HD犬中明显但明显减弱的胰岛素和胰岛素原峰在ND犬中几乎消失。因此，在四氧嘧啶糖尿病HD犬中，70%的胰岛被破坏。残余胰岛中胰高血糖素的显著增加可以解释尽管没有B细胞但胰岛大小未变的原因；然而，生长抑素的增加百分比大于胰高血糖素。血糖正常1）使生长抑素含量正常化，2）可能由于缺乏高血糖刺激而进一步减少胰岛素和胰岛素原的合成，3）反常地使胰腺胰高血糖素含量降至正常水平以下5倍。我们假设，随着血浆胰岛素正常化，每个胰岛中的胰高血糖素含量正常化，但由于大多数胰岛被破坏，胰腺胰高血糖素含量变得极低。（摘要截短为400字）
