Histogenesis of the endocrine pancreas in newborn rats after destruction by streptozotocin. An immunocytochemical study

Endocrine pancreatic tissue in newborn rats was studied 1 to 17 days after the destruction of B cells by an injection of streptozotocin. Regeneration of insulin cells was observed four days after streptozotocin injection, which was followed by recovery from the diabetic state and an increased pancreatic insulin content. Regeneration was characterised by new islets budding from small ducts. The pancreas of newborn rats, like the embryonic pancreas, thus retains a capacity to form endocrine tissue, although some degree of reduplication of preexisting B cells may also be involved in the process. Newborn rats injected with streptozotocin constitute an interesting model for the study of factors which may act on the regenerative potential of pancreatic endocrine tissue in the diabetic state.     

Localization of thyrotropin-releasing hormone-and insulin-immunoreactivity in the pancreas of neonatal rats after injection of streptozotocin at birth

Summary Streptozotocin treatment at birth induces, in the pancreas of rats, first depletion of insulin and thyrotropin-releasing hormone and then early regeneration of cells and insulin, but not TRH. This study was undertaken to investigate whether the reduction in pancreatic TRH content can be associated with changes in the intensity and the distribution of TRH-immunoreactivity, and to follow the pattern of regeneration of cells through insulin- and TRH-immunoreactivity.In control animals, strong TRH-immunoreactivity was seen in insulin-containing cells on days 1–4 after birth. At day 7, the TRH-immunoreactivity was already decreased. In contrast, insulin-immunoreactivity was present throughout the neonatal period. A sparse population of cells near ducts also contained both TRH- and insulin-immunoreactivity at 1–2 days age.In streptozotocin-treated animals, TRH-immunoreactivity is found only in a few scattered insulin-containing cells in altered islets on days 1–4. Near the ducts, there were new insulin-containing cells which did not contain TRH. From day 7 regeneration of endocrine cells was characterized by new, typical islets, but these contained insulin-, but not TRH-immunoreactivity. These findings suggest a differential control of the biosynthesis of insulin and TRH within the pancreas.     

Development of endocrine pancreatic islets in embryos of the grass snake Natrix natrix (Lepidosauria,Serpentes)

Differentiation of the pancreatic islets in grass snake Natrix natrix embryos, was analyzed using light, transmission electron microscopy, and immuno-gold labeling. The study focuses on the origin of islets, mode of islet formation, and cell arrangement within islets. Two waves of pancreatic islet formation in grass snake embryos were described. The first wave begins just after egg laying when precursors of endocrine cells located within large cell agglomerates in the dorsal pancreatic bud differentiate. The large cell agglomerates were divided by mesenchymal cells thus forming the first islets. This mode of islet formation is described as fission. During the second wave of pancreatic islet formation which is related to the formation of the duct mantle, we observed four phases of islet formation: (a) differentiation of individual endocrine cells from the progenitor layer of duct walls (budding) and their incomplete delamination; (b) formation of two types of small groups of endocrine cells (A/D and B) in the wall of pancreatic ducts; (c) joining groups of cells emerging from neighboring ducts (fusion) and rearrangement of cells within islets; (d) differentiated pancreatic islets with characteristic arrangement of endocrine cells. Mature pancreatic islets of the grass snake contained mainly A endocrine cells. Single B and D or PP–cells were present at the periphery of the islets. This arrangement of endocrine cells within pancreatic islets of the grass snake differs from that reported from most others vertebrate species. Endocrine cells in the pancreas of grass snake embryos were also present in the walls of intralobular and intercalated ducts. At hatching, some endocrine cells were in contact with the lumen of the pancreatic ducts.     

Immunohistochemical localization of gamma-aminobutyric acid (GABA) in the rat pancreas

Summary The localization of gamma-aminobutyric acid (GABA) in rat pancreas was investigated using antiserum raised against GABA conjugated to bovine serum albumin with glutaraldehyde. Immunoreactive cells were only found in the center of the pancreatic islets, and these cells were surrounded by nonimmunoreactive cells. When two serial sections of rat pancreas were consecutively stained with GABA antiserum and with antibodies against insulin, both antisera stained the same population of endocrine cells within the islets. In rats pretreated with streptozotocin, a B-cell toxin, we observed a marked decrease in the number of cells exhibiting GABA-like immunoreactivity. These observations indicate that GABA is present in the B cells of rat pancreatic islets.This work was supported by the grants from the Ministry of Education, Science, and Culture, Japan     

Morphological changes in the endocrine pancreas of mice after treatment with streptozotocin combined with cyclophosphamide and neurotropin.

