text:
Read 280.pdf text version
Online Submissions: wjg.wjgnet.com [email protected] doi:10.3748/wjg.15.280
© 2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol 2009 January 21; 15(3): 280-288 World Journal of Gastroenterology ISSN 1007-9327
Liver cirrhosis and diabetes: Risk factors, pathophysiology, clinical implications and management
Diego Garcia-Compean, Joel Omar Jaquez-Quintana, Jose Alberto Gonzalez-Gonzalez, Hector Maldonado-Garza
Diego Garcia-Compean, Joel Omar Jaquez-Quintana, Jose Alberto Gonzalez-Gonzalez, Hector MaldonadoGarza, Department of Gastroenterology, Faculty of Medicine, University Hospital, Ave Madero y Gonzalitos, Col Mitras Centro, Monterrey 64700, Mexico Author contributions: Garcia-Compean D wrote the manuscript; Jaquez-Quintana JO did the bibliographic research; GonzalezGonzalez JA and Maldonado-Garza H reviewed the text. Correspondence to: Diego Garcia-Compean, Department of Gastroenterology, Faculty of Medicine, University Hospital, Ave Madero y Gonzalitos, Col Mitras Centro, Monterrey 64700, Mexico. [email protected] Telephone: +52-81-83487315 Fax: +52-81-89891381 Received: November 12, 2008 Revised: November 19, 2008 Accepted: November 26, 2008 Published online: January 21, 2009
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Insulin resistance; Type 2 diabetes mellitus; Liver cirrhosis; Hepatocellular carcinoma; Chronic hepatitis C Peer reviewer: Yasuji Arase, MD, Department of Gastroenterology, Toranomon Hospital, 2-2-2Toranomonminato-ku, Tokyo 105-8470, Japan Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H. Liver cirrhosis and diabetes: Risk factors, pathophysiology, clinical implications and management. World J Gastroenterol 2009; 15(3): 280-288 Available from: URL: http://www.wjgnet.com/1007-9327/15/280.asp DOI: http://dx.doi.org/10.3748/wjg.15.280
About 30% of patients with cirrhosis have diabetes mellitus (DM). Nowadays, it is a matter for debate whether type 2 DM in the absence of obesity and hypertriglyceridemia may be a risk factor for chronic liver disease. DM, which develops as a complication of cirrhosis, is known as "hepatogenous diabetes". Insulin resistance in muscular and adipose tissues and hyperinsulinemia seem to be the pathophysiologic bases of diabetes in liver disease. An impaired response of the islet -cells of the pancreas and hepatic insulin resistance are also contributory factors. Non-alcoholic fatty liver disease, alcoholic cirrhosis, chronic hepatitis C (CHC) and hemochromatosis are more frequently associated with DM. Insulin resistance increases the failure of the response to treatment in patients with CHC and enhances progression of fibrosis. DM in cirrhotic patients may be subclinical. Hepatogenous diabetes is clinically different from that of type 2 DM, since it is less frequently associated with microangiopathy and patients more frequently suffer complications of cirrhosis. DM increases the mortality of cirrhotic patients. Treatment of the diabetes is complex due to liver damage and hepatotoxicity of oral hypoglycemic drugs. This manuscript will review evidence that exists in relation to: type 2 DM alone or as part of the metabolic syndrome in the development of liver disease; factors involved in the genesis of hepatogenous diabetes; the impact of DM on the clinical outcome of liver disease; the management of DM in cirrhotic patients and the role of DM as a risk factor for the occurrence and exacerbation of hepatocellular carcinoma.
Up to 96% of patients with cirrhosis may be glucose intolerant and 30% may be clinically diabetic[1]. Currently, it is a matter for debate whether type 2 diabetes mellitus (DM), in the absence of other risk factors contributing to metabolic syndrome (obesity and hypertriglyceridemia), could be a risk factor for the development and progression of liver disease[2-4]. On the other hand, the diabetes which develops as a complication of cirrhosis is known as "hepatogenous diabetes" and is not recognized by the American Diabetes Association and the World Health Organization as a specific independent entity[5]. The liver has an important role in carbohydrate metabolism since it is responsible for the balance of blood glucose levels by means of glycogenogenesis and glycogenolysis[5-11]. In the presence of hepatic disease, the metabolic homeostasis of glucose is impaired as a result of disorders such as insulin resistance, glucose intolerance and diabetes[6,8,11,12]. Insulin resistance occurs not only in muscular tissue, but also in adipose tissue[13], and this combined with hyperinsulinemia seem to be important pathophysiologic bases of diabetes in liver disease[1,3,5,6,14-17]. Additionally, the etiology of liver disease is important in the incidence of DM, since non-alcoholic fatty liver disease (NAFLD), alcohol, hepatitis C virus (HCV) and hemochromatosis are frequently associated with DM[1-3,7,18]. DM in patients with compensated liver cirrhosis may be subclinical, since fasting serum glucose levels may be normal. In these cases, it is necessary to perform an oral
Garcia-Compean D et al . Liver cirrhosis and diabetes
glucose tolerance test (OGTT) to detect an impairment of glucose metabolism [19] . The natural history of hepatogenous diabetes is different from that of hereditary type 2 DM, since it is less frequently associated with microangiopathy. In contrast, the patient with cirrhosis and diabetes suffers more frequently from complications of cirrhosis, which can cause death[2,4,19]. Treatment of diabetes in the cirrhotic patient is complex because of the presence of liver damage and the hepatotoxicity of oral hypoglycemic drugs. Therefore, pharmacological therapy must be closely monitored for the risk of hypoglycemia[3,5,19]. This review will present evidence that exists in the literature in relation to: (1) type 2 DM alone or as part of the metabolic syndrome in the development of liver disease; (2) factors involved in the genesis of hepatogenous diabetes; (3) the impact of DM on the clinical outcome of liver disease; (4) the management of DM in cirrhotic patients. Similarly, we will review the role of type 2 DM and hepatogenous diabetes as risk factors for the occurrence and exacerbation of hepatocellular carcinoma (HCC).
Type 2 diabetes mellitus
Figure 1 Type 2 diabetes mellitus may give raise to non-alcoholic fatty liver disease (NAFLD) which could progress to cirrhosis and hepatocellular carcinoma (HCC).
