Pancreatic Extracts for the Treatment of Diabetes (1889-1914): Acomatol.

BACKGROUND: Historical review on the early development of organotherapy for diabetes [pancreatic extracts (PE)] and its relationship with the social and political circumstances. AREAS OF UNCERTAINTY: The diagnosis of diabetes relied only in the presence of glycosuria and cardinal symptoms. Blood glucose determinations were not regularly available, requiring large volumes for sampling. Micromethods for glycemia were developed just in the last years of the investigated period. Hypoglycemia remains undiscovered. Isolation and purification of PE were difficult tasks due to the unknown chemical structure of the antidiabetic hormone. DATA SOURCES: (1) Berliner Medizinhistoriches Museum der Charité (Humboldt University). (2) GeDenKort Charité-Wissenschaft in Verantwortung. (3) Geheim Staatsarchiv Preußischer Kulturbesitz. (4) Archival Collections, University of Toronto: Thomas Fisher Rare Book Library. Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. J. R. Macleod Papers. (5) National Library of Medicine: Pubmed search for the topic of history of insulin. History of Medicine-on syllabus archive. (6) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); Brown-Séquard (M. J. Aminoff); Diabetes: The Biography (R. Tattersall); The Endocrine Organs (E. Schäfer); The Internal Secretions (E. Gley); Health, race and German politics between national unification and Nazism, 1870-1945 (P. Weindling). THERAPEUTIC ADVANCES: Demonstration that diabetes is a pancreatic disease. The outstanding progress of medical physiology led to the birth of endocrinology and the key concepts of homeostasis. Experimental scientists designed new procedures for complete pancreatectomy and elaboration of PE containing the antidiabetic principle. Organotherapy achieved complete success in the treatment of myxedema and partial success in the treatment of experimental and clinical diabetes. CONCLUSIONS: The organotherapy of diabetes was an obliged step to facilitate the identification of the antidiabetic hormone. Organotherapy of diabetes was a paradigm for the integration of basic and applied knowledge about hormone action and development of endocrine pharmacology.

Effect of Catha edulis (khat) on pancreatic functions in streptozotocin-induced diabetes in male Sprague-Dawley rats.

People consume Catha edulis (khat) for its euphoric effect, and type 1 diabetics have claimed that khat could reduce elevated levels of blood sugar. However, khat has been suggested to provoke diabetes mellitus through destruction of pancreatic ß-cells. This study investigated the effect of an ethanolic khat extract on pancreatic functions in type 1 diabetes (T1DM)-induced male Sprague-Dawley rats and to assess its in vitro cytotoxicity in rat pancreatic ß-cells (RIN-14B). T1DM was induced in a total of 20 rats with a single intraperitoneal injection of 75 mg/kg of streptozotocin. The rats were distributed into four groups (n=5): the diabetic control, 8 IU insulin-treated, 200 mg/kg khat-treated, and 400 mg/kg khat-treated groups. Another 5 rats were included as a nondiabetic control. Body weight, fasting blood sugar, and caloric intake were recorded weekly. Four weeks after treatment, the rats were sacrificed, and blood was collected for insulin, lipid profile, total protein, amylase, and lipase analysis, while pancreases were harvested for histopathology. In vitro, khat exerted moderate cytotoxicity against RIN-14B cells after 24 and 48 h but demonstrated greater inhibition against RIN-14B cells after 72 h. Neither 200 mg/kg nor 400 mg/kg of khat produced any significant reduction in blood sugar; however, 200 mg/kg khat extract provoked more destruction of pancreatic ß-cells as compared with the diabetic control. Ultimately, neither 200 mg/kg nor 400 mg/kg of khat extract could produce a hypoglycemic effect in T1DM-induced rats. However, 200 mg/kg of khat caused greater destruction of pancreatic ß-cells, implying that khat may cause a direct cytotoxic effect on pancreatic ß-cells in vitro.

The ageing pancreas: a systematic review of the evidence and analysis of the consequences.

