Diabetic Hamsters Research Articles

Abnormalities in glucose-stimulated insulin release, 45Ca uptake, and 86Rb efflux in diabetic Chinese hamster islets.

We loaded islets from normal and diabetic Chinese hamsters with 86Rb (an analogue for K+) and measured 86Rb efflux during stimulation with 20 mM D-glucose. Genetically diabetic Chinese hamsters were selected from a subline (L) known for subnormal pancreatic insulin release and excessive pancreatic glucagon release in vitro. 86Rb accumulation in 1 mM glucose was normal in the diabetic islets. Similar to the pattern of 86Rb efflux previously seen from normal rat and mouse islets, 20 mM glucose suppressed 86Rb efflux within 1-2 min, and efflux remained suppressed until return to 1 mM glucose in both normal and diabetic hamster islets. After the first 2 min of 20 mM glucose, suppression of 86Rb efflux was somewhat greater in the diabetic hamster islets than in the normals. In addition, glucose-stimulated insulin release and 45Ca uptake were significantly reduced in the diabetic islets. Therefore, in the diabetic hamster islets, there is at least no impairment in the initial suppression of 86Rb efflux by glucose. This suggests that the diabetic beta-cells recognize glucose and carry out the initial steps in the stimulus-secretion coupling sequence normally. The later, excessive suppression of 86Rb efflux may be due to impaired Ca2+-induced changes in 86Rb efflux, suggesting that defective regulation of intracellular Ca2+ activity, rather than defective regulation of K+ permeability, may lead to the impaired insulin secretion.

Pancreatic carcinogenicity of N-nitrosobis(2-oxopropyl)-amine in diabetic and non-diabetic Chinese hamsters

To examine the role of diabetes in pancreatic cancer, 4 groups of Chinese hamsters—2 from genetically diabetic and 2 from non-diabetic lines—were treated with N-nitrosobis(2-oxo-propyl)amine (BOP) at different dose levels and intervals. In one group (referred to as the VA group), BOP was given weekly at a 5 mg/kg body wt. level for 18 or 23 weeks, whereas the other group (the EP group) received a weekly dose of 2.5 mg/kg body wt. for life. Except for diet and experimental design, all other laboratory conditions were similar in the two institutions. No VA hamster developed tumors. Three of 22 non-diabetic EP hamsters (but none of the diabetic hamsters) developed pancreatic hyperplastic and neoplastic lesions, comprising ductular cell adenomas (3 hamsters), carcinoma in situ (1 hamster), a well-differentiated adenocarcinoma (1 hamster), and a poorly differentiated adenocarcinoma (1 hamster) with regional lymph node metastases. In addition, over 50% of the EP hamsters had neoplasms for which the incidences and morphology did not vary between diabetic and non-diabetic groups or between the sexes. These were primarily of the liver (cholangiomas), lungs (adenomas) and skin (trichoepitheliomas, squamous cell carcinomas). The differing carcinogenic response of the two hamster groups to BOP apparently is not related to the total BOP dose, but rather to other factors, including the length of observation time.

Proton microprobe analysis of 15 elements in pancreatic B cells and exocrine pancreas in diabetic Chinese hamsters.

Diabetes mellitus spontaneously develops in certain sublines of non-obese Chinese hamsters, and the diabetic L-subline is known for subnormal pancreatic insulin release in vitro. The cause of the secretory defect is unknown. Freeze-dried pancreas sections from genetically diabetic Chinese hamsters and normal controls were subjected to proton bombardment and the concentration of 15 elements in B cells and acini was calculated from the X-rays emitted. Diabetic B cells contained significantly less Al (-61%) and significantly more Cu (+92%), Mg (+6%) and Rb (+13%) than their normal counterparts. The diabetic acini showed similar, significant changes. The molar ratio between K and Na was about 10 in endocrine as well as exocrine pancreas from both groups of animals, implying that neither sample preparation nor irradiation had induced significant diffusive changes. In conclusion, the high K/Na ratio suggests that the diabetic B cell has a well-functioning Na+/K+ pump. However, significant and parallel changes in Al-, Cu-, Mg- and Rb-levels were found in both the B cells and acinar portion of the diabetic pancreas. It is not clear whether these elemental changes cause the islet secretory defect or result from it.