Epidemiology Several studies suggest that type 2 DM may have an etiological role in chronic liver disease and HCC regardless of alcohol and viruses[4] (Figure 1). A total of 173 643 patients with type 2 DM and 650 620 patients without type 2 DM, in whom chronic liver disease was excluded at the time of enrollment and a year later, were observed over a 10-year period in a cohort study. The incidence of non-alcoholic chronic liver disease and HCC was significantly higher in diabetic patients compared with non-diabetic patients. This risk was 2-fold greater and was independent of alcoholic liver disease, viral hepatitis and demographic factors[4]. Although this study has the strength of having a very large number of individuals, it has been criticized because it included a population comprised almost entirely of men (98%) from the Department of Veterans Affairs, and the diagnoses of type 2 DM, chronic liver disease and HCC were taken from a database, and consequently they were not verified biochemically and histopathologically. Additionally, other factors that are part of the metabolic syndrome (which already have a proven influence on the occurrence of NAFLD such as obesity and dyslipidemia) were not taken into account[20]. In a study with a large number of patients carried out in Denmark, the standardized incidence of HCC was higher in men (4.0, 95% CI: 3.5-4.6) and women (2.1, 95% CI: 1.6-2.7) with type 2 DM compared with the general population[21]. Other studies with fewer patients have yielded similar results[22,23]. In a recent case-control study that included 465 patients, DM prevalence was higher in patients with HCC than in controls (31.2% vs 12.7%, OR 3.12 95%
CI: 2.22-4.43). The DM had been diagnosed prior to the occurrence of HCC in 84% of cases with an average duration of 181.4 mo indicating that it was type 2 DM in most cases[24]. The above data suggests that type 2 DM itself might be a risk factor for the occurrence of HCC. Other studies showed that in the presence HCV, liver fibrosis and alcohol, the risk is higher. Recently, it was observed that patients suffering from chronic hepatitis C (CHC), DM and advanced fibrosis had a 3-fold greater risk than non-diabetic patients with mild to moderate fibrosis of developing HCC in 5 years of follow-up (13% vs 5%)[25]. NAFLD NAFLD comprises a series of liver disorders such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. It is estimated that one third of American adult individuals may suffer from fatty liver[26], which is considered the most benign manifestation of NAFLD. The primary fatty liver results from the accumulation of fat, mainly of triglycerides in liver cells in the presence of insulin resistance, and frequently occurs as part of the metabolic syndrome which is made up of obesity, type 2 DM and dyslipidemia[27]. Non-alcoholic steatohepatitis (NASH) is a severe manifestation of NAFLD, since it causes not only steatosis, but tissue inflammation, cell damage and fibrosis. Nevertheless, the prevalence of NASH is estimated at 2%-3%. NASH is regarded as an entity that can progress to cirrhosis and liver failure, and currently it is estimated to be the most common cause of cryptogenic cirrhosis[28,29]. Pathophysiology The mechanisms by which type 2 DM might cause NAFLD are complex and have been studied in a fragmented manner mainly in isolated biological systems. It has been observed that the fatty liver, obesity and insulin resistance act as co-factors to cause liver damage[1,3,4]. Fatty liver is the result of an intracellular accumulation of triglycerides because of increased uptake of free fatty acids and de novo liponeogenesis in the hepatocytes. At the same time, there is a reduction in the hepatic secretion of very low density lipoproteins. The liver damage consists of cellular necrosis and inflammation, and these disorders result from an increase in mitochondrial oxidative stress on triglycerides with the consequential generation of free radicals and peroxisomes[30,31]. The mitochondrial oxidative
Type 2 DM
World J Gastroenterol
January 21, 2009
Volume 15
Number 3
FFA Hyperglycemia Adipose tissue Hyperinsulinemia Insulin Resistance + DNL Steatosis FFA + Adiponectin Leptin TNF + + Oxidative stress (mitochondria) FFA FFA + Peroxisomes Free radicals + Inflamation necrosis + VLDL + + Hepatocyte
Figure 2 Liver damage caused by type 2 DM. Insulin resistance promotes release of free fatty acids (FFA) from adipose tissue. The FFAs are accumulated in the liver cells, and de novo liponeogenesis (DNL) contributes also. The reduced secretion of very low density lipoprotein (VLDL) by hepatic cells saturates hepatocytes producing steatosis. Mitochondrial oxidative stress is increased as a result of excess intracellular FFAs and the influence of adipokines (leptin and tumor necrosis factor alpha (TNF-). Excess of oxidative stress produces free radicals which in turn induces inflammation and cellular necrosis. Tissue inflammation stimulates the stellate cells to produce collagen.
Stellate cell
Hemochromatosis HCV Mortality Cryptogenic cirrhosis Alcohol NAFLD Cirrhosis and DM
and glucose intolerance may be found in most of these patients[35,36]. The diabetes manifests clinically as the liver function deteriorates, thus hepatogenous diabetes can be considered as an indicator of advanced liver disease[37]. The etiology of chronic liver disease is crucial in the development of hepatogenous diabetes: alcohol, HCV, hemochromatosis and NASH (Figure 3). NASH: NASH is a severe manifestation of NAFLD. NASH is associated with visceral obesity, hypertriglyceridemia, and virtually all patients have insulin resistance. Therefore, it is not surprising that type 2 DM is present in 30%-45% of patients with NASH[38]. On the other hand, it has been observed that obesity itself is an independent risk factor for severe liver disease[39]. Obesity is characterized by expanded adipose tissue which is in a state of chronic inflammation resulting in an increase in the secretion of adipokines. These adipose tissue cytokines have a systemic effect particularly on the liver, which leads to an altered metabolic state with insulin resistance, hyperglycemia and hyperinsulinemia; these abnormalities disrupt the liver metabolism of lipids[40]. Cytokines, of which TNF- is the most studied member, stimulate the liver stellate cells directly inducing hepatic fibrosis[41]. The body weight reduction improves metabolic abnormalities that accompany the metabolic syndrome such as hyperlipidemia and fatty liver[42]. CHC and HCV: In a study conducted by The National Health and Nutrition Examination Survey, a 3-fold higher risk of DM was identified in individuals over 40 years of age with CHC, compared with those patients with non-C chronic hepatitis[43]. Knobler et al observed a prevalence of DM of 33% in non-cirrhotic patients with CHC, compared with 5.6% in a control group[44]. In patients chronically infected with HCV, fatty liver was observed in 30%-70% of cases[45].
Figure 3 Etiology of liver cirrhosis most frequently associated with diabetes mellitus.
stress is increased also by the action of adipokines (cytokines produced by the adipocytes) such as leptin and tumor necrosis factor- (TNF-), which are produced in excess[32]. The reduction of adiponectin, which is a regulatory adipokine, favors the activity of inflammatory adipokines[33]. These chemical mediators, derived from inflammation and cell necrosis, as well as the adipokines activate the liver stellate cells and induce them to increase production of collagen, connective tissue growth factor and accumulation of extracellular matrix, in turn favoring fibrosis[34] (Figure 2).
Epidemiology Depending on the etiology, the degree of liver damage and the diagnostic criteria, the reported incidence of glucose intolerance varies from 60 to 80% and that of diabetes between 20 and 60%[3,5,16,19]. It is known that from the early stages of chronic liver disease, insulin resistance
Garcia-Compean D et al . Liver cirrhosis and diabetes
In patients with CHC, a high prevalence of glycometabolic abnormalities is reported such as glucose intolerance in more than 40% and DM in more than 17%. Additionally, the insulin resistance observed in these patients is an independent risk factor for steatosis in relation to the severity of fibrosis[7,46-48]. The mechanisms by which HCV produces insulin resistance and DM are not clearly known. It has been observed that HCV induces insulin resistance regardless of body mass index and fibrosis stage. In a study conducted in a transgenic animal model, the HCV core protein was able to induce insulin resistance, steatosis and DM. TNF- overproduction seems to have been the primary mechanism. This cytokine phosphorylates the serine residues of the insulin receptor (IRS-1 and IRS-2), and stimulates the overproduction of suppressor of cytokines (SOC-3). SOC-3 inhibits phosphorylation of Akt and phosphatidylinositol 3-kinase. All these disorders, related to intracellular signaling of insulin, could block the transactivation of GLUT-4, which would result in block of glucose uptake at the cellular level. Indeed, in the transgenic mouse, TNF- correlates with the hyperinsulinism and TNF- block occasioned by the administration of anti-TNF- drugs such as infliximab avoids the appearance of insulin resistance. Therefore, the mechanisms by which HCV induces insulin resistance include: production of TNF-, serine phosphorylation of IRS and overexpression of SOCs. Furthermore, the overproduction of TNF- in patients with CHC correlates with a faster progression of fibrosis and a lower response to interferon[40]. On the other hand, HCV genotype may be of importance in the occurrence of glucose metabolic disorders, as genotypes 1 and 4 are significantly associated with insulin resistance more frequently than genotypes 2 and 3 (37% vs 17%)[47]. It is well demonstrated that genotypes 1 and 4 are associated with a lower viral sustained response to antiviral therapy than genotypes 2 and 3. Insulin resistance may be a cofactor that increases the failure of the response to antiviral treatment observed in these patients. In accordance with this, in a recent study in patients with HCV genotype 1, those with HOMA > 2 (insulin resistance) had a 2-fold lower sustained response to treatment than patients with HOMA < 2 (32.8% vs 60.5%, respectively)[49]. For sustaining this idea, it is important to note that in experiments carried out with Huh-7 cells infected with HCV RNA, viral replication was blocked by adding interferon to the system. However, the ability of interferon to block viral replication was abolished when insulin was added to interferon at a dose of 128 mcU/mL (similar to that seen in the hyperinsulinemic states)[50]. Finally, it has been reported that patients with CHC and insulin resistance have a less sustained response to peginterferon plus ribavirin treatment compared with patients without insulin resistance[40,49]. It seems that once the insulin resistance and DMinducing mechanisms in CHC are fired, their courses are not affected by the presence or absence of viral activity. Indeed, in a recent study it was observed that HCV clearance by pegylated interferon and ribavirin treatment