Senior people constitute the fastest growing segment of the population. The elderly are at risk for malnutrition, thought to be caused by reduced food intake or involution of the physiological capacity of the GI tract. Age-related changes are well known in other secretory organs such as liver, kidney and intestine. The pancreas, representing a metabolically active organ with uptake and breakdown of essential nutritional components, changes its morphology and function with age. During childhood, the volume of the pancreas increases, reaching a plateau between 20 and 60 years, and declines thereafter. This decline involves the pancreatic parenchyma and is associated with decreased perfusion, fibrosis and atrophy. As a consequence of these changes, pancreatic exocrine function is impaired in healthy older individuals without any gastrointestinal disease. Five per cent of people older than 70 years and ten per cent older than 80 years have pancreatic exocrine insufficiency (PEI) with a faecal elastase-1 below 200 µg g-1 stool, and 5% have severe PEI with faecal elastase-1 below 100 µg g-1 stool. This may lead to maldigestion and malnutrition. Patients may have few symptoms, for example steatorrhoea, diarrhoea, abdominal pain and weight loss. Malnutrition consists of deficits of fat-soluble vitamins and is affecting both patients with PEI and the elderly. Secondary consequences may include decreased bone mineral density and results from impaired absorption of fat-soluble vitamin D due to impaired pancreatic exocrine function. The unanswered question is whether this age-related decrease in pancreatic function warrants therapy. Therapeutic intervention, which may consist of supplementation of pancreatic enzymes and/or vitamins in aged individuals with proven exocrine pancreas insufficiency, could contribute to healthy ageing.

Guerilla Warfare on the Pancreas? A Case of Acute Pancreatitis From a Supplement Known to Contain Anabolic-Androgenic Steroids.

INTRODUCTION: Performance-enhancing drugs (PEDs) are commonly consumed in the United States with high prevalence of use in athlete populations and increased use by deployed service members. Many PEDs may contain anabolic-androgenic steroids (AAS), which are legally restricted and prohibited by many agencies due to their health risk. CASE DESCRIPTION: A unique case of acute pancreatitis associated with the use of the PED "Guerilla Warfare," a labeled AAS-containing supplement, is presented. The patient is a healthy 20-year-old male Marine who presented with multiple episodes of abdominal cramps each day for a month with decreased appetite and nonbilious vomiting. He reported a 6-week history of "Guerilla Warfare" PED use and review of systems identified fatigue and 12 lb reported weight loss. He presented with normal vital signs, tenderness in upper abdominal quadrants, elevated lipase (909 units/L), lactate dehydrogenase (193 units/L), and an enlarged pancreas with surrounding inflammation on computed tomography. SUMMARY: This constitutes the first report of acute pancreatitis with the use of "Guerilla Warfare," and the second reported case with the use of any AAS-containing PED. Increased awareness of significant PED-associated adverse effects by both the civilian and military communities is needed to better characterize these risks moving forward.

The effect of H19-miR-29b interaction on bleomycin-induced mouse model of idiopathic pulmonary fibrosis.

Pulmonary fibrosis, characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicable on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been reported yet. In the present study, we investigated the hypothesis that H19 play a promotive role in bleomycin-induced epithelial-mesenchymal transition of alveolar epithelial cell, and H19 exerts its effect through miR-29b regulation. H19 expression was positively correlated with COL1A1 and Acta2 expression; H19 knockdown inhibited COL1A1 and Acta2 expression. Moreover, H19 interacted with miR-29b through directly binding to the 3'UTR; miR-29b inhibited COL1A1 expression by directly binding to the 3'UTR. In conclusion, we revealed the promotive effect of H19 on BLM-induced IPF, and demonstrated the mechanism by which H19/miR-29b interaction exerts its effect on regulating pulmonary fibrosis. The present study provided a potential therapy to treat IPF.

Pancreatic functions in adolescents with beta thalassemia major could predict cardiac and hepatic iron loading: relation to T2-star (T2*) magnetic resonance imaging.