Diabetic Chinese hamsters: metabolic effects of long term guar gum consumption

The effect of 13 weeks of guar gum or cellulose diet consumption upon metabolic parameters was examined in diabetic and control adult Chinese hamsters. Diabetic hamsters displayed typical diabetic metabolic profiles. Both 8% guar gum and 8% cellulose diets maintained body weights in all 4 groups during the study. Diabetic and control hamsters fed guar gum drank less water as the study progressed. At weeks 9 and 13, diabetic hamsters fed guar gum excreted less urine compared to those fed cellulose. Diabetic hamsters fed guar gum had reduced urinary glucose excretion at weeks 1, 9 and 13 compared to those fed cellulose. Control hamsters fed either diet had normal urine volumes with only traces of glucose. Similar fasting plasma glucose levels were measured initially for all diabetic hamsters; all 3 subsequent measurements revealed lower levels for the group fed guar gum. Control hamsters had normal fasting plasma glucose levels. Comparable fasting plasma insulin levels were measured for all diabetic hamsters; these levels increased during the study. Control hamster fasting plasma insulin levels were 3 times higher and did not change. Throughout the study, diabetic hamsters fed guar gum consistently had healthier metabolic profiles than those fed cellulose.

Calmodulin in various insulin secreting cell types.

The involvement of the Ca2+ binding protein, calmodulin, in the regulation of insulin release was studied. Calmodulin was measured in isolated rat islets, rat insulinoma cells, the insulin secreting cell line (RINm5F) and in islets isolated from normal and diabetic Chinese hamsters. Total content of calmodulin was determined by a radioimmunoassay using a rabbit anti-calmodulin serum and was found to lie in the range of 4 to 7 micrograms/ml protein. When rat islets were maintained in tissue culture for 6 days at 2.8 or 8.3 mM glucose, the content of calmodulin of the two groups was similar. Likewise there was no difference in calmodulin content between islets from normal and diabetic hamsters. This study suggests that a variation of the total cellular calmodulin does not play a role in the process of insulin secretion.

Effect of antilymphocyte serum and neonatal thymectomy upon onset of diabetes in the Chinese hamster.

Prediabetic Chinese hamsters were treated with antilymphocyte serum (ALS), or thymectomized in order to test the hypothesis that beta-cell loss leading to diabetes in this animal model was related to cell-mediated autoimmunity. In addition, passive transfer of diabetes from the Chinese hamster to the nude mouse was attempted by transplantation of lymphocytes. Treatment of prediabetic Chinese hamsters with ALS or thymectomy did not alter development or severity of diabetes in this animal model. Lymphocytes from newly diagnosed diabetic Chinese hamsters did not cause hyperglycemia in nude mice. These three lines of evidence suggest that cell-mediated autoimmunity does not contribute to the etiology of diabetes in the Chinese hamster. The Chinese hamster remains a good model for the study of those forms of diabetes not related to cell-mediated autoimmune phenomena.

Levels of salivary lysozyme, lactoperoxidase, and lactoferrin in diabetic hamsters.