did not reduce the risk of DM in patients with chronic hepatitis and normal fasting blood glucose during a period of 8 years of follow-up after treatment. Patients with a sustained response had a similar incidence of DM compared with those who did not respond to treatment (14.8% vs 18.5%, respectively)[51]. Alcohol: Patients with alcoholic liver disease have a high relative risk of suffering diabetes[52]. This risk is directly related to the amount of ingested alcohol, as it rises 2-fold in patients ingesting more than 270 g of alcohol per week compared with those ingesting less than 120 g/wk[53]. Acute alcohol ingestion produces a significant reduction in insulin-mediated glucose uptake. On the other hand, patients with chronic alcoholism frequently have chronic pancreatic damage and injury of pancreatic islet -cells resulting in DM[1]. Hemochromatosis: Hereditary hemochromatosis is a disease characterized by iron accumulation in several organs-particularly in the liver - as a result of a disorder of the metabolism of this metal. This abnormality is produced by a mutation of the HFE gene. In addition, the iron can infiltrate the pancreas and myocardium. In the pancreas, the concentration of iron is predominantly in the acinus of exocrine secretion. However, infiltration of Langerhans islets with damage to the insulinproducing -cells can also be observed. This is the reason why DM can be obser ved in 50%-85% of patients with hereditary hemochromatosis in advanced stages [54]. Additionally, glucose metabolic disorders resulting from the liver damage probably contribute to the high frequency of DM[1,5]. Pathophysiology of hepatogenous diabetes The pathophysiology of hepatogenous diabetes is complex and not precisely known. Insulin resistance in peripheral tissues (adipose and muscular tissue) plays a central role in the glucose metabolism disturbance[1,2,9,11,14-17]. It has also been proposed that reduced insulin extraction by the damaged liver and portosystemic shunts result in hyperinsulinemia which is potentiated by raised levels of contra-insulin hormones (glucagon, growth hormone, insulin-like growth factor, free fatty acids and cytokines)[2,11,15,17]. However, a recent study reports that in patients with Child B grade liver cirrhosis the hyperinsulinism may be produced by an increase of the pancreatic -cell sensitivity to glucose, whereas disturbance of hepatic insulin extraction does not seem to have a significant role[55]. It has also been speculated that genetic and environmental factors and some etiologic agents in liver disease such as HCV, alcohol, and iron infiltration impair the insulin secretion activity of the -cells of the pancreas[9]. In conclusion it seems that glucose intolerance may result from two abnormalities that occur simultaneously: (1) insulin resistance of muscle and (2) an inadequate response of the -cells to appropriately secrete insulin to overcome the defect in insulin action. On the other hand DM develops as the result of progressive impairment in insulin secretion together with the development of he-
World J Gastroenterol
January 21, 2009
Volume 15
Number 3
Hepatic clearance of insulin Portosystemic shunts Glucagon Growth hormone IGF-1 Free fatty acids Cytokines
Liver cirrhosis
Insulin resistance Hyperinsulinemia Liver Diabetes Non-oxidative and oxidative Metabolic impairment Glucose intolerance Muscle
Function of cells of the pancreas
Non-hepatic factors Genetic Environmental
Hepatic factors Alcohol Iron deposits HCV HCC
Figure 4 Pathophysiology of hepatogenous diabetes. One of the main abnormalities is insulin resistance in muscular cells and the hepatic tissue. Insulin resistance in muscle impairs non-oxidative and oxidative glucose metabolism. The reduction of insulin clearance by the damaged liver and the presence of portosystemic shunts in one hand and the desensitization of the beta cells of the pancreas produced by diverse factors on the other hand may produce hyperinsulinemia. With progression of the diabetes there is a reduction in sensitivity of -cells for production of insulin.
patic insulin resistance leading to fasting hyperglycemia and a diabetic glucose tolerance profile[14,15] (Figure 4). Discrimination between hepatogenous diabetes and type 2 DM may be difficult. In a recent study comparing patients with hepatogenous diabetes vs patients with type 2 DM, the ratios of postprandial plasma glucose (PP2h) to fasting plasma glucose (FPG) (2.27 vs 1.69), fasting insulin (23.2 vs 11.6 microIU/mL) and HOMA-Insulin Resistance index (8.38 vs 3.52) were significantly higher in patients with hepatogenous diabetes. Therefore, insulin resistance in liver cirrhosis is higher than in type 2 DM, and impairment of hepatic insulin degradation may be an important mechanism of hyperinsulinemia in liver cirrhosis[56].
DM increases morbidity and mortality of liver cirrhosis patients The effect of type 2 DM and hepatogenous diabetes on the clinical outcome of cirrhosis and HCC has been evaluated in only few studies. In cross-sectional retrospective studies in patients with cirrhosis of any etiology it has been observed that the DM is associated with an increased risk of complications[5,38,57,58]. According to the Verona study, which is based on a population of more than 7000 individuals suffering from type 2 DM, the risk of death at 5 years was 2.52-fold greater (CI 1.96-3.2) than in the general population[59]. Other studies report that DM, obesity and steatosis are associated with liver disease and more severe fibrosis in CHC[60,61]. It is important to note that neither the Child-Pugh nor Model for End-Stage Liver Disease (MELD) Scores
(which are widely used as prognostic instruments of morbidity and mortality in the short and long term for cirrhotic patients) include in their parameters DM or glucose intolerance[62,63]. Nevertheless, interesting data have been observed in some prospective longitudinal studies involving cirrhotic patients where DM has been studied as an independent prognostic factor. In a retrospective and prospective study 354 (98 with diabetes) of 382 eligible patients were followed for 6 years after inclusion into the study: 110 were alive at the end of follow-up. Prognostic factors identified by Kaplan-Meier analysis, followed by Cox's stepwise regression demonstrated in sequence, albumin, ascites, age, encephalopathy, bilirubin, diabetes, and platelets as prognostic factors of mortality. The larger mortality rate in patients with diabetes, was not due to complications of diabetes but to an increased risk of hepatocellular failure[58]. Diabetes was no longer a risk factor as a covariate in a subgroup of 271 patients when varices were added but was again significant when patients who died of gastrointestinal bleeding were excluded. In another study carried out in patients suffering from cirrhosis and refractory ascites on the waiting list for liver transplantation it was observed that the HCC and DM, but not the Child-Pugh score, were independent predictive factors of mortality. The patients suffering from refractory ascites and DM showed a 1- and 2-year probability of survival of 32% and 18%, respectively. By contrast survival rates of patients with refractory ascites without DM were 62% and 58%, respectively[64]. Nishida et al performed the OGTT on a group of 56 patients with cirrhosis and normal fasting blood glucose. A total of 38% of patients were diagnosed with DM, 23% with glucose intolerance, and 39% were normal. After 5 years of follow-up, patients with diabetes and glucose intolerance had significantly higher mortality than normal patients (44% and 32% vs 5%, respectively). From a multiple regression analysis only serum albumin and DM were independent negative predictive factors of survival[19]. Hepatogenous diabetes has a clinical behavior different from that of hereditary type 2 DM, since it is less frequently associated with retinopathy and cardiovascular and renal complications[5,58]. In cirrhotic patients with diabetes, the most recurrent cause of death is liver failure[4,19,58]. DM increases the severity and mortality of HCC At present, type 2 DM is considered a risk factor for the occurrence of HCC. Hepatogenous diabetes together with hepatitis B and C virus infection and alcoholic liver cirrhosis increases the risk of HCC by 10-fold[1,2]. Patients with HCC and DM have a mortality risk higher than patients with HCC without DM. In another study involving 160 patients suffering from HCC, those who had DM had a 1-year mortality rate higher than those patients without DM. Additionally, they had more extensive disease[65]. Pathophysiologic mechanisms The mechanisms by which diabetes worsens the clinical course of liver cirrhosis have not been clearly established. Firstly, DM accelerates liver fibrosis and inflammation
Garcia-Compean D et al . Liver cirrhosis and diabetes
giving rise to more severe liver failure. Secondly, DM may potentiate the incidence of bacterial infections in cirrhotic patients which are associated with increased mortality[66,67]. In relation to the first mechanism, insulin resistance increases adipokine production (cytokines secreted by adipose tissue), such as leptin and TNF-, which activates the inflammatory pathways that exacerbate liver damage[68]. In contrast, another cytokine produced by adipose tissue, adiponectin, is a regulator of insulin sensitivity and tissue inflammation[69]. A reduction in the adiponectin levels reflects peripheral and hepatic insulin resistance[70]. There has been speculation that hypoadiponectinemia may play a role in liver disease progression[70,71]. Regarding the second mechanism, DM may worsen immunodepression in cirrhotic patients thus increasing the incidence of severe infections which may have deleterious effect on liver function. It should be noted that cirrhotic patients with spontaneous bacterial peritonitis have a high hospital mortality rate due to sepsis, liver failure and hepatorenal syndrome. On the other hand, patients with esophageal variceal bleeding have a high incidence of infections that increase their in-hospital mortality rate[72]. Notwithstanding, it has not been established if DM increases the mortality rate in patients with other complications of cirrhosis. In future, the precise mechanisms by which DM may worsen liver function should be clarified, since manipulation of these may be useful for reduction of complications.