The effect of neurotropin (NSP) in combination with streptozotocin (STZ) and cyclophosphamide (CY) on blood glucose and pancreatic histopathology on day 7 and day 14 after the initiation of the treatment was studied in C57Bl/6 male mice. STZ (40 mg/kg) and NSP (1 mg/kg) were applied intraperitoneally on five consecutive days and CY (150 mg/kg)--twice on day 1 and day 3. In single B cells dilatation of the endoplasmic reticulum was found. On day 7 in proximity to some endocrine cells in the mice treated with STZ, STZ + CY + NSP and STZ + CY macrophages were observed. On day 14 lymphocytic infiltration of the islets was demonstrated only in the groups of mice injected with STZ, STZ + CY while in the group treated with the combination STZ + CY + NSP no infiltration was seen. All experimental groups showed no biochemical evidence for hyperglycemia probably due to the mild destruction of a small number of B cells. The results indicate that NSP might possess a restorative action on insulitis induced by multiple low dose streptozotocin administration in mice.     

大鼠生后发育期间胰腺IAPP免疫组织化学定位研究

本文应用免疫组织化学ＰＡＰ法对正常雄性Ｗｉｓｔａｒ大鼠生后发育期间胰腺ＩＡＰＰ－ＩＲ阳性细胞进行了定位研究。结果表明;生后１天的大鼠胰岛内即已存在ＩＡＰＰ－ＩＲ阳性细胞,双染法证实ＩＡＰＰ与胰岛素共存于胰岛Ｂ细胞的胞质内。ＩＡＰＰ细胞免疫反应强度随生后发育而变化,２８天以后趋于稳定。胰腺外分泌部也有散在的ＩＡＰＰ－ＩＲ细胞。本文初步探讨了上述结果的生物学意义。     

链脲佐菌素诱导糖尿病大鼠胰腺外分泌部A、B细胞密度的变化

本文应用A蛋白金银—过氧化物酶抗过氧化物酶(PAGS-PAP)双重染色法,观察了链脲佐菌素(streptozotocin,STZ)诱导的糖尿病大鼠胰腺外分泌部含高血糖素的单个A细胞(单A细胞)及合胰岛素的单个B细胞(单B细胞)密度的变化.在一次大剂量腹腔注射STZ后第5天和第10天,大鼠胰腺外分泌部单A细胞密度较对照组大鼠增加,而单B细胞密度在注射STZ后第5天较对照组大鼠减少,但在第15天与对照组大鼠接近.在第15天,一些单B细胞分布在靠近胰岛的腺泡中,岛周腺泡含单B细胞的胰岛百分率明显高于对照组.由于胰腺外分泌部的单A、单B细胞在分布特征上与中间细胞相似,在糖尿病时其数量变化也与中间细胞一致,因此,本研究所观察到的单A、单B细胞与前人报道的中间细胞有密切关系.上述单A、单B细胞密度的变化提示,在STZ诱导的糖尿病大鼠,胰腺中的B细胞被STZ破坏后,其外分泌部可能有某些细胞通过中间细胞向单A、单B细胞发生了转化或者单A、单B细胞即此转化过程中的中间细胞.     

Antidiabetic effect through islet cell protection in streptozotocin diabetes: A preliminary assessment of two thiazolidin-4-ones in Swiss albino mice

This study was undertaken on the basis of several reports in the literature that pancreatic beta cells are capable of replication/regeneration and also being afforded protection against damage induced by streptozotocin. Nicotinamide was reported to give protection against streptozotocin-induced damage in rats. In the present study, two thiazolidine-4-ones with nicotinamide substitution were administered to Swiss albino mice with streptozotocin diabetes for 15 days. Concurrently, one group received nicotinic acid. Both the test compounds reversed the hyperglycaemia diabetic mice. Damage to pancreatic islets was also reduced in these groups compared to diabetic control and nicotinic acid treated groups. Since these compounds have been earlier found have antioxidant activity, one of the possible mechanisms of action could be by reducing oxidative stress in pancreas. Further, possibly by releasing nicotinamide in vivo, the molecules could have contributed to the NAD pool in pancreas and afforded protection. It is concluded that the test compounds have potential to be developed for multiple beneficial action in conditions like metabolic syndrome.     

