Age-related difference of the association of cardiovascular risk factors with the cardio-ankle vascular index in the Cardiovascular Prognostic Coupling Study in Japan (the Coupling Registry).

The value of the cardio-ankle vascular index (CAVI) increases with age. All large-scale studies of the CAVI have investigated patients <80 years old. Thus, the clinical characteristics of high CAVI in patients aged 80 or more remain unclear. Therefore, we investigated (1) the CAVI in very elderly patients and (2) the determinants of a high CAVI in high-risk patients, including very elderly patients. The Cardiovascular Prognostic Coupling Study in Japan (Coupling Registry) is a prospective observational study of Japanese outpatients with any cardiovascular risk factors. We enrolled 5109 patients from 30 institutions (average age 68.7 ± 11.4 years, 52.4% males). We investigated the determinants of the CAVI by separating the patients into three groups: 970 middle-aged (<60 years), 3252 elderly (60-79 years), and 887 very elderly (≥80 years) patients. The CAVI values of the males were significantly higher those of the females in all age groups (<60 years: 7.81 ± 1.11 vs. 7.38 ± 0.99, P < .001; 60-79 years: 9.20 ± 1.29 vs. 8.66 ± 1.07, P < .001; ≥80 years: 10.26 ± 1.39 vs. 9.51 ± 1.12, P < .001). In all age groups, the CAVI of the patients with diabetes/glucose tolerance disorder was higher than that of the patients without diabetes/glucose tolerance disorder (<60 years: 7.82 ± 1.22 vs 7.58 ± 1.03, P = .002; 60-79 years: 9.23 ± 1.20 vs 8.78 ± 1.19, P < .001; ≥80 years: 10.04 ± 1.24 vs 9.75 ± 1.32, P = .002). The determinants of the CAVI in these very elderly patients were age, male sex, low BMI, and mean blood pressure. Diabetes/glucose tolerance disorder and glucose were independently associated with the CAVI in the patients aged <60 years and 60-79 years, but not in those aged ≥80 years after adjusting for other covariates.

Rationale, design, and baseline characteristics of the Cardiovascular Prognostic COUPLING Study in Japan (the COUPLING Registry).

Vascular biomarkers, including the cardio-ankle vascular index (CAVI), are increasingly being recognized as important indicators of cardiovascular risk. CAVI has been shown to have good discriminative ability for detecting new-onset hypertension, but results of studies investigating cardiovascular risk prediction are inconsistent. Furthermore, there is a lack of data on the prognostic value of changes in CAVI over time. The Cardiovascular Prognostic Coupling study was designed to determine the impact of baseline CAVI and changes in CAVI on cardiovascular events in a Japanese cohort. The design of the ongoing, multicenter, prospective, observational registry and baseline characteristics of the enrolled population are reported. Eligible consecutive patients were aged ≥30 years, had ≥1 cardiovascular risk factor, and were being treated according to relevant Japanese guidelines. The primary outcome is time to onset of a major cardiovascular event (a composite of cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, stroke of unknown etiology, myocardial infarction, cardiovascular intervention for angina pectoris, and sudden death). Screening and enrollment occurred over a period of 3 years, followed by ≥7 years of follow-up, with CAVI determined annually. A total of 5279 patients were registered, of whom 5109 had baseline data available and will be included in future analyses. Mean CAVI at baseline was 8.8 ± 1.4. The proportion of patients with CAVI of <8, 8-10 or >10 was 25.3%, 57.0%, and 17.7%, respectively. Data from this registry should provide information on the significance of baseline CAVI and change in CAVI as indicators of cardiovascular prognosis in a representative patient population.

Treatment with atorvastatin attenuates progression of insulin resistance and pancreatic fibrosis in the Otsuka Long-Evans Tokushima fatty rats.