Clinical manifestations Clinical manifestations of DM in the early stages of cirrhosis are virtually absent. In a recently published study involving compensated cirrhotic patients with normal fasting serum glucose and without a family history of type 2 DM, up to 77% had DM or glucose intolerance diagnosed by means of OGTT. In 38% of cases, DM was subclinical[19]. As liver function deteriorates, the incidence of diabetes increases so that clinical diabetes may be seen as a marker of liver failure. Hepatogenous diabetes has particular clinical characteristics: (1) unlike the hereditary type 2 DM, it is less frequently associated with risk factors such as age, body mass index, and family history of diabetes; (2) it is less frequently associated with retinopathy and cardiovascular and renal complications; (3) it is more frequently associated with hypoglycemic episodes as a result of impaired liver function[2,19]. Although the incidence of obesity, DM and metabolic syndrome have increased in the world, reaching epidemic proportions, the role of DM as a prognostic factor of morbidity and mortality in cirrhotic patients has been scarcely studied. In addition, the impact of early diagnosis and treatment of DM on the clinical course of cirrhosis is unknown.
Treatment Few studies have evaluated what is the most efficacious therapy for DM in cirrhotic patients and what is the impact of treatment of DM on the clinical course of liver disease. The treatment of DM of cirrhotic patients has particular characteristics that make it different from type 2 DM without liver disease: (1) about half the patients have malnutrition; (2) when clinical DM is diagnosed, the patient has advanced liver disease; (3) most of the oral hypoglycemic agents are metabolized in the liver; (4) patients often have episodes of hypoglycemia[3]. The initial treatment of patients suffering from mild to moderate hyperglycemia and compensated liver disease may be a lifestyle change, since at this stage the insulin resistance is a dominant factor. However, these therapeutic measures may be compromised by very restrictive diets, since they might aggravate malnutrition in some patients. On the other hand, physical exercise which improves insulin resistance may not be an appropriate measure in patients with active liver disease[15]. When DM manifests in advanced stages of liver disease, the use of oral hypoglycemic drugs may be required. However, most of these drugs are metabolized in the liver, therefore, the blood glucose levels during treatment shall be closely monitored in order to avoid hypoglycemia[73]. In these cases, biguanides, which reduce resistance to insulin, may be useful. Metformin is a biguanide that is relatively contraindicated in patients with advanced liver failure and patients who continue to ingest alcohol, because of the risk of lactic acidosis[74]. On the other hand, insulin secretagogues, despite the fact that they are safe drugs in patients with liver disease, probably are not useful, since they do not modify insulin resistance and patients with alcoholic cirrhosis often have pancreatic islet -cell damage[75]. These patients have chronic compensatory hyperinsulinemia until the islet -cells are exhausted. Alpha-glucosidase inhibitors can be useful in patients suffering from liver cirrhosis, since their mechanism of action is to reduce carbohydrate absorption in the bowel, thus reducing the risk of postprandial hyperglycemia that is common in these patients. In a randomized, double-blind study involving 100 patients with compensated liver cirrhosis and insulin-treated DM, the control of postprandial and fasting blood glucose levels improved significantly with the use of acarbose, an alpha-glucosidase[76]. In another crossover placebo-controlled study involving patients with hepatic encephalopathy, acarbose produced a significant improvement in postprandial blood glucose level. Additionally, the patients had a reduction in plasma ammonia levels and an increase in the frequency of bowel movements[77]. The reduction in ammonia levels was probably the result of a decrease in the proliferation of intestinal proteolytic bacteria caused by bowel movement[77]. Thiazolidines may be particularly useful in cirrhotic patients with DM, since they increase the insulin sensitivity. However, troglitazone has been withdrawn from the market because of its potential hepatotoxic effects.
World J Gastroenterol
4 5 6
January 21, 2009
Volume 15
Number 3
Nevertheless, rosiglitazone and pioglitazone appear to be safer drugs[78], but it is recommended that these drugs should not be initiated if there is evidence of active liver disease or if alanine transaminase levels are above 2.5 times the upper limit of normal. The use of these drugs should be monitored closely whenever necessary. Insulin requirements in the cirrhotic patient with diabetes may vary. In patients with compensated cirrhosis, requirements may be greater compared to patients with decompensated cirrhosis, since insulin resistance predominates in the former while in the latter liver metabolism of insulin is greatly reduced. Therefore, therapy with insulin must be preferably performed in hospitalized patients with close monitoring of blood glucose levels for development of hypoglycemia[79]. Finally, liver transplantation rapidly normalizes glucose tolerance and insulin sensitivity. It is thought that this effect is due to an improvement in the hepatic clearance and peripheral glucose disposal. The latter effect could be secondary to a correction of chronic hyperinsulinemia[16,80]. It has been observed that liver transplantation, in reducing insulin resistance, cures hepatogenous diabetes in 67% of cirrhotic-diabetic patients. In 33% of patients diabetes was not corrected because of persistence of a reduced -cell function measured by means of an OGTT. This abnormality would make these patients eventually eligible for combined islet transplantation[81].
7 8 9 10 11 12
13 14
Future research in the field of DM in cirrhotic patients should clarify the following issues: (1) the role of isolated type 2 DM in the genesis of chronic liver disease and the factors involved in this complication; (2) the impact of hepatogenous diabetes in the natural history of cirrhotic patients; (3) the impact of early diagnosis and treatment of hepatogenous diabetes (through OGTT) in reducing mortality; (4) the benefits of controlling the DM in the management of complications of liver cirrhosis; (5) the mechanisms by which hepatogenous diabetes increases morbidity and mortality of cirrhotic patients, as well as the impact of the manipulation of these mechanisms on the patients; (6) the establishment of clearer guidelines for management of diabetes in the cirrhotic patient. Perhaps the combination of DM with the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients.