Immunohistochemical localization of gamma-aminobutyric acid (GABA) in the rat pancreas

The localization of gamma-aminobutyric acid (GABA) in rat pancreas was investigated using antiserum raised against GABA conjugated to bovine serum albumin with glutaraldehyde. Immunoreactive cells were only found in the center of the pancreatic islets, and these cells were surrounded by nonimmunoreactive cells. When two serial sections of rat pancreas were consecutively stained with GABA antiserum and with antibodies against insulin, both antisera stained the same population of endocrine cells within the islets. In rats pretreated with streptozotocin, a B-cell toxin, we observed a marked decrease in the number of cells exhibiting GABA-like immunoreactivity. These observations indicate that GABA is present in the B cells of rat pancreatic islets.     

Insulin secretion in monosodium glutamate (MSG) obese rats submitted to aerobic exercise training

The present study was designed to evaluate the effects of aerobic exercise training on glucose tolerance and insulin secretion of obese male Wistar rats (monosodium glutamate [MSG] administration, 4 mg/g-body weight, each other day, from birth to the 14th day). Fourteen weeks after the drug administration, the rats were separated into two groups: MSG-S (sedentary) and MSG-T (T = swimming, 1 h/day, 5 days/week, with an overload of 5% body weight for 10 weeks). Rats of the same age and strain injected with saline were used as control (C) and subdivided into two groups: C-S and C-T. Insulin and glucose responses during an oral glucose tolerance test (GTT) were evaluated by the estimation of the total areas under serum insulin (AI) and glucose (AG) curves. Glucose-induced insulin secretion by isolated pancreatic islets was also evaluated. MSG-S rats showed higher AI than C-rats while MSG-T rats presented lower AI than MSG-S rats. No differences in AG were observed among the 4 groups. Pancreatic islets from MSG-rats showed higher insulin secretion in response to low (2.8) and moderate (8.3 mM) concentrations of glucose than those from their control counterparts and no differences were observed between MSG-S and MSG-T rats. These results provide evidences that the hyperinsulinemia at low or moderate glucose concentrations observed in MSG-obese rats is, at least in part, a consequence of direct hypersecretion of the B cells and that chronic aerobic exercise is able to partially counteract the hyperinsulinemic state of these animals without disrupting glucose homeostasis.     

Immunocytochemical evidence for the presence of S-100 protein in insulin-containing cells of cultured fetal rat islets

S-100 protein was long considered to be specific to glial and Schwann cells, but was subsequently proved to be present in various organs. In particular, S-100 proteinimmunoreactivity was demonstrated in the parathyroid gland, adenohypophysis and endocrine pancreas. In the present study cultured fetal rat islets were investigated in view of the possible presence of S-100 protein immunoreactivity in their cells. In the initial 5-day period, continuity between islets and ducts could be demonstrated, and the islets appeared to bud from the ducts. During this time, S-100 protein-immunoreactive cells were found in either the budding islets or ducts. The colocalization of S-100 protein and insulin was demonstrated immunocytochemically. In contrast, the newly formed islets from endocrine monolayers did not display S-100 protein immunoreactivity. After this initial period, numerous free-floating islets were observed, but only some of them contained S-100 protein immunoreactivity. S-100 protein-immunoreactive cells had the same distribution as those storing insulin, again suggesting the coexistence of the two peptides. The results suggest that S-100 protein might be involved in the regulation of islet function.     

Active participation of apoptosis and mitosis in sublingual gland regeneration of the rat following release from duct ligation

Summary This study was designed to establish how mitotic cell proliferation and apoptotic cell death participate in the regeneration of atrophied rat sublingual glands. To induce atrophy to the sublingual gland of rats, the excretory duct was ligated unilaterally near the hilum, and after 1 week of ligation (day 0) the duct ligation was released to enable gland regeneration. The regenerating glands were examined with routine histology, immunohistochemistry for proliferating cell nuclear antigen (PCNA) as a marker of proliferating cells, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) as a marker of apoptotic cells, and transmission electron microscopy. At day 0, a few acini and many ducts remained in the atrophic sublingual glands, and newly formed immature acini were observed at day 3. Thereafter acinar cells progressively matured and increased in number, although the number of ducts decreased. Many PCNA- and some TUNEL-positive cells were seen in acini and ducts during regeneration. The labeling indices for both cell types were statistically significantly different from that of the control at several time points of the regeneration. Apoptotic and mitotic cells were also confirmed to be present in the experimental sublingual glands by electron microscopy. These observations suggest that apoptosis as well as mitosis of duct and acinar cells actively participate in and play important roles in sublingual gland regeneration.     