PURPOSE: The effects of statins on insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are still controversial and its effects on pancreatic fibrosis are poorly defined. The purpose of this study is to examine the effects of atorvastatin on these issues using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of IR, T2DM and pancreatic fibrosis. METHODS: Male OLETF rats were divided into 2 groups at 6weeks of age. The first group received a standard diet until the end of experimental period at age 28weeks. The second group was given a diet containing 0.05% atorvastatin from 6weeks of age, before the onset of IR and pancreatic fibrosis. The age-matched Long-Evans Tokushima Otsuka rats without presence of IR, T2DM and pancreatic fibrosis, received a standard diet and were used as a normal control. RESULTS: Atorvastatin slightly decreased serum fasting glucose and insulin levels, but significantly improved index of IR compared with the untreated OLETF rats. In addition, atorvastatin markedly decreased transforming growth factor-ß1 mRNA expression, myeloperoxidase activity and proportion of fibrotic area, and elevated superoxide dismutase activity in the pancreas compared with the untreated OLETF rats. CONCLUSIONS: These findings suggest that atorvastatin exerts favorable influence on progression of IR and pancreatic inflammation and fibrosis via pleiotropic effect such as anti-oxidative property.

Effect of endogenous cholecystokinin on the course of acute pancreatitis in rats.

AIM: To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis. METHODS: Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 µL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment. RESULTS: Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-ß-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1ß were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture. CONCLUSION: The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.

Body mass index influences the outcome of acute pancreatitis: an analysis based on the Japanese administrative database.

OBJECTIVE: This study aimed to investigate the relationship between body mass index (BMI) and risk of death in patients with acute pancreatitis (AP) using a Japanese national administrative database. METHODS: We analyzed a total of 6002 patients with AP. We collected patient information, including sex, age, BMI, severity of AP based on the Japan Pancreas Society scoring system, and prognosis. We classified BMI into 5 categories (underweight [BMI, <18.5], normal range [18.5-24.9], preobese [25-29.9], obese class I [30-34.9], and obese class II/III [>35]) and investigated the relationship between each category and risk of death in AP. RESULTS: There was a good correlation between the Japanese AP severity score and in-hospital mortality. Overall mortality of severe pancreatitis was 7.0% (n = 2245). Mortality in each BMI category was as follows: underweight, 6.4%; normal range, 3.6%; preobese, 2.4%; obese class I, 3.2%; and obese class II/III, 5.7%. Underweight and obese class II/III patients had significantly higher relative risk (RR) of death in AP compared with preobese patients after adjusting for sex, age, and severity of AP (RR, 2.7; 95% confidence interval, 1.6-4.5; and RR, 6.4; 95% confidence interval, 1.9-20.9, respectively). CONCLUSIONS: Underweight or overweight was the independent risk factor for mortality in AP.

Valsartan, a specific angiotensin II receptor blocker, inhibits pancreatic fluid secretion via vagal afferent pathway in conscious rats.

BACKGROUND/AIM: The renin-angiotensin system (RAS) exists in the pancreas, but the role of RAS in the regulation of pancreatic exocrine secretion under physiological conditions has been little known. The present study addressed the RAS's effect on the pancreatic secretion by using valsartan, a specific angiotensin II receptor blocker, in conscious rats. METHOD: Male Wistar rats prepared with pancreatic, biliary, duodenal and jugular vein cannulas were used. To examine the role of RAS in the pancreatic secretion, valsartan at 1, 5, or 25 mg/kg was administered into the duodenum via cannula, and volume of pancreatic juice and protein concentration were determined. In addition, to examine the role of RAS in hormone-stimulated pancreatic hypersecretion, pancreatic secretion was examined in response to stimulation of secretin or cholecystokinin after intraduodenal infusion of valsartan at 25 mg/kg. Furthermore, to examine the mechanism of action of RAS on pancreatic secretion, intravenous infusion of atropine or perivagal application of capsaicin was conducted and then the pancreatic secretion was examined following intraduodenal infusion of valsartan at 25 mg/kg. RESULTS: Volume of pancreatic juice, but not protein output, significantly decreased after administration of valsartan. However, administration of valsartan did not exert significant effects on secretin- or cholesystokinin-stimulated pancreatic secretion. Treatment with atropine and perivagal application of capsaicin completely abolished the suppressive effect of valsartan on pancreatic juice secretion. CONCLUSION: Present results suggest that RAS plays a stimulatory role in pancreatic juice secretion via cholinergic afferent pathway without affecting protein secretion and hormonally stimulated pancreatic secretion under physiological conditions.