17 18
20 21
1 2 3 Hickman IJ, Macdonald GA. Impact of diabetes on the severity of liver disease. Am J Med 2007; 120: 829-834 El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-468 Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 2007; 30: 734-743 22 23
El-Serag HB, Everhart JE. Diabetes increases the risk of acute hepatic failure. Gastroenterology 2002; 122: 1822-1828 Holstein A, Hinze S, Thiessen E, Plaschke A, Egberts EH. Clinical implications of hepatogenous diabetes in liver cirrhosis. J Gastroenterol Hepatol 2002; 17: 677-681 Picardi A, D'Avola D, Gentilucci UV, Galati G, Fiori E, Spataro S, Afeltra A. Diabetes in chronic liver disease: from old concepts to new evidence. Diabetes Metab Res Rev 2006; 22: 274-283 Custro N, Carroccio A, Ganci A, Scafidi V, Campagna P, Di Prima L, Montalto G. Glycemic homeostasis in chronic viral hepatitis and liver cirrhosis. Diabetes Metab 2001; 27: 476-481 Postic C, Dentin R, Girard J. Role of the liver in the control of carbohydrate and lipid homeostasis. 2004; 30: 398-408 Barthel A, Schmoll D. Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2003; 285: E685-E692 Cotrozzi G, Casini Raggi V, Relli P, Buzzelli G. [Role of the liver in the regulation of glucose metabolism in diabetes and chronic liver disease] Ann Ital Med Int 1997; 12: 84-91 Tappy L, Minehira K. New data and new concepts on the role of the liver in glucose homeostasis. Curr Opin Clin Nutr Metab Care 2001; 4: 273-277 Nielsen MF, Caumo A, Aagaard NK, Chandramouli V, Schumann WC, Landau BR, Schmitz O, Vilstrup H. Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis: assessment during physiological glucose and insulin concentrations. Am J Physiol Gastrointest Liver Physiol 2005; 288: G1135-G1143 Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307-312 Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeyer G. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 1994; 19: 616-627 Petrides AS, Stanley T, Matthews DE, Vogt C, Bush AJ, Lambeth H. Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology 1998; 28: 141-149 Merli M, Leonetti F, Riggio O, Valeriano V, Ribaudo MC, Strati F, Tisone G, Casciani CU, Capocaccia L. Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation. Hepatology 1999; 30: 649-654 Petrides AS, Groop LC, Riely CA, DeFronzo RA. Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis. J Clin Invest 1991; 88: 561-570 Lecube A, Hernandez C, Genesca J, Esteban JI, Jardi R, Simo R. High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury. Diabetes Care 2004; 27: 1171-1175 Nishida T, Tsuji S, Tsujii M, Arimitsu S, Haruna Y, Imano E, Suzuki M, Kanda T, Kawano S, Hiramatsu N, Hayashi N, Hori M. Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. Am J Gastroenterol 2006; 101: 70-75 Di Bisceglie AM. What every hepatologist should know about endocrinology: obesity, diabetes, and liver disease. Gastroenterology 2004; 126: 604-606 Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S, Borch-Johnsen K, Olsen JH. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997; 89: 1360-1365 Fujino Y, Mizoue T, Tokui N, Yoshimura T. Prospective study of diabetes mellitus and liver cancer in Japan. Diabetes Metab Res Rev 2001; 17: 374-379 Tazawa J, Maeda M, Nakagawa M, Ohbayashi H, Kusano F, Yamane M, Sakai Y, Suzuki K. Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C. Dig Dis Sci 2002; 47: 710-715 Donadon V, Balbi M, Casarin P, Vario A, Alberti A.
Garcia-Compean D et al . Liver cirrhosis and diabetes
Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: Potential role of insulin. World J Gastroenterol 2008; 14: 5695-5700 Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008; 47: 1856-1862 Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-1395 Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2007; 25: 883-889 Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999; 29: 664-669 Tellez-Avila FI, Sanchez-Avila F, Garcia-Saenz-de-Sicilia M, Chavez-Tapia NC, Franco-Guzman AM, Lopez-Arce G, Cerda-Contreras E, Uribe M. Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis. World J Gastroenterol 2008; 14: 4771-4775 Chalasani N, Gorski JC, Asghar MS, Asghar A, Foresman B, Hall SD, Crabb DW. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 2003; 37: 544-550 Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J Gastroenterol Hepatol 2004; 16: 1095-1105 Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, Fernandez-Escalante JC, Pons-Romero F. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001; 34: 1158-1163 Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 1705-1725 Bertolani C, Marra F. The role of adipokines in liver fibrosis. Pathophysiology 2008; 15: 91-101 Buzzelli G, Chiarantini E, Cotrozzi G, Relli P, Matassi L, Romanelli RG, Gentilini P. Estimate of prevalence of glucose intolerance in chronic liver disease. Degree of agreement among some diagnostic criteria. Liver 1988; 8: 354-359 Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110: 1107-1119 Del Vecchio Blanco C, Gentile S, Marmo R, Carbone L, Coltorti M. Alterations of glucose metabolism in chronic liver disease. Diabetes Res Clin Pract 1990; 8: 29-36 Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 2006; 40: 68-76 Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356-1362 Romero-Gomez M. Insulin resistance and hepatitis C. World J Gastroenterol 2006; 12: 7075-7080 Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2007; 13: 3540-3553 Hatzitolios A, Savopoulos C, Lazaraki G, Sidiropoulos I, Haritanti P, Lefkopoulos A, Karagiannopoulou G, Tzioufa V, Dimitrios K. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol 2004; 23: 131-134 Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592-599 Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc 2000;
75: 355-359 Anty R, Gelsi E, Giudicelli J, Marine-Barjoan E, Gual P, Benzaken S, Saint-Paul MC, Sadoul JL, Huet PM, Tran A. Glucose intolerance and hypoadiponectinemia are already present in lean patients with chronic hepatitis C infected with genotype non-3 viruses. Eur J Gastroenterol Hepatol 2007; 19: 671-677 Lecube A, Hernandez C, Genesca J, Simo R. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study. Diabetes Care 2006; 29: 1096-1101 Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, Sobesky R, Martinot-Peignoux M, Maylin S, Nicolas-Chanoine MH, Paradis V, Vidaud M, Valla D, Bedossa P, Marcellin P. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134: 416-423 Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003; 125: 1695-1704 Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, Corpas R, Cruz M, Grande L, Vazquez L, Munoz-De-Rueda P, LopezSerrano P, Gila A, Gutierrez ML, Perez C, Ruiz-Extremera A, Suarez E, Castillo J. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005; 128: 636-641 Sanyal AJ, Chand N, Comar K, Mirshahi F. Hyperinsulinemia blocks the inhibition of hepatitis C virus (HCV) replication by interferon: a potential mechanism for failure of interferon therapy in subjects with HCV and nonalcoholic liver disease. Hepatology 2004; 40 (4 Suppl 1): 179A Giordanino C, Bugianesi E, Smedile A, Ciancio A, Abate ML, Olivero A, Pellicano R, Cassader M, Gambino R, Bo S, Ciccone G, Rizzetto M, Saracco G. Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol 2008; 103: 2481-2487 Zein NN, Abdulkarim AS, Wiesner RH, Egan KS, Persing DH. Prevalence of diabetes mellitus in patients with endstage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. J Hepatol 2000; 32: 209-217 Wei M, Gibbons LW, Mitchell TL, Kampert JB, Blair SN. Alcohol intake and incidence of type 2 diabetes in men. Diabetes Care 2000; 23: 18-22 Adams PC, Kertesz AE, Valberg LS. Clinical presentation of hemochromatosis: a changing scene. Am J Med 1991; 90: 445-449 Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G. Mechanisms of hyperinsulinaemia in Child's disease grade B liver cirrhosis investigated in free living conditions. Gut 2002; 51: 870-875 Kim MG, Choi WC. [Differential diagnosis of diabetes mellitus caused by liver cirrhosis and other type 2 diabetes mellitus] Korean J Hepatol 2006; 12: 524-529 de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999; 22: 756-761 Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic significance of diabetes in patients with cirrhosis. Hepatology 1994; 20: 119-125 Trombetta M, Spiazzi G, Zoppini G, Muggeo M. Review article: type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment Pharmacol Ther 2005; 22 Suppl 2: 24-27 Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999; 29: 1215-1219