The aim of this study is to assess the correlation between cardiac and hepatic T2* MRI findings with the endocrine and exocrine pancreatic functions in known patients with ß-thalassaemia major (ß-TM). A total of 50 adolescent patients with ß-TM and 44 healthy controls were investigated via: serum amylase, lipase, triglyceride index, oral glucose tolerance test and T2* MRI, to assess iron content in the heart and liver. Diabetes was found in 20%, and 40% of patients had impaired fasting glucose (IFG). Cardiac T2* was less than 10 ms in 22% indicating heavy load with iron in cardiac tissues. There was a significant decrease in median serum amylase (63.5 vs 87.5 IU/L, p=0.003) and lipase (63 vs 90 IU/L, p=0.017) among patients in comparison with the control group. Patients with ß-TM and diabetes had lower serum amylase (32 vs 68 IU/L), lipase (28 vs 79 IU/L), cardiac and hepatic T2* MRI (7 vs 25.5 ms; 3 vs 6 ms, p<0.001 for all) than those without diabetes. Similar results were found among patients with IFG when compared with others (p<0.001 for all). Cardiac and hepatic T2* were inversely correlated to triglyceride index (r=-0.376, p=0.014 and r=-0.475, p=0.001, respectively) and positively correlated to amylase (r=0.791 and r=0.790) and lipase (r=0.784 and r=0.783; p<0.001 for all). The endocrine and exocrine pancreatic functions might become an equivalent predictor to cardiac and hepatic iron overload, especially in countries where MRI is not available or where it is expensive. The early occurrence of these abnormalities warrants more intensive chelation therapy.

Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal

This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and beta cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and beta cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent (AU)

Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

CONTEXT: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. SETTING: International referral centre for the management of CHI. PATIENTS: Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. INTERVENTION: Near-total pancreatectomy. MAIN OUTCOME MEASURES: Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. RESULTS: Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g). Clinical exocrine insufficiency was observed in 22 (49%) patients. No statistically significant difference in weight and height standard deviation score (SDS) was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients. CONCLUSIONS: The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation.

Medical management of pain in chronic pancreatitis.

Chronic pancreatitis is a common disorder caused by various etiological factors. It usually manifests with abdominal pain and exocrine (steatorrhea, malnutrition) or endocrine insufficiency (diabetes mellitus). Abdominal pain is the dominant symptom in these patients. Medical, endoscopic and surgical modalities are available for therapy. This review focuses on the pharmacological approaches to manage pancreatic pain. Before embarking on medical management of pain it is prudent to exclude complications like pancreatic cancer, pseudocysts, inflammatory mass, biliary or duodenal obstruction which may contribute to abdominal pain. Pharmacological measures for pain relief include central analgesics, enzyme supplements and antioxidants. Other measures include endoscopic and surgical therapy which are not discussed here. Appropriate management of exocrine and endocrine insufficiency and successful control of diabetes are also important in the management of chronic pancreatitis.

Oral administration of ginseng ameliorates cyclosporine-induced pancreatic injury in an experimental mouse model.

BACKGROUND: This study was performed to investigate whether ginseng has a protective effect in an experimental mouse model of cyclosporine-induced pancreatic injury. METHODS: Mice were treated with cyclosporine (30 mg/kg/day, subcutaneously) and Korean red ginseng extract (0.2 or 0.4 g/kg/day, oral gavage) for 4 weeks while on a 0.01% salt diet. The effect of ginseng on cyclosporine-induced pancreatic islet dysfunction was investigated by an intraperitoneal glucose tolerance test and measurements of serum insulin level, ß cell area, macrophage infiltration, and apoptosis. Using an in vitro model, we further examined the effect of ginseng on a cyclosporine-treated insulin-secreting cell line. Oxidative stress was measured by the concentration of 8-hydroxy-2'-deoxyguanosine in serum, tissue sections, and culture media. RESULTS: Four weeks of cyclosporine treatment increased blood glucose levels and decreased insulin levels, but cotreatment with ginseng ameliorated the cyclosporine-induced glucose intolerance and hyperglycemia. Pancreatic ß cell area was also greater with ginseng cotreatment compared with cyclosporine monotherapy. The production of proinflammatory molecules, such as induced nitric oxide synthase and cytokines, and the level of apoptotic cell death also decreased in pancreatic ß cell with ginseng treatment. Consistent with the in vivo results, the in vitro study showed that the addition of ginseng protected against cyclosporine-induced cytotoxicity, inflammation, and apoptotic cell death. These in vivo and in vitro changes were accompanied by decreases in the levels of 8-hydroxy-2'-deoxyguanosine in pancreatic ß cell in tissue section, serum, and culture media during cotreatment of ginseng with cyclosporine. CONCLUSIONS: The results of our in vivo and in vitro studies demonstrate that ginseng has a protective effect against cyclosporine-induced pancreatic ß cell injury via reducing oxidative stress.

