Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment.

BACKGROUND: Association of Alzheimer's Disease (AD) with Type 2 Diabetes (T2D) has been well established. Cyclo(His-Pro) plus zinc (Cyclo-Z) treatment ameliorated diabetes in rats and similar improvements have been seen in human patients. Treatment of amyloid precursor protein (APP) transgenic mice with Cyclo-Z exhibited memory improvements and significantly reduced Aß-40 and Aß-42 protein levels in the brain tissues of the mice. SCOPE OF REVIEW: Metabolic relationship between AD and T2D will be described with particular attention to insulin sensitivity and Aß degradation in brain and plasma tissues. Mechanistic effect of insulin degrading enzyme (IDE) in decreasing blood glucose and brain Aß levels will be elucidated. Cyclo-Z effects on these biochemical parameters will be discussed. MAJOR CONCLUSION: Stimulation of IDE synthesis is effective for the clinical treatment of metabolic diseases including AD and T2D. GENERAL SIGNIFICANCE: Cyclo-Z might be the effective treatment of AD and T2D by stimulating IDE synthesis.

Raw vegetable food containing high cyclo (his-pro) improved insulin sensitivity and body weight control.

Cyclo (his-pro), controlled-energy diet, soy protein hydrolysate (SPH), and raw vegetable food (RVF) are known to improve insulin sensitivity and body weight (BW) control. Enhancement of high cyclo (his-pro) content in SPH (HCS) was performed by refluxing SPH with 1 N KH(2)CO(3) dissolved in 70% ethanol for 2 weeks at room temperature. Using this material, we examined the effects of HCS plus RVF on glucose metabolism and BW control in genetically diabetic Goto-Kakizaki (G-K) and insulin-resistant aged overweight Sprague-Dawley (S-D) rats. Thirty 7-week-old G-K rats and 18 16- to 18-month-old S-D rats were divided into 3 groups and treated with normal chow (NC), RVF diet, or HCS diet for 8 weeks. Raw vegetable food diet was made of 1:3 RVF and 2:3 NC; HCS diet was made of 1:27 portion HCS, 8:27 RVF, and 2:3 NC. Oral glucose tolerance significantly improved in both RVF- (P<.01) and HCS-treated (P<.001) G-K rats and worsened in NC-fed rats compared with the baseline values. Similarly, oral glucose tolerance also improved in aged overweight S-D rats when treated with RVF (P<.05) and with HCS (P<.01), compared with the baseline values. Although HCS diet treatment very significantly lowered fed plasma insulin levels compared with NC diet treatment in G-K rats (P<.01), RVF diet treatment alone did not decrease plasma insulin levels. In contrast, there was no change of insulin levels in overweight aged S-D rats after either RVF or HCS diet treatment. Postfeeding glucose levels in G-K rats fed RVF or HCS significantly fell, compared with the rats fed NC (P<.05). Interestingly, fasting blood glucose levels in RVF- or HCS-fed rats were very significantly lower than in NC-fed rats (P<.001). There was no change of blood glucose levels in S-D rats due to treatments with different diet. In G-K rats, food intake did not decrease during the first 3 weeks but fell very significantly from the fifth to eighth weeks with RVF (P<.01) and HCS (P<.001) treatments in G-K rats. However, food intake reduction in aged S-D rats was shown only for the HCS-treated rat group (P<.05). Water intake slightly decreased in G-K rats with either RVF or HCS treatment (P<.05) but very significantly decreased in S-D rats with HCS treatment (P<.01). Body weight gain in young G-K rats and BW in aged S-D rats significantly decreased only when rats were treated with HCS diet (P<.05). These data suggest that regular consumption of HCS diet helps to control blood glucose metabolism in diabetic G-K rats and BW control in aged obese S-D rats.

Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury.