27 28
31 32
33 34 35
53 54 55
37 38 39 40 41 42
56 57 58 59
World J Gastroenterol
January 21, 2009
Volume 15
Number 3
63 64
65 66 67 68 69 70
Taura N, Ichikawa T, Hamasaki K, Nakao K, Nishimura D, Goto T, Fukuta M, Kawashimo H, Fujimoto M, Kusumoto K, Motoyoshi Y, Shibata H, Abiru N, Yamasaki H, Eguchi K. Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol 2006; 101: 2752-2759 Flores-Rendon AR, Gonzalez-Gonzalez JA, Garcia-Compean D, Maldonado-Garza HJ, Garza-Galindo AA. Model for end stage of liver disease (MELD) is better than the ChildPugh score for predicting in-hospital mortality related to esophageal variceal bleeding. Ann Hepatol 2008; 7: 230-234 Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol 2005; 42 Suppl: S100-S107 Moreau R, Delegue P, Pessione F, Hillaire S, Durand F, Lebrec D, Valla DC. Clinical characteristics and outcome of patients with cirrhosis and refractory ascites. Liver Int 2004; 24: 457-464 Amarapurkar DN, Patel ND, Kamani PM. Impact of diabetes mellitus on outcome of HCC. Ann Hepatol 2008; 7: 148-151 Garcia-Tsao G. Bacterial infections in cirrhosis: treatment and prophylaxis. J Hepatol 2005; 42 Suppl: S85-S92 Cheruvattath R, Balan V. Infections in Patients With Endstage Liver Disease. J Clin Gastroenterol 2007; 41: 403-411 Roden M. Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab 2006; 2: 335-348 Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin--a key adipokine in the metabolic syndrome. Diabetes Obes Metab 2006; 8: 264-280 Jonsson JR, Moschen AR, Hickman IJ, Richardson MM, Kaser S, Clouston AD, Powell EE, Tilg H. Adiponectin and its receptors in patients with chronic hepatitis C. J Hepatol 2005; 43: 929-936 Svegliati-Baroni G, Ridolfi F, Di Sario A, Casini A, Marucci L, Gaggiotti G, Orlandoni P, Macarri G, Perego L, Benedetti A, Folli F. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal
73 74
75 76
79 80
transduction pathways. Hepatology 1999; 29: 1743-1751 Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, Lee SD. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004; 39: 746-753 Marks V, Teale JD. Drug-induced hypoglycemia. Endocrinol Metab Clin North Am 1999; 28: 555-577 Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004; 20: 23-28 Choudhury S, Hirschberg Y, Filipek R, Lasseter K, McLeod JF. Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis. J Clin Pharmacol 2000; 40: 634-640 Gentile S, Turco S, Guarino G, Oliviero B, Annunziata S, Cozzolino D, Sasso FC, Turco A, Salvatore T, Torella R. Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis. Diabetes Obes Metab 2001; 3: 33-40 Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, Magliano PL, Gravina AG, Torella R. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005; 3: 184-191 Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002; 25: 815-821 Petrides AS. Hepatogenic diabetes: pathophysiology, therapeutic options and prognosis. Z Gastroenterology 1999; 16 (Suppl 1): 15-21 Blanco JJ, Herrero JI, Quiroga J, Sangro B, Gomez-Manero N, Pardo F, Cienfuegos JA, Prieto J. Liver transplantation in cirrhotic patients with diabetes mellitus: midterm results, survival, and adverse events. Liver Transpl 2001; 7: 226-233 Perseghin G, Mazzaferro V, Sereni LP, Regalia E, Benedini S, Bazzigaluppi E, Pulvirenti A, Leao AA, Calori G, Romito R, Baratti D, Luzi L. Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation. Hepatology 2000; 31: 694-703 S- Editor Cheng JX L- Editor Cant MR E- Editor Ma WH
9 pages
Report File (DMCA)
Our content is added by our users. We aim to remove reported files within 1 working day. Please use this link to notify us:
Report this file as copyright or inappropriate


text:
Ip Man 4
Change of Gangster
Clueless (2001) Starring Hacken Lee
The Prodigy
Master Z: Ip Man Legacy
Three Husbands
A wondrous prostitute plies her trade while living on a boat in Hong Kong. With a superhuman libido and three loving husbands, she doggedly devotes herself to her work. Using…
Tai-hung, in his 50s, lives happily with his wife. Informed of the death of his high school friend, Tai-hung's secret past resurfaces. The feature debut from promising new Hong Kong…
Still Human
A paralysed and hopeless Hong Kong man meets his new Filipino carer, who has put her dream on hold and come to the city to earn a living. These two…
Iceman: The Time Traveler
The imperial guard and his three traitorous childhood friends ordered to hunt him down get accidentally buried and kept frozen in time. 400 years later pass and they are defrosted…
Kung Fu League
Golden Job
Europe Raiders
Big Brother
Detective Dee: The Four Heavenly Kings
Dee, the detective serving Chinese empress Wu Zetian, is called upon to investigate a series of strange events in Loyang, including the appearance of mysterious warriors wearing Chiyou ghost masks,…
Ten Years Thailand
A collection of short films by five Thai directors imagining their country ten years into the future.
Doraemon the Movie: Nobita's Treasure Island
The Monkey King 3
The third installment of the blockbuster fantasy series sees the return of the Monkey King (Aaron Kwok) in his most action-packed adventure yet! While continuing their epic journey to the…
Operation Red Sea
Bleeding Steel
Jackie Chan stars as a hardened special forces agent who fights to protect a young woman from a sinister criminal gang. At the same time, he feels a special connection…
The Hitman's Bodyguard
The world's top bodyguard gets a new client, a hit man who must testify at the International Court of Justice. They must put their differences aside and work together to…
Wonder Woman
G.E.M.: G-Force
G-FORCE is a music documentary that tells an aspiring story of how an ordinary teenage girl from Hong Kong (G.E.M.) overnight becomes the biggest female singer in China. Through her…
Ghost in the Shell
In the near future, Major is the first of her kind: a human saved from a terrible crash, then cyber-enhanced to be a perfect soldier devoted to stopping the world's…
Smurfs: The Lost Village
In this fully animated, all-new take on the Smurfs, a mysterious map sets Smurfette and her friends Brainy, Clumsy and Hefty on an exciting race through the Forbidden Forest leading…
Power Rangers
Saban's Power Rangers follows five ordinary teens who must become something extraordinary when they learn that their small town of Angel Grove — and the world — is on the…
John Wick: Chapter 2
The Great Wall
Patriots Day
In the aftermath of an unspeakable act of terror, Police Sergeant Tommy Saunders joins courageous survivors, first responders and investigators in a race against the clock to hunt down the…
The Monkey King: The Legend Begins
A re imagined version by Hollywood of the release The Monkey King: Havoc in Heavens Palace. The Origin and Birth Place of The Monkey King Story.
La La Land
Lady Bloodfight
Boo! A Madea Halloween
Madea winds up in the middle of mayhem when she spends a hilarious, haunted Halloween fending off killers, paranormal poltergeists, ghosts, ghouls, and zombies while keeping a watchful eye on…
A Plastic Ocean
A documentary focused on plastic pollution in the world's oceans.

subset: commoncrawl


text:
Buccellati's honeycomb technique fits perfectly with the interpretation of Larionov's "The Spider's Web". The scalloped borders of the web are in white gold, set with brilliant-cut diamonds, providing the perfect setting for the mounted spider with its high jewellery diamond body.
We use our own and third party cookies to improve your experience and our services. If you continue, we consider that you accept their use. You can get more information on your website at cookies policy.


text:
How to set up a Pte Ltd Company in Singapore
This article aims to guide you through the process of setting up a Pte Ltd Company in Singapore. Requirements: Company address – You will need a corporate address for registration with ACRA. It can be the physical office spaceLearn more


text:
LOUISVILLE, Ky. — Fort Knox has been selected for a new Army headquarters.