Graptopetalum paraguayense and resveratrol ameliorates carboxymethyllysine (CML)-induced pancreas dysfunction and hyperglycemia.

Hyperglycemia is associated with advanced glycation end products (AGEs). Recently, AGEs were found to cause pancreatic damage, oxidative stress, and hyperglycemia through the AGE receptor. Carboxymethyllysine (CML) is an AGE but whether it induces pancreatic dysfunction remains unclear. Graptopetalum paraguayense, a vegetable consumed in Taiwan, has been used in folk medicine and is an antioxidant that protects against liver damage. We investigated the protective properties of G. paraguayense 95% ethanol extracts (GPEs) against CML-induced pancreatic damage. The results indicated that resveratrol, GPE, and gallic acid (the active compound of GPE) increased insulin synthesis via upregulation of pancreatic peroxisome proliferator activated-receptor-γ (PPARγ) and pancreatic-duodenal homeobox-1 (PDX-1) but inhibited the expression of CML-mediated CCAAT/enhancer binding protein-ß (C/EBPß), a negative regulator of insulin production. Moreover, resveratrol and GPE also strongly activated nuclear factor-erythroid 2-related factor 2 (Nrf2) to attenuate oxidative stress and improve insulin sensitivity in the liver and muscle of CML-injected C57BL/6 mice and resulted in reduced blood glucose levels. Taken together, these findings suggested that GPE and gallic acid could potentially be used as a food supplement to protect against pancreatic damage and the development of diabetes.

Neuroendocrine and cardiac metabolic dysfunction and NLRP3 inflammasome activation in adipose tissue and pancreas following chronic spinal cord injury in the mouse.

CVD (cardiovascular disease) represents a leading cause of mortality in chronic SCI (spinal cord injury). Several component risk factors are observed in SCI; however, the underlying mechanisms that contribute to these risks have not been defined. Central and peripheral chronic inflammation is associated with metabolic dysfunction and CVD, including adipokine regulation of neuroendocrine and cardiac function and inflammatory processes initiated by the innate immune response. We use female C57 Bl/6 mice to examine neuroendocrine, cardiac, adipose and pancreatic signaling related to inflammation and metabolic dysfunction in response to experimentally induced chronic SCI. Using immuno-histochemical, -precipitation, and -blotting analysis, we show decreased POMC (proopiomelanocortin) and increased NPY (neuropeptide-Y) expression in the hypothalamic ARC (arcuate nucleus) and PVN (paraventricular nucleus), 1-month post-SCI. Long-form leptin receptor (Ob-Rb), JAK2 (Janus kinase)/STAT3 (signal transducer and activator of transcription 3)/p38 and RhoA/ROCK (Rho-associated kinase) signaling is significantly increased in the heart tissue post-SCI, and we observe the formation and activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome in VAT (visceral adipose tissue) and pancreas post-SCI. These data demonstrate neuroendocrine signaling peptide alterations, associated with central inflammation and metabolic dysfunction post-SCI, and provide evidence for the peripheral activation of signaling mechanisms involved in cardiac, VAT and pancreatic inflammation and metabolic dysfunction post-SCI. Further understanding of biological mechanisms contributing to SCI-related inflammatory processes and metabolic dysfunction associated with CVD pathology may help to direct therapeutic and rehabilitation countermeasures.

