Impaired insulin secretion and insulin resistance are a characteristic feature of Type II (non-insulin-dependent) diabetes mellitus [1,2]. In spite of extensive studies on the pathophysiology of diabetes, islet pathology and its pathogenesis remain controversial.Classical studies using histochemical methods to identify endocrine cells have reported varying results, including the severe loss of beta cells [3], modest changes with amyloid deposition [4,5] and even no change of islet beta-cell population [6]. Immunohistochemical techniques for the identification of specific populations of islet endocrine cells, showed a nearly 50 % reduction in beta-cell volume density in European Type II non-obese diabetic patients compared with non-diabetic control subjects [7]. Other studies have reported a 24 % reduction of islet beta-cell area density, a 58 % increase in A cell area density and a deposition of amyloid that correlated with the severity of islet pathology [8]. In another study of European Type II diabetic patients, a separate research group has reported Diabetologia (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients Abstract Aims/hypothesis. We examined the pancreatic islet lesions in Japanese patients with Type II diabetes mellitus to determine if the damage was related to oxidative stress. Methods. Morphometric analyses were performed on immunostained sections of the tail portion of the pancreas from 14 diabetic and 15 non-diabetic patients. Amyloid deposition and oxidative stress-induced tissue damage were evaluated by Congo-red staining and immunostaining. Resistance to oxidative stress was assessed from immunostaining results for Cu, Zn-superoxide dismutase (SOD). Expression of (pro)insulin mRNA was assessed by in situ hybridisation. Results. The pancreas from diabetic patients had amyloid deposition in about 15 % of the islets, intensified reactions of 8-OHdG and HNE, as well as reduced expression of SOD. Islet volume density of beta cells and total beta-cell mass in the pancreas from diabetic patients were reduced by 22 % (p < 0.001) and 30 % (p < 0.05). Islet volume density and total mass of (pro)insulin mRNA-positive cells were similarly reduced in diabetic patients by 22 % (p < 0.001) and 39 % (p < 0.05), respectively. Islet volume density of A cells was increased by 20 % (p < 0.001) but total mass did not change. There were no changes in volume densities of islet, D and PP cells. Reduced beta-cell volume density correlated with increased positive staining of 8-OHdG. Conclusion/interpretation. Japanese Type II diabetic patients show a reduction of beta-cell mass and evidence of increased oxidative stress-related tissue damage that is correlated with the extent of the beta-cell lesions. [Diabetologia (2002) 45: 85±96]

The Goto-Kakizaki (GK) rat is a spontaneously diabetic animal model of non-insulin-dependent diabetes mellitus, which is characterized by progressive loss of beta cells in the pancreatic islets with fibrosis. In the present study, we examined the effects of sucrose feeding on the islet pathology in this model. Six-week-old GK rats were fed with 30% sucrose for 6 weeks to induce severe hyperglycemia, and their condition was compared with that of nontreated rats. Age-matched normal Wistar rats were also given sucrose for the same periods and used for comparison. The sucrose-treated GK rats showed elevated blood glucose levels on oral glucose tolerance tests at 60 minutes and 120 minutes, representing 123% and 127% of values in untreated GK rats, respectively. At the end of the study, the mean beta-cell volume density in GK rats was 50% less than that in untreated Wistar rats. Sucrose feeding further reduced the volume densities of beta cells to only 50% of the levels of age-matched GK rats. Apoptotic cells were found in islet beta cells only in GK rats fed sucrose (mean 0.067%). There appeared to be more islets that immunohistochemically stained strongly positive with 8-hydroxy-deoxyguanosine as a marker of oxidative damage of DNA in GK rats fed sucrose compared with those not given sucrose. GK rats not fed sucrose showed significantly lower proliferative activity of beta cells measured by 5-bromo-2'-deoxyuridine uptake and intensified expression of Bcl-2 immunoreactivities at 6 weeks of age compared with those in age-matched Wistar rats. These two indices were reduced in both GK and Wistar rats with increasing age and were not affected by sucrose feeding in either group. The present study thus indicated that sucrose feeding promoted the apoptosis of beta cells in GK rats through increased oxidative stress without altering their proliferative activity.

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