In an attempt to clarify the mechanism(s) of increased susceptibility to oral infection in diabetics, we examined the levels of salivary antibacterial factors, including lysozyme, lactoperoxidase, and lactoferrin, in diabetic hamsters whose condition was induced with streptozotocin. Saliva was collected from these hamsters periodically for 19 weeks after the administration of streptozotocin. Diabetes persisted with significant hyperglycemia throughout the experiment after a single injection of streptozotocin. There was no significant difference between groups in the amount of saliva secreted. In diabetic hamsters, lysozyme activity decreased by 56% and lactoperoxidase activity decreased by 53% compared with the control hamsters 19 weeks after the administration of streptozotocin. There was no significant difference between groups in the amount of salivary lactoferrin. However, the ratio of lactoferrin to total protein increased to approximately double the amount of that of the control hamsters. Insulin treatment had a significant effect on lysozyme and lactoperoxidase activity, recovering 73 and 74% those of the controls, respectively, and the ratio of lactoferrin to total salivary protein reverted to normal values. Growth inhibition of Lactobacillus plantarum ATCC 8014 with whole saliva and amylase activity significantly decreased in diabetic hamsters. The position of each protein band of whole saliva on sodium dodecyl sulfate-polyacrylamide gel electrophoresis was almost the same for control and diabetic hamsters; however, there was some variability in band intensity.

Elevated levels of vasoactive intestinal peptide in the eye and urinary bladder of diabetic and prediabetic Chinese hamsters.

The eyes and urinary bladder of non-diabetic, prediabetic and diabetic Chinese hamsters were evaluated by radioimmunoassay and immunocytochemistry to determine the content and distribution of vasoactive intestinal peptide (VIP). The average concentration of VIP was increased in the eyes of all diabetic (pmol/g = 68%, pmol/organ = 50%) and prediabetic (pmol/g = 152%, pmol/organ = 115%) hamsters compared with age-matched non-diabetic animals. Immunocytochemistry showed that the elevation of VIP was primarily related to greater intensity of fluorescence of the nerve fibres in the vasculature of the choroid. The average content of VIP in the urinary bladder was greater in diabetic animals only on the basis of pmol/organ (135%) and in prediabetics on the basis of pmol/g (87%) compared with non-diabetic animals. Qualitative immunocytochemistry suggested that the elevated level of VIP was related to a larger distribution of nerve fibres in the urinary bladder of diabetic hamsters. The high level of VIP in the eyes and urinary bladder of diabetic and prediabetic hamsters is an interesting observation which should receive further study to determine whether it is an aetiological agent underlying the pathogenesis of ophthalmic complications and neurogenic bladder or the result of some pathological process which affects these organs.

Voluntary exercise, food intake, and plasma metabolites in streptozotocin-diabetic Syrian hamsters

Diabetes mellitus was induced in Syrian hamsters by treatment with streptozotocin. The efficacy of and survival from this treatment are compared across several drug regimens, and in exercising versus sedentary hamsters. Stable diabetes, with plasma glucose levels typically below 400 mg/dl, is accompanied by a decrease of approximately 50% in voluntary wheel running in a 14L:10D cycle. Wheel running in diabetics is, however, almost completely abolished in continuous light. The diabetic hamsters are hyperphagic on chow, eating about 60% more than controls, exclusively by increasing the size of individual meals. Their intake is normalized on a high fat diet. The high fat diet greatly exacerbates the extant ketonemia in diabetics, and produces hypertriglyceridemia. Exercise has no apparent effect on plasma metabolic fuels of diabetic hamsters.

Morphometric analysis of the vagus nerve in non-diabetic and ketonuric diabetic Chinese hamsters

Morphometric analysis of axons from the ventral division of the vagus nerve of ketonuric diabetic Chinese hamsters and age-sex matched non-diabetic controls was performed to determine the frequency distribution and numerical and volume density. Myelinated fibres of diabetics displayed a significant reduction in diameter ( P<0·001) compared with controls, which was correlated inversely with progressive ketonuria ( P<0·05). The reduced calibre of myelinated fibres was the result of thin myelin sheaths rather than a reduction in axon diameter. A marked decrease in numerical density ( P<0·05) and volume density ( P<0·005) was found in the myelinated fibres of diabetics compared with controls. Non-myelinated axons showed a significant shift to smaller diameter ( P<0·001) in diabetics, which was correlated inversely with duration of ketonuria ( P<0·05). Numerical density of non-myelinated axons was increased ( P<0·01) in diabetic hamsters whereas volume density was comparable in diabetic and control animals. These data provide morphological evidence of impairment in the parasympathetic nervous system which may be a major factor underlying previously reported gastrointestinal and pancreatic islet dysfunction in the diabetic Chinese hamster.