High-fat diets containing soybean or canola oil affect differently pancreas function of young male rats.

The excessive fat intake generally might induce obesity and metabolic disturbances. Thus, the goal of the study was to assess the role of high-fat diets containing soybean or canola oil on intra-abdominal adiposity and pancreatic morphology and function of young rats. After weaning, rats were fed with a control diet (7S) or a high-fat diet containing soybean oil (19S) or canola oil (19C) until they were 60 days old, when they were sacrificed. Food intake (g/day), body mass and length, retroperitoneal and epididymal fat mass, HOMA-IR, HOMA-ß and area of pancreatic islets were assessed. The results were considered different with a significant level of p<0.05. Both 19S and 19C groups showed higher body mass, length, and retroperitoneal fat mass. The 19C group showed higher HOMA-IR (+43% and +78%) and HOMA-ß (+40% and +59%) than 19S and 7S groups, respectively. Both 19S and 19C groups showed lower pancreatic islets area in relation to 7S group. Meantime, 19C presented lower percentage of pancreatic islets area in comparison to 19S (-41%) and 7S group (-70%, p<0.0001). Independent of soybean or canola oil, the high fat diet promoted development of the obesity. Comparing 19C and 19S groups, the higher concentrations of monounsaturated fatty acids, present in the canola oil were worse than higher concentrations of polyunsaturated fatty acids, present in the soybean oil.

Long-term outcomes after Frey's procedure for chronic pancreatitis with an inflammatory mass of the pancreatic head, with special reference to locoregional complications.

BACKGROUND: Frey's procedure might be a good alternative to pylorus-preserving pancreaticoduodenectomy (PPPD) for patients with an inflammatory mass of the head of the pancreas, because it is technically easy and associated with low morbidity and good pain relief. PURPOSE: To analyze the short-term and long-term outcomes of Frey's procedure in comparison with PPPD and to evaluate the efficacy of Frey's procedure against preoperative locoregional complications. PATIENTS AND METHODS: From August 1997 through December 2007, 6 patients underwent Frey's procedure (as described by Frey and Smith), and 10 patients underwent PPPD. The mean follow-up times were 70.8 months (Frey's procedure) and 119.8 months (PPPD). Preoperative biliary stricture and duodenal stenosis were observed in 4 and 3 patients, respectively, of patients undergoing Frey's procedure. Pain intensity was assessed with a pain scoring system. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of-Life Questionnaire-Core 30. Exocrine and endocrine pancreatic function was measured during follow-up. RESULTS: Significant reductions in total pain scores and all QOL scale scores were observed immediately after surgery in all patients (P<0.05). Frey's procedure was superior to PPPD with regard to physical status 7 years after surgery (P<0.05). One patient in the Frey group had a grade B pancreatic fistula, and 2 patients in the PPPD group had intra-abdominal bleeding and delayed gastric emptying. There were no re-operations or surgery-related deaths in either group. Diabetes developed postoperatively in 2 patients in the PPPD group. No patients with preoperative duodenal or biliary stricture or both had a relapse. Three patients in the PPPD group died during follow-up of diseases unrelated to chronic pancreatitis. CONCLUSION: Frey's procedure is safe and effective with regard to pain relief, preservation of pancreatic function, and improvement of QOL over the long term. Moreover, this procedure can also be used to treat preoperative biliary stricture and duodenal stenosis associated with an inflammatory mass of the pancreatic head.

The role of circadian clocks in metabolic disease.

The circadian clock is a highly conserved timing system, resonating physiological processes to 24-hour environmental cycles. Circadian misalignment is emerging as a risk factor of metabolic disease. The molecular clock resides in all metabolic tissues, the dysfunction of which is associated with perturbed energy metabolism. In this article, we will review current knowledge about molecular mechanisms of the circadian clock and the role of clocks in the physiology and pathophysiology of metabolic tissues.

