Paradoxical Reduction in Pancreatic Glucagon with Normalization of Somatostatin and Decrease in Insulin in Normoglycemic Alloxan-Diabetic Dogs: A Putative Mechanism of Glucagon Irresponsiveness to Hypoglycemia*

Abstract

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)

Effect Of Walnut Leaf, Coriander And Pomegranate On Blood Glucose And Histopathology Of Pancreas Of Alloxan Induced Diabetic Rats

“…Decrease number of islets in pancreatic tissue observed in diabetic rats could be due to conversion of large islets to small. Reduction of numbers and volume density of islets by 70% was also reported in diabetic dogs (Sudha Rastogi et al, 1990). The histopathological study of diabetic treated groups indicates; increase volume density of islets, percent of β cells and size of islet in the group received walnut leaf, which may be a sign of regeneration.…”

Anti-Diabetic Activity of a Fraction from Cissus verticillata and Tyramine, its Main Bioactive Constituent, in Alloxan-Induced Diabetic Rats

“…Immunohistochemical studies demonstrated that the pancreas from alloxan-induced diabetic animals showed a 70% reduction of beta cell areas. At the same time, there was an increase in the areas occupied by delta cells and no alteration in glucagon-producing cells [29] . Another study [30] showed decreases in the number of insulin positive cells and increases in the number of cells expressing somatostatin in rats submitted to alloxan-induced diabetes.…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…However, the beneficial effect of SST on glucose homeostasis does not appear to extend across species (or experimental models). Specifically, continuous treatment of severely diabetic Balb/C mice with octreotide did not influence blood glucose or insulin levels, however it reduced GH hypersecretion and prevented the proliferation of kidney glomeruli (Rastogi et al, 1990). Octreotide did not reduce hyperglycemia in alloxan-diabetic male Wistar rats, however a reduction of kidney weight without normalization of the glomerular filtration rate was reported (Usenmez et al, 2000).…”

“…Administration of insulin also reduced the elevated levels of pancreatic SST and glucagon content in Sprague-Dawley (Papachristou et al, 1989) and Wistar (Kadowaki et al, 1980) rats with streptozotocininduced diabetes and in dogs with alloxan-induced diabetes (Rastogi et al, 1990). It is important to note that at least in animal models with chemically-induced type 1 diabetes, pancreatic D-cells show reduced or no response to increased glucose, which may explain the inadequate increase of SST secretion following food ingestion (Grill and Efendic 1983;Hermansen 1981).…”