Senate Majority Leader Mitch McConnell announced the news on Tuesday.
Officials say Fort Knox will be the fourth corps headquarters location activated and will be called Fifth Corps (V Corps).
"Fort Knox has proven itself as a leader in our nation's armed forces time and again, and I'm delighted to announce Secretary McCarthy and General McConville answered my call to station V Corps headquarters in Kentucky," Senator McConnell said in a statement. "As the Army continues modernizing its force structure to counter evolving global threats, Fort Knox is best choice to meet our urgent national defense needs. With its unmatched level of community support, Fort Knox will offer V Corps a warm welcome."
It beat out 30 other installations to get the honor.
Fort Knox Garrison Commander Col. CJ King says there is a lot of support for the announcement, both on and off the base.
"We were in Elizabethtown this morning, [there was] a lot of excitement there," Col. King said.
Army leaders say the new headquarters was urgently needed to fulfill National Defense Strategy requirements and support American forces and operations in Europe.
One of the major benefits of headquartering at Fort Knox is that the is already space for the new soldiers, the Lt. Gen. Timothy J. Maude Complex, which sits empty right now.
"There's really no real building that needs to be done, maybe a little bit of refurbishment, moving things around," Col. King said.
The new headquarters is expected to bring an additional 635 soldiers which would mean an uptick to Fort Knox's local economy.
Of the soldiers who will be part of this corps, 200 will support a command post in Europe.
Officials say the Fifth Corps will be activated by fall 2020.
►Make it easy to keep up-to-date with more stories like this. Download the WHAS11 News app now. For Apple or Android users.
Have a news tip? Email firstname.lastname@example.com, visit our Facebook page or Twitter feed.


text:
August 2016
Florence Marcus
c/o firstname.lastname@example.com
c/o email@example.com
Florence Marcus is a veteran of WW II. She said: "I enlisted in the Coast Guard because I wanted to serve our country." Florence loves to compose poetry and also make colorful collages on various subjects. She is soon to be the ripe old age of 92 years.
Florence Marcus
Petty Officer Second-Class attached to Air & Sea Rescue
Petty Officer Second-Class attached to Air & Sea Rescue
A Delightful Experience
From my window I spotted a bright colored feather.
It was stuck in the bird feeder that I had put together.
Attached to the feather was a gorgeous looking bird.
I slowly opened my creaking window,
And he stared at me when he heard.
I leaned over and carefully untangled his feather.
I said "Pretty bird, I hope you will soon feel better."
To my amazement he touched my hand with his beak,
Then after a second , he emitted a very loud squeek.
"Thank you", I think he was trying to say.
He glanced back at me and then flew away.
As I was closing the window, to my utter surprise,
Pretty bird returned to the feeder where he calmly perched,
Then he gazed deeply into my eyes.
I blew a kiss to the bird I had rescued,
Lifted my hand and sadly waved goodbye
As he gracefully flapped his wings,
And vanished once again in the sky.
I'll always remember the kiss from his beak,
And the squeaky sound that he made.
He seemed to be talking to me.
He wasn't the least bit afraid.
Whenever I recall our encounter,
It gives my heart a lift.
I'll always be pleased that I was instrumental
In helping nature's beautiful gift.
Florence Marcus
collage by author
collage by author
©2016 Florence Marcus
Editor's Note: If this poem(s) moves you please consider writing to the author (email address above) to tell him or her. You might say what it is about the poem that moves you. Writing to the author is the beginning of community at Verse Virtual. It is very important. -FF


text:
WHEN: Sat – 6 PM
WHERE: Tonari's – in Fair Oaks (on fair oaks)
Last meet before FC, even if you don't like sushi, come and visit with us!
Sorry for the last minute nature of the planning. I have a lot on my plate, and I need feedback quicker.
"MAP to Sushi":http://www.mapquest.com/maps/map.adp?searchtype=address&country=US&addtohistory=&searchtab=home&address=+7330+FAIR+OAKS+BLVD&city=CARMICHAEL&state=ca&zipcode=+95608
AFTERMEET: Ravyn's (Mandy) place in roseville, anyone who doesn't want sushi can bring a dish for a mini potluck.
"MAP to Ravyn's":http://www.mapquest.com/maps/map.adp?searchtype=address&country=US&addtohistory=&searchtab=home&address=+5+Marcia+way+%23107&city=Roseville&state=ca&zipcode=95747
Apartment #107


text:
'They would roar and roar': Grand Bend residents glad to see exotic animals ordered out
LONDON, ONT. -- Some residents of Grand Bend are saying 'good riddance', as the deadline comes for exotic animals to be removed from a local animal retreat.
"At night it was unbelievable. They would roar and roar," said resident Wendy Mawsen, who lives behind the Roaring Cat Retreat.
The roadside zoo has been home to dozens of exotic animals, including several lions, and various other large cats. Following a legal battle with the municipality of Lambton Shores, a court has ordered that they be removed by June 2nd.
Mawsen said she believes it's for the best.
"One evening they had two out on the road. They got out, back in March or April. And they came down the side-road, the cats. And I came home one day, there was a big lama standing in my driveway, and it walked down to my neighbours, not these neighbours but the next neighbours and they had a pig in the back yard and a bunch of things."
Neighbour Dan Mudge said there have been several escapes, luckily by some of the less dangerous animals. But that doesn't give him any comfort.
"It's pretty unnerving when they're roaring. When you can come out your back door and I can come over and see the four kids living next to me and the cats start roaring they run into the house."
The property is the former Pine Ridge Zoo. Lambton Shores Mayor Bill Weber said it was rezoned to residential about seven years ago.
"It doesn't fit in the community, it doesn't fit in the neighbourhood. What was there 40 years ago... times change. The zoning has changed. The neighbourhood has built up, and the property was changed to residential."
The Roaring Cat Retreat owners, Mark and Tammy Drysdale, told CTV News they're trying to make arrangements for the animals, but ultimately they hope to have the order reversed.
"Our ultimate goal would be to have our animals back home," said Tammy Drysdale. "That's what we're hopeful for, that we can have our animals back home with us."
Meanwhile, neighbours CTV News spoke with all said they feel for the animals, but Wendy Mawsen added that they'll feel a lot better when they're gone.
"When they got out over there, I mean they were just little ones, but they're still lions."


text:
Every party has the freedom to form an alliance:Digvijay
Warning: A non-numeric value encountered in /home/northcyp/public_html/wp-content/themes/publisher1/includes/func-review-rating.php on line 212
Warning: A non-numeric value encountered in /home/northcyp/public_html/wp-content/themes/publisher1/includes/func-review-rating.php on line 213
New Delhi: Congress general secretary Digvijay Singh Saturday evaded comment whether the party would be entering any alliance in Uttar Pradesh, saying everyone should wait for the results.
"To talk on whether Congress will enter an alliance or not, we will have to wait for the results to be declared," he told reporters.
"Every party has the freedom to form an alliance," he added.
Digvijay Singh further said that if Congress got majority in Uttar Pradesh it would form the government otherwise sit in the opposition.
Reacting to exit polls which have predicted a hung assembly with the Mulayam Singh Yadav-led Samajwadi Party winning the maximum seats, he said: "I would throw such exit polls in a dustbin. Exit polls have been proved wrong in the past and they will again be proved wrong this time."
The seventh and final phase of polling to pick a 403-seat assembly in the country's most populous state – Uttar Pradesh took place Saturday. Counting of votes in the state will take place March 6 along with the votes polled in Punjab, Manipur, Uttarakhand and Goa.
Although elections took place in five states, most interest nationally is on Uttar Pradesh, where the ruling Bahujan Samaj Party (BSP) is facing an opposition determined to unseat it.