Ghrelin's second life: from appetite stimulator to glucose regulator.

Ghrelin, a 28 amino acid peptide hormone produced by the stomach, was the first orexigenic hormone to be discovered from the periphery. The octanoyl modification at Ser³, mediated by ghrelin O-acyltransferase (GOAT), is essential for ghrelin's biological activity. Ghrelin stimulates food intake through binding to its receptor (GRLN-R) on neurons in the arcuate nucleus of the hypothalamus. Ghrelin is widely expressed throughout the body; accordingly, it is implicated in several other physiological functions, which include growth hormone release, gastric emptying, and body weight regulation. Ghrelin and GRLN-R expression are also found in the pancreas, suggesting a local physiological role. Accordingly, several recent studies now point towards an important role for ghrelin and its receptor in the regulation of blood glucose homeostasis, which is the main focus of this review. Several mechanisms of this regulation by ghrelin have been proposed, and one possibility is through the regulation of insulin secretion. Despite some controversy, most studies suggest that ghrelin exerts an inhibitory effect on insulin secretion, resulting in increased circulating glucose levels. Ghrelin may thus be a diabetogenic factor. Obesity-related type 2 diabetes has become an increasingly important health problem, almost reaching epidemic proportions in the world; therefore, antagonists of the ghrelin-GOAT signaling pathway, which will tackle both energy- and glucose homeostasis, may be considered as promising new therapies for this disease.

Dietary d-limonene alleviates insulin resistance and oxidative stress-induced liver injury in high-fat diet and L-NAME-treated rats.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common etiologies of chronic liver disease worldwide. The pathogenesis of metabolic syndrome associated with NAFLD is still under debate. AIM OF THE SCOPE: This study has investigated the hepatic biochemical and histological changes and also insulin resistance in metabolic syndrome associated with NAFLD. METHODS: Young male Wistar rats fed a high-fat diet (HFD 42.2% beef tallow) together with N ( ω )-nitro-L-arginine methyl ester (L-NAME; 80 mg/L in drinking water) for 8 weeks and subsequently with 2% d-limonene for the final 4 weeks. RESULTS: HFD-fed rats treated with L-NAME showed increased systolic blood pressure, heart rate, fasting blood glucose, plasma insulin, hepatic marker enzymes, hepatic lipids, circulatory lipid peroxidation by-products, and hepatic phase I enzyme activities with decreased circulatory nonenzymic antioxidant concentrations and hepatic phase II enzyme activities. Dietary supplementation with d-limonene reversed the HFD and L-NAME-induced changes and restored pathological alteration of liver and pancreas. CONCLUSIONS: These data provide new insights into the therapeutic approach of d-limonene against the development of the metabolic syndrome associated with NAFLD.

The flavonoid-rich fraction of Coreopsis tinctoria promotes glucose tolerance regain through pancreatic function recovery in streptozotocin-induced glucose-intolerant rats.