Cyclooxygenase-2 (COX-2), a widely distributed enzyme, plays an important role in inflammation. We have studied the role of COX-2 in acute pancreatitis and pancreatitis-associated lung injury using both the pharmacological inhibition of COX-2 and genetic deletion of COX-2. Pancreatitis was induced in mice by 12 hourly injections of cerulein. The severity of pancreatitis was assessed by measuring serum amylase, pancreatic trypsin activity, intrapancreatic sequestration of neutrophils, and acinar cell necrosis. The severity of lung injury was evaluated by measuring lactate dehydrogenase levels in the bronchoalveolar lavage fluid and by quantitating neutrophil sequestration in the lung. In both the pharmacologically inhibited and genetically altered mice, the severity of pancreatitis and pancreatitis-associated lung injury was reduced compared with the noninhibited strains of COX-2-sufficient mice. This reduction in injury indicates that COX-2 plays an important proinflammatory role in pancreatitis and its associated lung injury. Our findings support the concept that COX-2 inhibitors may play a beneficial role in the prevention of acute pancreatitis or in the reduction of its severity.

Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity.

Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell injury in response to supramaximal secretagogue stimulation could be prevented by the cell permeant cathepsin B inhibitor E64d (Saluja A, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, and Steer ML. Gastroenterology 113: 304-310, 1997). The present studies evaluated the role of intrapancreatic trypsinogen activation, this time under in vivo conditions, in two models of pancreatitis by using another highly soluble cell permeant cathepsin B inhibitor, L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-L-isoleucyl-L-proline methyl ester (CA-074me). Intravenous administration of CA-074me (10 mg/kg) before induction of either secretagogue-elicited pancreatitis in mice or duct infusion-elicited pancreatitis in rats markedly reduced the extent of intrapancreatic trypsinogen activation and substantially reduced the severity of both pancreatitis models. These observations support the hypothesis that, during the early stages of pancreatitis, trypsinogen activation in the pancreas is mediated by the lysosomal enzyme cathepsin B. Our findings also suggest that pharmacological interventions that inhibit cathepsin B may prove useful in preventing acute pancreatitis or reducing its severity.

Thermal stress-induced HSP70 mediates protection against intrapancreatic trypsinogen activation and acute pancreatitis in rats.

BACKGROUND & AIMS: Prior thermal stress induces heat shock protein 70 (HSP70) expression in the pancreas and protects against secretagogue-induced pancreatitis, but it is not clear that this thermal stress-induced protection is actually mediated by HSP70 since thermal stress may have other, non-HSP related, effects. METHODS: In the present study, we have administered antisense (AS) oligonucleotides, which prevent pancreatic expression of HSP70 to rats, in vivo, to evaluate this issue. In a separate series of experiments, designed to examine the role of pancreatitis-induced HSP70 expression in modulating the severity of pancreatitis, rats not subjected to prior thermal stress were given AS-HSP70 before cerulein administration, and trypsinogen activation as well as the severity of pancreatitis were evaluated. RESULTS: Hyperthermia induced HSP70 expression, prevented intrapancreatic trypsinogen activation, and protected against cerulein-induced pancreatitis. Administration of AS-HSP70 but not sense-HSP70 reduced the thermal stress-induced HSP70 expression, restored the ability of supramaximal cerulein stimulation to cause intrapancreatic trypsinogen activation, and abolished the protective effect of prior thermal stress against pancreatitis. In non-thermally stressed animals, pretreatment with AS-HSP70 before the induction of pancreatitis exacerbated all the parameters associated with pancreatitis. CONCLUSIONS: These findings lead us to conclude that HSP70 induction, rather than some other thermal stress-related phenomenon, mediates the thermal stress-induced protection against pancreatitis and that it protects against pancreatitis by preventing intrapancreatic activation of trypsinogen. The worsening of pancreatitis, which occurs when non-thermally stressed animals are given AS-HSP70 before cerulein, suggests that cerulein-induced HSP70 expression in nontreated animals acts to limit the severity of pancreatitis.