Insulin, glucagon, and somatostatin release from the prediabetic Chinese hamster.

Diabetes mellitus in the adult Chinese hamster is characterized by subnormal pancreatic insulin release in vitro, decreased insulin content, and lack of obesity. The cause of the islet B-cell failure is not clear. We measured insulin, glucagon, and somatostatin release from in vitro perfused pancreases of young (mean age 10 and 20 weeks), genetically diabetic animals (subline AC, mean plasma glucose 8.0 and 16.6 mmol/l, respectively). Compared to age- and sex-matched normal hamsters (subline M, mean plasma glucose 5.3 mmol/l), the younger diabetic animals had a significantly elevated mean plasma glucose level, but net in vitro pancreatic release of insulin, glucagon, and somatostatin was normal. Pancreatic content of insulin and glucagon was also not significantly different from normal. At age 20 weeks, when the plasma glucose of the diabetic animals was even more elevated, pancreatic content and release of insulin were significantly subnormal, whereas glucagon and somatostatin release were normal, and pancreatic content of glucagon was normal. In a similar group of young (mean age 10 weeks) diabetic animals, non-fasting plasma insulin levels were within the normal range, but the corresponding glucose levels were excessive in most of the animals (13 out of 19). In conclusion, 10-week-old diabetic hamsters show mild hyperglycaemia which cannot be accounted for directly by decreased pancreatic release in response to a glucose plus arginine stimulus in vitro. Decreased ability of the B cell to respond in vivo to hyperglycaemia or peripheral resistance to insulin may contribute to later B-cell failure in the older diabetic hamster.

Systematic evaluation of microangiopathy in diabetic Chinese hamsters: II. Morphometric analysis of basement membrane thickness in the quadriceps muscle of 19-23 month old Chinese hamsters

Capillary basement membrane thickening appears to be one of the primary manifestations of microangiopathy which affects numerous capillary beds in diabetic man. Although many diabetic animal models exhibit microangiopathy in the eyes and kidneys, few studies have demonstrated the existence of muscle capillary basement membrane thickening similar to that which occurs in human diabetics.(1) Furthermore, a limited number of investigations have been systematically designed to correlate quantification of basement membrane thickness with metabolic perturbations, age, duration, and severity of diabetes. Systematic characterization of diabetic microangiopathy may help to elucidate some of the factors underlying basement membrane thickening and serve as guidelines for therapeutic studies which are designed to prevent or inhibit basement membrane thickening. Clinically, muscle biopsies are easily obtained, and this type of characterization may also prove useful in the diagnosis of diabetic microangiopathy. Therefore, the purpose of this study was to determine if basement membrane thickening is present in the quadriceps muscle capillaries of 19-23 month old diabetic Chinese hamsters in comparison with age-matched controls.

Systematic evaluation of microangiopathy in diabetic Chinese hamsters: I. Morphometric analysis of minimal glomerular basement membrane thickness in 19-23 month old Chinese hamsters

Microangiopathy has been recognized as a critical complication which afflicts the human diabetic population and magnifies the risk for permanent injury and/or mortality. One of the major manifestations of diabetic microvascular disease in man appears to be capillary basement membrane thickening (CBMT) which has been termed the “hallmark of diabetic microangiopathy”. CBMT of diabetic patients seems to be a product of vascular injury imposed by the interaction of metabolic derangement, environmental factors and genetics (1). Although the degree of thickening varies with age, duration of diabetes, severity of metabolic impairment and location in the body, capillary basement membranes from the kidney, skeletal muscle and heart are usually expanded in diabetic man. However, due to the sparsity of systematic studies and inherent problems with human experimentation, the pathogenesis of CBMT remains controversial. In an attempt to achieve a better understanding of the etiology and progression of CBMT, diabetic animal models have recently been the focal point of intensive research (2).

Deficient humoral antibody response of the spontaneously diabetic Chinese hamster.