Pancreatic fate of D-[3H] mannoheptulose

D-Mannoheptulose was recently postulated to be transported into cells by GLUT2. The validity of such an hypothesis was assessed by comparing the uptake of tritiated D-mannoheptulose by pancreatic islets versus pieces of pancreas and, in the latter case, by comparing results obtained in control rats versus animals injected with streptozotocin (STZ). The uptake of D-[3H] mannoheptulose by islets represents a time-related and temperature-sensitive process, inhibited by cytochalasin B and enhanced by D-glucose. The uptake of the tritiated heptose was much lower in pieces of pancreatic tissue and inhibited by D-glucose, at least in the STZ rats. Whether in pieces of pancreas exposed in vitro to D-[3H] mannoheptulose or after intravenous injection of the tritiated heptose, the radioactive content of the pancreatic tissue was lower in STZ rats than in control animals. This contrasted with an unaltered radioactive content of liver and muscle in the STZ rats, at least when treated with insulin. Suitably radiolabelled D-mannoheptulose or an analogue of the heptose could thus conceivably be used for quantification of the endocrine pancreatic mass.     

Can pancreatic duct-derived progenitors be a source of islet regeneration?

The regenerative process of the pancreas is of interest because the main pathogenesis of diabetes mellitus is an inadequate number of insulin-producing β-cells. The functional mass of β-cells is decreased in type 1 diabetes, so replacing missing β-cells or triggering their regeneration may allow for improved type 1 diabetes treatment. Therefore, expansion of the β-cell mass from endogenous sources, either in vivo or in vitro, represents an area of increasing interest. The mechanism of islet regeneration remains poorly understood, but the identification of islet progenitor sources is critical for understanding β-cell regeneration. One potential source is the islet proper, via the dedifferentiation, proliferation, and redifferentiation of facultative progenitors residing within the islet. Neogenesis, or that the new pancreatic islets can derive from progenitor cells present within the ducts has been reported, but the existence and identity of the progenitor cells have been debated.In this review, we focus on pancreatic ductal cells, which are islet progenitors capable of differentiating into islet β-cells. Islet neogenesis, seen as budding of hormone-positive cells from the ductal epithelium, is considered to be one mechanism for normal islet growth after birth and in regeneration, and has suggested the presence of pancreatic stem cells. Numerous results support the neogenesis hypothesis, the evidence for the hypothesis in the adult comes primarily from morphological studies that have in common the production of damage to all or part of the pancreas, with consequent inflammation and repair. Although numerous studies support a ductal origin for new islets after birth, lineage-tracing experiments are considered the “gold standard” of proof. Lineage-tracing experiments show that pancreatic duct cells act as progenitors, giving rise to new islets after birth and after injury. The identification of differentiated pancreatic ductal cells as an in vivo progenitor for pancreatic β-cells has implications for a potentially important, expandable source of new islets for diabetic replenishment therapy.     

Enhancement of mouse pancreatic regeneration and HIT-T15 cell proliferation with rat pancreatic extract

In this study, the effects of rat pancreatic extract (RPE) on regeneration of impaired mouse pancreas and proliferation of beta-cell line (HIT-T15) were investigated. RPE from the regenerating pancreas (2 days after 60% pancreatectomy) was treated to cure streptozotocin (STZ) induced diabetes in BALB/c mice. RPE-treated BALB/c mice for 21 consecutive days became euglycemic by day 30 and remained normoglycemic during a 150 day follow-up. Saline treated mice remained hyperglycemic sustained uncontrolled hyperglycemia. Islet neogenesis was observed in RPE-treated mice and confirmed by use of immunocytochemistry. Morphometric analysis of pancreas in reverted RPE-treated mice showed a new population of small islets compared with saline controls and an increased islet number. When HIT-T15 cells were treated with RPE, HIT-T15 cell proliferation and insulin secretion increased with increases in the RPE concentration. These results imply that RPE have the regeneration factors and help in the cure of diabetes.     