AIM OF THE STUDY: Infusions of Coreopsis tinctoria Nutt. flowering tops have been used traditionally in Portugal to control hyperglycaemia and a previous study revealed that daily administration of the infusion during a 3-week period promoted the recovery of glucose tolerance by a mechanism different from inhibition of glucose absorption and direct promotion of insulin secretion. We know report the study of the ethyl acetate fraction of Coreopsis tinctoria flowers infusion aiming to confirm flavonoids as bioactive metabolites. To give one step forward into the antihyperglycaemic mechanism of action of this traditionally used plant we also studied the activity of Coreopsis tinctoria flavonoids on the pancreatic function of glucose-intolerant rats. A standard antioxidant, Trolox, was also studied for comparative purposes as the antioxidant mechanism has been frequently purposed as one of the mechanisms mediating antihyperglycaemic effects of flavonoid-rich extracts. MATERIAL AND METHODS: Thirteen compounds, mainly of flavanone and chalcone flavonoidal type, have been identified in this fraction by HPLC-DAD-ESI-MS/MS, and the major one (marein) quantified by HPLC-UV. The fraction (125 mg containing 20 mg of marein/kg b.w.) and Trolox (50 mg/kg b.w.) were administered daily by oral gavage to normal and STZ (40 mg/kg b.w.)-induced glucose-intolerant Wistar rats for 3 weeks. Blood glucose levels were measured weekly by Oral Glucose Tolerance Test. Pancreatic function was evaluated by plasma lipase of treated and non-treated glucose-tolerant and- intolerant rats after the 3-week treatment period. RESULTS: After 2 weeks oral treatment with Coreopsis tinctoria AcOEt fraction the animals were no longer glucose-intolerant, an effect maintained over the remaining experimental period. Additionally, plasma lipase values of glucose-intolerant animals treated with the AcOEt fraction (13.5 ± 0.84 U/L) showed a clear reduction when compared with the glucose-intolerant group (34.60 ± 1.76 U/L; P<0.001) and normoglycaemic control (8.35 ± 0.69 U/L) demonstrating recovery of pancreatic function. On the other hand, treatment with standard antioxidant Trolox had no effect on glucose homeostasis of glucose-intolerant rats. The oral treatment with Coreopsis tinctoria fraction caused no hepatotoxicity, as determined by blood alanine and aspartate transaminases, and had also no effect on glucose homeostasis and pancreatic function of normal rats. CONCLUSIONS: AcOEt fraction, containing the same amount of marein as the infusion, promoted glucose tolerance regain in the rats more quickly, which means that the bioactivity is probably due to the several flavonoids present in Coreopsis tinctoria extracts and not to marein alone. The results also strongly suggest that these compounds act by promoting pancreatic cell function recovery from STZ-induced injury, possibly through a mechanism of action other than merely antioxidant mediated.

Evaluation and management of pain in autosomal dominant polycystic kidney disease.

Transient episodes of pain are common in autosomal dominant polycystic kidney disease (ADPKD). A small fraction of patients have disabling chronic pain. In this review, we discuss the etiologies of pain in ADPKD; review how ADPKD patients should be assessed; and discuss medical, surgical, and other management options.

Enhancement of organ regeneration in animal models by a stem cell-stimulating plant mixture.

Adult stem cells play an important role in the regeneration of damaged organs. Attempts have already been made to enhance stem cell production by cytokines, in order to increase the improvement of cardiac functions after myocardial infarction. In our present study we investigated the possibility whether instead of cytokine injection dietary stimulation of stem cell production accelerates the organ regeneration in animals. A dietary supplement, Olimpiq StemXCell (Crystal Institute Ltd., Eger, Hungary), containing plant extracts (previously proved to increase the number of circulating CD34(+) cells) was consumed in human equivalent doses by the experimental animals. In the first experiment carbon tetrachloride was applied to CBA/Ca mice, to induce liver damage, and liver weights between StemXCell-fed and control animals were compared 10 days after the treatment. In the second model experimental diabetes was induced in F344 rats by alloxan. Blood sugar levels were measured for 5 weeks in the control and StemXCell-fed groups. The third part of the study investigated the effect of StemXCell on cardiac functions. Eight weeks after causing a myocardial infarction in Wistar rats by isoproterenol, left ventricular ejection fraction was determined as a functional parameter of myocardial regeneration. In all three animal models StemXCell consumption statistically significantly improved the organ regeneration (relative liver weights, 4.78 +/-0.06 g/100 g vs. 4.97 +/- 0.07 g/100 g; blood sugar levels at week 5, 16 +/- 1.30 mmol/L vs. 10.2 +/- 0.92 mmol/L; ejection fraction, 57.5 +/- 2.23 vs. 68.2 +/- 4.94; controls vs. treated animals, respectively). Our study confirms the hypothesis that dietary enhancement of stem cell production may protect against organ injuries and helps in the regeneration.