Poorly differentiated neuroendocrine carcinoma of the pancreas responsive to combination therapy with gemcitabine and S-1.

Poorly differentiated neuroendocrine carcinoma is a very rare malignancy, but it is characterized by agressive histological features and a poor clinical prognosis. We report a 42-year-old man who had poorly differentiated neuroendocrine carcinoma of the pancreas with multiple liver metastases. We administrated combined chemotherapy with S-1 and gemcitabine. This treatment was efficacious and well tolerated, and then this patient obtained objective partial response for 7 months and survived for 13 months after the diagnosis. This case suggests that S-1 and gemcitabine combination produce beneficial responses for patients with this disease.

Treatment with pravastatin attenuates progression of chronic pancreatitis in rat.

As appropriate therapies for pancreatic fibrosis and inflammation are limited, prognosis of chronic pancreatitis has not improved to date. Recent studies have shown that statins improve inflammation and fibrosis in several organs. We therefore examined the therapeutic effect of pravastatin on progression of chronic pancreatitis by starting this treatment after induction of pancreatic fibrosis in rats. Chronic pancreatitis was induced by continuous pancreatic ductal hypertension (PDH) for 14 days according to our previous study. Pravastatin at a dose of 10 mg/kg/day was administrated directly into the duodenum via cannula from 2 days after induction of PDH. Progression of pancreatic fibrosis and expression levels of transforming growth factor-ß1 and tumor necrosis factor-α mRNA were markedly attenuated after commencement of pravastatin compared with untreated group with PDH. In addition, pravastatin treatment markedly improved pancreatic exocrine function and significantly elevated expression level of interleukin (IL)-10 and superoxide dismutase activity in the pancreas compared with the untreated group with PDH. These results revealed that pravastatin substantially attenuates the progression of pancreatic inflammation, fibrosis and exocrine dysfunction probably by its anti-oxidative property and overproduction of IL-10 in animal model of chronic pancreatitis. These results provide an experimental evidence that pravastatin exerts beneficial effect for progression of chronic pancreatitis.

Transient stasis of pancreatic fluid flow together with mild injury of the pancreatic duct cause chronic pancreatitis.

BACKGROUND: Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas. AIMS: The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury. METHODS: Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 µl/100 g body weight of 0.01% agarose (group A), 40 µl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography. RESULTS: In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42. CONCLUSIONS: Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts.

Animal models of chronic pancreatitis.

Animal models for CP in rats can be classified into 2 groups: one is noninvasive or nonsurgical models and the other is invasive or surgical models. Pancreatic injury induced by repetitive injections of supramaximal stimulatory dose of caerulein (Cn) or by intraductal infusion of sodium taurocholate (NaTc) recovered within 14 days, whereas that caused by repetitive injection of arginine or by intraductal infusion of oleic acid was persistent. However, the destroyed acinar tissues were replaced by fatty tissues without fibrosis. Transient stasis of pancreatic fluid flow by 0.01% agarose and minimum injury of the pancreatic duct by 0.1% NaTc solution induced progressive pancreatic injury although one alone is insufficient to cause persistent pancreatic injury. However, the damaged tissue was replaced by fatty tissue without fibrosis. Continuous pancreatic ductal hypertension (PDH) caused diffuse interlobular and intralobular fibrosis closely resembling human CP.

Three cases of locally advanced pancreatic cancer successfully treated with chemoradiation and chemotherapy.