Betacellulin improves glucose metabolism by promoting conversion of intraislet precursor cells to beta-cells in streptozotocin-treated mice

Betacellulin (BTC) induces differentiation of pancreatic beta-cells and promotes regeneration of beta-cells in experimental diabetes. The present study was conducted to determine if BTC improved glucose metabolism in severe diabetes induced by a high dose of streptozotocin (STZ) in mice. Male ICR mice were injected with 200 microg/g ip STZ, and various doses of BTC were administered daily for 14 days. The plasma glucose concentration increased to a level of >500 mg/dl in STZ-injected mice. BTC (0.2 microg/g) significantly reduced the plasma glucose concentration, but a higher concentration was ineffective. The effect of BTC was marked by day 4 but became smaller on day 6 or later. The plasma insulin concentration and the insulin content were significantly higher in mice treated with 0.1 and 0.2 microg/g BTC. BTC treatment significantly increased the number of beta-cells in each islet as well as the number of insulin-positive islets. Within islets, the numbers of 5-bromo-2-deoxyuridine/somatostatin-positive cells and pancreatic duodenal homeobox-1/somatostatin-positive cells were significantly increased by BTC. These results indicate that BTC improved hyperglycemia induced by a high dose of STZ by promoting neoformation of beta-cells, mainly from somatostatin-positive islet cells.     

Immunohistochemical localization of estrogen receptor-α in sex ducts and gonads of newborn piglets

Estrogen receptor-alpha (ER-alpha) expression in piglet uteri has previously been reported from day 15 after birth. Nevertheless, uterine tissue has been reported to be estrogen sensitive from the day of birth. Since estrogen action in the uterine tissue is suggested to be mediated principally by ER-alpha, the present study aimed to evaluate the presence of ER-alpha in uteri of 1- to 2-day-old piglets by means of immunohistochemistry. In addition, sex ducts and gonads of both sexes were examined. The results clearly demonstrate the presence of ER-alpha immunopositive cells in uterine tissue, which explains its estrogen responsiveness. Immunostaining was most intense in the glandular epithelial cells and is suggested to indicate participation of ER-alpha in adenogenesis. In oviducts, almost all epithelial cells were immunostained moderately positive, while the stroma cells were stained comparably more positive. The functional significance of this intensity difference is uncertain but could indicate that part of the estrogen action on the epithelium is mediated through the stroma cells, as is known for the uterus. In ovaries, the surface epithelium and stroma cells were immunostained, whereas germ and granulosa cells were immunonegative. It is speculated that ER-alpha might be involved in yet unknown intraovarian mechanisms. In male sex ducts, immunostaining was virtually confined to the epithelium of efferent ducts. All cells in the epididymis as well as in vas deferens were immunonegative. The unique presence of ER-alpha in efferent ducts corresponds with localization in other species, where it has been shown to be involved in fluid reabsorption. The obtained data on localization of ER-alpha correspond with the present knowledge, obtained in ER-alpha knockout mice, of the biological function of ER-alpha within male and female gonads and sex ducts.     

Glucagon secretion by dispersed alpha cell enriched islets from streptozotocin treated hamsters in perifusion

Streptozotocin (70 mg/kg) was administered intravenously to female Syrian hamsters. The hamsters received insulin (5U/animal/day). Insulin treatment was withdrawn 3 days before sacrifice in one group, while another group was maintained on insulin until sacrifice. Ten to 14 days following streptozotocin administration the animals were killed, and the pancreatic islets isolated and subsequently dispersed. Islet DNA content was decreased while the glucagon content was elevated by streptozotocin treatment. The glucagon secretory responsiveness of the dispersed alpha cells of control animals was stimulated by glucopenia and decreased by glucose. Alpha cells of streptozotocin hamsters were not only suppressed but were actually stimulated by high glucose concentrations. Treatment with insulin in vivo but not in vitro, resulted in a restoration of the alpha cells responsiveness to glucose suppression. Dispersed alpha cells from control and streptozotocin treated animals were stimulated by arginine. Basal and total glucagon secretion was greatest in dispersed alpha cells from streptozotocin treated animals. We concluded: that the paradoxical response of alpha cells to glucose noted in diabetes is not due to short term insulin deprivation or the lack of morphologic contact with beta cells; that the alpha cells require and insulin stimulated islet metabolite and extra islet materials to respond appropriately to glucose; and that the alpha cells response to arginine is mediated independently of glucose regulation.     