The antibody responses of spontaneously diabetic Chinese hamsters to sheep erythrocytes was investigated. After primary challenge, total antibody production of the diabetics was only 50% or less than that of nondiabetic controls, and little or no switchover to IgG production occurred. After second challenge, total antibody of diabetics was still reduced compared with controls. Some switchover to IgG did occur after second challenge but was only 40% that of controls. Poor antibody response was not related to abnormal glucose metabolism since low titers and lack of IgG was found in euglycemic prediabetics. Additionally, genetic nondiabetics rendered hyperglycemic by streptozotocin responded normally, similar to euglycemic controls. The impaired humoral antibody response of the diabetic hamster is similar to that reported for some human diabetics and makes this animal model attractive for studying the consequences and possible causes of diabetes-dependent impairment of immune responses.

自然発症糖尿病チャイニーズハムスターにおける過酸化脂質の動態と大動脈病変

自然発症糖尿病チャイニーズハムスターにおける過酸化脂質の動態と大動脈病変

自然発症糖尿病チャイニーズハムスターにおける血漿脂質, リポ蛋白およびアポ蛋白

自然発症糖尿病チャイニーズハムスターにおける血漿脂質, リポ蛋白およびアポ蛋白

Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/db mice, diabetic Chinese hamsters, and normal and streptozotocin-diabetic rats

Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/db mice, diabetic Chinese hamsters, and normal and streptozotocin-diabetic rats

Islet innervation of nondiabetic and diabetic Chinese hamsters. I. Acetylcholinesterase histochemistry and norepinephrine fluorescence.

Cholinergic and adrenergic innervation of pancreatic islets from age- and sex-matched nondiabetic (M subline) and diabetic (AC subline) Chinese hamsters was analyzed by acetylcholinesterase (AChE) histochemistry and norepinephrine fluorescence. The AChE activity was significantly diminished in islets of diabetic animals compared with that of nondiabetic controls. The reduction in cholinergic innervation displayed an inverse relationship with respect to nonfasting plasma glucose and ketone levels. On the basis of qualitative analysis, adrenergic activity also appeared to be depressed in islets of diabetic animals. These date suggest that autonomic control of islet function is altered in diabetic Chinese hamsters when plasma glucose and ketone levels arae elevated and may exacerbate metabolic complications in this animal model.

Diabetes-associated endometrial disruption in the ketonuric, diabetic Chinese hamster.

The effects of the ketonuric-diabetic (KD) condition on uterine endometrial morphology were studied in the genetically diabetic Chinese hamster. All KD hamsters were matched for age, body weight and cyclic state with nondiabetic control animals. All KD hamsters were reproductively acyclic as compared to controls. The uterine epithelium of KD hamsters was devoid of surface microvilli, secretory activity, and exhibited a height reduction as compared to controls. The basal lamina underlying the luminal epithelium was 2-5 times as thick in the KD condition than control. The endometrial stroma was disrupted in the KD hamsters, with the endometrium composed of rounded cells surrounded by a thickened intercellular matrix. This was in marked contrast to the stroma of controls which consisted of an orderly array of fibroblasts and collagen fibers. Stromal vessels had a thickened basement membrane in diabetic animals. The results of this study indicate that epithelial and stromal disruption are associated with the KD state in the Chinese hamster and are probably causally associated with reproductive failure.

Peripheral neurology of the diabetic Chinese hamster.

Genetically diabetic Chinese hamsters were examined anatomically and physiologically for evidence of peripheral neuropathy. Control animals were from non-diabetic strains. Conduction velocities in both motor and sensory components of the hind limb nerves were reduced 16-22% in diabetic compared with control hamsters. However, there was no reduction in nerve fibre diameters or other signs of abnormal morphology that could be correlated with these physiological effects. It is concluded that the diabetic hamster is useful as a model of human diabetic peripheral neuropathy, but the analogy is not precise. The neuropathy of moderately diabetic hamsters is generally less severe than human diabetic neuropathy in its clinical stages.