We report three cases with unresectable locally advanced pancreatic cancer (PC) treated with a combination of chemoradiotherapy (CRT) and systemic chemotherapy, using gemcitabine (GEM) and/or S-1. All three cases were diagnosed as having locally advanced unresectable PC without distant metastatic lesions based on computed tomography, endoscopic retrograde pancreatography and/or blushing cytology. In Cases 1 and 2, we applied a so-called sandwich therapy, which consisted of induction chemotherapy before CRT and maintenance chemotherapy after CRT. The induction and maintenance chemotherapy in Cases 1 and 2 used a combination of GEM and S-1, whereas maintenance therapy with GEM or S-1 was applied in Case 3. S-1-based CRT was performed in Cases 1 and 2, and GEM-based CRT in Case 3. Survivals were 27 and 65 months, respectively, in two cases, and the disease remained stable in the other case 30 months after diagnosis. We show three cases with unresectable locally advanced PC who achieved long-term survival (27-65 months) after treatment with a combination of CRT and systemic chemotherapy, using GEM and/or S-1. Our findings indicate that sandwich therapy might be particularly effective for locally advanced PC.

Decreased production of immunoglobulin M and A in autoimmune pancreatitis.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis caused by an autoimmune abnormality. It is well known that high serum concentrations of IgG4 are helpful for making a diagnosis of AIP; however, it is unclear whether there are abnormalities in the production of other immunoglobulins in AIP. METHODS: We examined the immune condition of AIP patients before and after glucocorticoid treatment, focusing on serum levels of IgG, IgG4, IgM and IgA, and compared the results with those in other hepato-pancreatic diseases, such as autoimmune hepatitis, primary biliary cirrhosis, chronic pancreatitis and pancreatic carcinoma. RESULTS: IgM and IgA were decreased in patients with untreated AIP. IgM and IgG or IgG4 were negatively correlated in patients with AIP. The ratios of IgG to IgM and IgG to IgA in patients with AIP were significantly increased compared with the other diseases. The diagnostic sensitivity of IgG to IgM and IgG to IgA was 0.800 and 0.950, and the specificity of each ratio was 0.703 and 0.728, respectively, in the differentiation of AIP from the other diseases. IgM was not significantly changed after glucocorticoid treatment in the patients with AIP, while IgG, IgG4 and IgA decreased. CONCLUSIONS: The ratios of IgG to IgM and IgG to IgA may serve as novel diagnostic markers to differentiate AIP from other hepato-pancreatic diseases. Furthermore, low concentrations of IgM and IgA may be involved in the pathogenesis of AIP.

[Influence of job-related factors on the clinical course of chronic hepatitis].

Although many workers suffer from chronic hepatitis, the influence of labor on its clinical course is not clear. We prospectively followed 89 workers with chronic hepatitis for 3 years, and examined the relationship between job-related factors, such as job class, job type, working hours and work effort, and the liver function test. There were no job-related factors that had any influence on the activity of hepatitis. Moreover, no significant relationship was found between job-related factors, including tiredness, and the acute exacerbation of hepatitis. No significant changes of aminotransferase levels and of platelet counts divided by each job-related factor were found during the observation period, but the platelet counts decreased in workers with acute exacerbation, but without clinical significance. These results suggest that job-related factors have little influence on the clinical course of chronic hepatitis during a relatively short observation period.

Supramaximal CCK-58 does not induce pancreatitis in the rat: role of pancreatic water secretion.