Scoparia dulcis, a traditional antidiabetic plant, protects against streptozotocin induced oxidative stress and apoptosis in vitro and in vivo

Oxidative stress is implicated in the pathogenesis of diabetic complications. The experiments were performed on normal and experimental male Wistar rats treated with Scoparia dulcis plant extract (SPEt). The effect of SPEt was tested on streptozotocin (STZ) treated Rat insulinoma cell lines (RINm5F cells) and isolated islets in vitro. Administration of an aqueous extract of Scoparia dulcis by intragastric intubation (po) at a dose of 200 mg/kg body weight significantly decreased the blood glucose and lipid peroxidative marker thiobarbituric acid reactive substances (TBARS) with significant increase in the activities of plasma insulin, pancreatic superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in streptozotocin diabetic rats at the end of 15 days treatment. Streptozotocin at a dose of 10 mug/mL evoked 6-fold stimulation of insulin secretion from isolated islets indicating its insulin secretagogue activity. The extract markedly reduced the STZ-induced lipidperoxidation in RINm5F cells. Further, SPEt protected STZ-mediated cytotoxicity and nitric oxide (NO) production in RINm5F cells. Treatment of RINm5F cells with 5 mM STZ and 10 mug of SPEt completely abrogated apoptosis induced by STZ, suggesting the involvement of oxidative stress. Flow cytometric assessment on the level of intracellular peroxides using fluorescent probe 2'7'-dichlorofluorescein diacetate (DCF-DA) confirmed that STZ (46%) induced an intracellular oxidative stress in RINm5F cells, which was suppressed by SPEt (21%). In addition, SPEt also reduced (33%) the STZ-induced apoptosis (72%) in RINm5F cells indicating the mode of protection of SPEt on RIN m5Fcells, islets, and pancreatic beta-cell mass (histopathological observations). Present study thus confirms antihyperglycemic effect of SPEt and also demonstrated the consistently strong antioxidant properties of Scoparia dulcis used in the traditional medicine.     

Oxidative stress and cannabinoid receptor expression in type‐2 diabetic rat pancreas following treatment with Δ9‐THC

The objectives of study were (a) to determine alteration of feeding, glucose level and oxidative stress and (b) to investigate expression and localization of cannabinoid receptors in type‐2 diabetic rat pancreas treated with Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC). Rats were randomly divided into four groups: control, Δ⁹‐THC, diabetes and diabetes + Δ⁹‐THC groups. Diabetic rats were treated with a single dose of nicotinamide (85 mg/kg) 15 min before injection of streptozotocin (65 mg/kg). Δ⁹‐THC was administered intraperitoneally at 3 mg/kg/day for 7 days. Body weights and blood glucose level of rats in all groups were measured on days 0, 7, 14 and 21. On day 15 after the Δ⁹‐THC injections, pancreatic tissues were removed. Blood glucose levels and body weights of diabetic rats treated with Δ⁹‐THC did not show statistically significant changes when compared with the diabetic animals on days 7, 14 and 21. Treatment with Δ⁹‐THC significantly increased pancreas glutathione levels, enzyme activities of superoxide dismutase and catalase in diabetes compared with non‐treatment diabetes group. The cannabinoid 1 receptor was found in islets, whereas the cannabinoid 2 receptor was found in pancreatic ducts. Their localization in cells was both nuclear and cytoplasmic. We can suggest that Δ⁹‐THC may be an important agent for the treatment of oxidative damages induced by diabetes. However, it must be supported with anti‐hyperglycaemic agents. Furthermore, the present study for the first time emphasizes that Δ⁹‐THC may improve pancreatic cells via cannabinoid receptors in diabetes. The aim of present study was to elucidate the effects of Δ⁹‐THC, a natural cannabinoid receptor agonist, on the expression and localization of cannabinoid receptors, and oxidative stress statue in type‐2 diabetic rat pancreas. Results demonstrate that the cannabinoid receptors are presented in both Langerhans islets and duct regions. The curative effects of Δ⁹‐THC can be occurred via activation of cannabinoid receptors in diabetic rat pancreas. Moreover, it may provide a protective effect against oxidative damage induced by diabetes. Thus, it is suggested that Δ⁹‐THC can be a candidate for therapeutic alternatives of diabetes symptoms. Copyright © 2014 John Wiley & Sons, Ltd.