In contrast to supramaximal CCK-8 or caerulein, acute or prolonged supraphysiological levels of endogenous CCK-58 do not cause pancreatitis. Compared with CCK-8, CCK-58 is a much stronger stimulant of pancreatic chloride and water secretion, equivalent to maximally effective secretin, but with a chloride-to-bicarbonate ratio characteristic of acinar fluid. Because supraphysiological endogenous CCK does not cause pancreatitis and because coadministration of secretin ameliorated caerulein- or CCK-8-induced pancreatitis, coincident with restoring pancreatic water secretion, we hypothesized that supramaximal CCK-58 would not induce pancreatitis. Conscious rats were infused intravenously with 2 or 4 nmol x kg(-1) x h(-1) of CCK-8 or synthetic rat CCK-58 for 6 h, and pancreases were examined for morphological and biochemical indexes of acute pancreatitis. A second group was treated as above while monitoring pancreatic protein and water secretion. CCK-8 at 2 nmol x kg(-1) x h(-1) caused severe edematous pancreatitis as evidenced by morphological and biochemical criteria. CCK-58 at this dose had minimal or no effect on these indexes. CCK-58 at 4 nmol x kg(-1) x h(-1) increased some indexes of pancreatic damage but less than either the 2 or 4 nmol x kg(-1) x h(-1) dose of CCK-8. Pancreatic water and protein secretion were nearly or completely abolished within 3 h of onset of CCK-8 infusion, whereas water and protein secretion were maintained near basal levels in CCK-58-treated rats. We hypothesize that supramaximal CCK-58 does not induce pancreatitis because it maintains pancreatic acinar chloride and water secretion, which are essential for exocytosis of activated zymogens. We conclude that CCK-58 may be a valuable tool for investigating events that trigger pancreatitis.

A new model of chronic pancreatitis in rats.

This study was designed to examine whether continuous pancreatic ductal hypertension (PDH) plays an important role in the onset and development of chronic pancreatitis (CP). Pancreatic, biliary, and duodenal cannulas were implanted in male Wistar rats. PDH was induced by vertically raising the free end of the pancreatic duct cannula to exert a hydrostatic pressure and maintained for 2 wk. PDH was gradually increased, but when the pancreatic juice (PJ) flow was interrupted, PDH was decreased to restore PJ flow. The induction of PDH resulted in a marked reduction of amylase activity in PJ and an increase in serum amylase activity. At 2 wk after persistent PDH, pancreatic exocrine function was markedly decreased in response to a bolus injection of secretin (100 pmol/kg) compared with the control group. Histological examination revealed interlobular as well as intralobular fibrosis in the form of nodular pancreatitis at 2 wk after the induction of PDH. Immunohistochemistry revealed the expression of fibronectin and collagen types I and III. Quantitative real-time RT-PCR showed an increase in transforming growth factor-beta(1) mRNA expression in the pancreas during PDH. The present results suggest that PDH plays an important role in the onset and development of CP. Furthermore, our animal model seems useful for investigating the mechanisms of CP in rats.

Effect of inhibition of alpha-glucosidase on age-related glucose intolerance and pancreatic atrophy in rats.

Oral administration of alpha-glucosidase inhibitor reduces postprandial serum glucose and insulin concentrations; thus, alpha-glucosidase inhibitor is used for the treatment of diabetes mellitus worldwide. In our study, we have evaluated the effect of alpha-glucosidase inhibitor, acarbose, on age-related glucose intolerance and pancreatic atrophy in the Long-Evans Tokushima Otsuka (LETO) rat. The first group of rats received a standard rat diet (control). The second group received a diet containing acarbose (150 mg/100 g food) from 12 to 28 weeks and then switched to a standard rat diet until 72 weeks of age (A12-28W). The third group was administered the same diet containing acarbose from 12 to 72 weeks of age (A12-72W). Fasting serum glucose and insulin concentrations gradually increased with increasing age in the control group, but these increases were completely prevented (A12-72W) or delayed (A12-28W) by acarbose treatment. In addition, acarbose treatment prevented the deterioration in insulin resistance with increasing age. At 72 weeks of age, pancreatic wet weight and DNA content in the A12-72W group were significantly higher than those in the control group. Although most islets were enlarged, and some portions of pancreatic tissue contained fatty and connective tissue in the control group, these alterations were mild in the A12-28W group and remained minimal in the A12-72W group. Our study suggests that acarbose is useful in the prevention of age-related glucose intolerance and pancreatic atrophy.

Autoimmune pancreatitis with IgG4-positive plasma cell infiltration in salivary glands and biliary tract.

A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows: total protein 90 g/L with gamma-globulin of 37.3% (33 g/L), total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L, gamma-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated (18 900 mg/L). Computed tomography (CT) showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography (ERP) revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis (AIP) with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.

Bezafibrate on lipids and glucose metabolism in obese diabetic Otsuka Long-Evans Tokushima fatty rats.

Type 2 diabetes is caused by insulin resistance and beta-cell dysfunction. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established animal model of human type 2 diabetes that exhibits chronic and slowly progressive hyperglycemia and hyperlipidemia and is accompanied by progressive fibrosis in the islets. The aim of the present study was to examine whether worsening of hyperglycemia, insulin resistance, and histologic alterations of the islets in OLETF rats is related to hyperlipidemia by treating these animals with a lipid-lowering drug, bezafibrate. The bezafibrate-treated groups of OLETF and their control counterpart Long-Evans Tokushima Otsuka (LETO) rats received a bezafibrate-rich diet (150 mg/100 g normal chow) for 16 weeks, from 12 to 28 weeks of age, while the other groups of rats received standard rat chow. Bezafibrate treatment significantly reduced serum triglyceride (TG) and free fatty acid (FFA) levels, suppressed the increase in islet size, and inhibited the expression of alpha-smooth muscle actin, a marker for activated pancreatic stellate cells that are involved in the fibrosis of the pancreas, in the islets in OLETF rats, but had no influences on food intake, body weight gain, abdominal adipose depots, and pancreatic insulin content in both strains of rats. Although bezafibrate significantly reduced circulating lipid levels and suppressed the increase in insulin secretion evaluated by area under the curve (AUC) analysis in response to an intravenous glucose tolerance test (IVGTT) until the end of the experiment, improvement of insulin resistance was observed only for the first 8 weeks after the onset of bezafibrate treatment. These results suggest that dyslipidemia is not responsible for the reduced insulin sensitivity, but the impairment of glucose tolerance is the primary defect in the OLETF rats, although improvement of dyslipidemia suppressed histologic alterations in the islets and temporally improved insulin resistance.

Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats.

Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats.

Treatment for hyperglycemia promotes pancreatic regeneration in rats without CCK-1 receptor gene expression.

INTRODUCTION AND AIM: Recent studies have suggested that CCK is not essential for normal pancreatic growth in mice. We examined whether the treatment of hyperglycemia participates in a non-CCK-1-receptor-mediated mechanism of pancreatic regeneration after partial (30%) pancreatectomy (Px) with use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model for type 2 diabetes mellitus without CCK-1 receptor gene expression. METHODOLOGY: Male OLETF rats were divided into five groups at 24 weeks of age. The first group was killed to examine the pancreas at 24 weeks of age (PrePx). The second group underwent a midline laparotomy and received a standard rat chow (ShamPx). The remaining three groups of rats received one of the following three treatments after Px: a standard rat chow (PxC), a diet containing acarbose (PxA), or a standard rat chow and once-daily subcutaneous injection of insulin (PxI) for 8 weeks. RESULTS: PxC rats had significantly higher serum glucose levels than did PxA and PxI rats. Pancreatic weight and pancreatic contents of protein in PxA and PxI rats were significantly higher than in PxC rats. The pancreas in PxC rats was atrophic, and marked inflammatory cell infiltration was observed in the pancreas. In addition, tumor necrosis factor-alpha (TNFalpha) was expressed in the inflammatory cells, acinar cells, and islets in PxC rats. However, histologic alterations, including expression of TNFalpha, remained at a minimum in PxA and PxI rats. CONCLUSION: We conclude that the control of serum glucose levels plays an important role in preventing pancreatic atrophy and participates in the non-CCK-1-receptor-mediated mechanisms of pancreatic growth in rats.