text:
The Blackstone Group
Steve Schwarzman, co-founder and CEO of the Blackstone Group, is the kind of oversized billionaire spendthrift that only Hollywood -- or in this case, Wall Street -- could create. For his 60th birthday party, the so-called "King of Wall Street" threw himself multi-million dollar bash starring Martin Short, Rod Stewart and Patti LaBelle leading an entire church choir singing "He's Got the Whole World in His Hands" [source: Gross].
Blackstone is a private equity firm specializing in leveraged buyouts (LBO), or hostile takeovers. Schwarzman and his business partner Peter G. Peterson have been buying and flipping struggling companies since the 1980s with the help of lots of cheap, available debt. The typical LBO purchase is 10 percent cash and 90 percent debt.
Private equity firms are notoriously… well, private. So it surprised many investors when Blackstone announced plans to go public in 2007. Unfortunately, in the rush to get a piece of this Wall Street wonder -- Blackstone's funds have averaged a 23 percent annual return since 1987, twice the S&P 500 average -- investors overlooked the odd details of the deal [source: Jubak].
First of all, the company being offered was a spinoff of the Blackstone Group called Blackstone Holdings. This spinoff didn't represent the vast earnings of Blackstone's investments, only the chunk of the company that managed those investments. Blackstone Holdings only took in $2.3 billion a year in fees, but the IPO underwriters still valued it at $40 billion [source: Jubak].
But the biggest problem -- and something that Schwarzman and his Blackstone insiders undoubtedly foresaw -- was that the bottom was about to drop out of the credit market, drying up the easy debt needed to make LBOs. In the IPO prospectus, Blackstone warned of uneven earnings over the next couple of months or years, but few people paid attention.
The result: Blackstone raised $4.1 billion with the IPO, Schwarzman and his co-founder Peter G. Peterson pocketed $2.6 billion, and investors ended up with a stock that lost 42 percent of its value during its first year [source: Kelly]. More than two years later, the stock is still trading between $10 and $15, less than half of its $31 IPO price.


text:
With "only" five months to go, Kate Middleton is allegedly embarking on some punishing fitness regimen.
First of all, how do they know? This piece in Radar disseminates all kinds of info very authoritatively — like that the "size-2 Brit" is 5'10" and 120 pounds — in this "exclusive." Among other things, we learn that Kate:
- Is "back on the rower, burning up to 500 calories an hour and shaping those all important back and arm muscles."
- Has "upped her daily hour-long gym workouts, which include cycling, jogging and light weights"
- Will "make the most of the snow, squeezing in at least one skiing trip abroad before April 29. With a whole day skiing burning up a whopping 2000 calories, it is the ultimate workout."
- Is "an avid follower of the high-protein Dukan Diet," which involves protein-only days and is big in France.
- Will "have to cut back on her favorite cocktail, the 'crack baby', a fresh passion fruit mix with vodka and champagne."
If the world's going to scrutinize Kate Middleton (and I guess we are!), let's focus on the positive fact that she's always seemed to exercise out of love of sports and achievements like rowing the English Channel — and we can always use more women who are active for the love of it in the public eye. And as these celeb regimens go, this one at least seems to involve less weirdness than some. But at the same time, this woman's going to be subject to a level of wedding-day scrutiny that's literally unparalleled: no one — but no one — should be comparing themselves to her. Or, for that matter, begrudging her a cocktail (although can we please motion to get it a new name, stat?)


text:
Portlaoise rapper and radio DJ in youth mental health project
Local young people came together last weekend for unique workshops, which gave them a chance to speak their minds, as well as learning some exciting new skills.
The weekend co-incided with the screening of a film documentary made about the life of Portlaoise rapper, Wally O'Loughlin who attempted suicide in 2009. This unique training weekend was funded by Laois Partnership and was called 'Hear Me See Me.'
Ann-Marie Kelly, well known from her Breakfast show on Midlands 103, filmed the documentary and was the project manager for the weekend. She was delighted with the results from the weekend's workshops, which was shown to the audience in the Dunamaise Arts Centre before the documentary was screened last Sunday.
"The group were great, they were more than I ever imagined they would be. They were really open and got heavily involved in the process," said Ann-Marie. "They responded really well and by the end of the weekend they got great confidence and produced really high quality work."
'Hear Me See Me' was born out of the realisation that Wally did not have the confidence or the tools to express himself, and the weekend aimed to address that. As a result, the training weekend brought 40 young people and youth workers together on common ground, to express themselves through the arts. 40 young people from transition year in Mountrath Community School were given the chance to take part in radio, music and film training.
They made two radio shows, a short film and recorded three songs, and all training was done by professionals in the industry. Special guest appearances were made by RTE's Eileen Dunne and the Republic of Telly's Bernard O'Shea who were both interviewed by the radio group. Paul Walsh from the band Royseven also facilitated a music workshop, along with Wally himself and Stewart Quinn from local band Transmitter.
Ann-Marie Kelly and Midlands 103's Will Faulkner facilitated the radio workshops. From Birr the film company Hello Camera faciliated the film workshops. Ann Marie said that she would love to complete another weekend like this. "Laois Partnership were great to give the funding, and I would love to do it again. Transition year students are great, really open and they are at the vital age of being vunerable." As well as a successful weekend's workshops, Ann-Marie and Wally also enjoyed a full house and standing ovation in the Dunamaise for the screening of the documentary. Check out Stage Left for information on upcoming screenings.


text:
(ASIA NEWS NETWORK/THE JAPAN NEWS) - More foreign tourists have been visting Umaiya, a long-established shop selling takoyaki octopus balls in Kita Ward, Osaka, since it was featured in the 2016 Kyoto and Osaka Michelin Guide. It was the first time takoyaki shops had been featured by Michelin, which ranks restaurants and other eateries across the globe, and 11 outlets were included that year.
The first thing you see when you visit Umaiya is its huge signboard, which looks larger than a tatami mat. It's shaped like an octopus and made of blackened tinplate, illustrating just how long the store has existed.
Umaiya is located near the entrance to Tengo-nakazakidori Shotengai, a shopping street nicknamed Oideyasu-dori. Oideyasu means "welcome" in the Kansai dialect.
Umaiya was established in 1953. "I feel happiest when customers tell me that the flavour hasn't changed," said fourth-generation owner Taizo Kita, 39.
Umaiya's takoyaki dough is made with a thin batter of flour mixed with a bonito-based dashi stock. The thin surface is crispy, the inside chewy.
If takoyaki balls are grilled for too long, they absorb the oil and become hard. So after they've been sufficiently grilled, Kita removes them from the heat quickly, and places them in special warmers made of copper.
Umaiya preserves the traditional method of Osaka, the home of takoyaki, to allow customers to enjoy the dashi flavor in the dough.
Kita's great-grandmother opened Umaiya, and his grandfather and father each took over the store in turn. Kita had a different job after graduating from university, but he returned 14 years ago, aiming to succeed his father in the family business.
"When I'd just begun working here, my grandfather often told me, 'If you have time to eat takoyaki from other stores, eat our takoyaki to remember our own taste,'" Kita said.
Ever since the start of the Heisei period in 1989, takoyaki has faced a period of change. A half century after its birth, the dish suddenly gained nationwide popularity, but Osaka natives accepted the boom grudgingly because it was led by people living in Tokyo and the surrounding area.
Nippon Konamon Association head Mana Kumagai explained that the takoyaki boom began in the Kanto region when a Yokohama-based company opened a takoyaki store in 1993 in Shibuya Ward, Tokyo, to capitalise on the food's popularity in the Kansai region.
Soon three takoyaki stores appeared in the same location and long lines of customers formed in front of them.
Kumagai's analysis of the phenomenon is that "people who enjoyed eating gourmet meals during the bubble era became interested in low-priced takoyaki".
One highlight of the changing times was the appearance of Tsukiji Gindako, now the nation's largest chain of takoyaki stores with 472 outlets nationwide.
In 1997, chain operator HotLand Co. opened its first takoyaki store in Gunma Prefecture, where the company was then headquartered. As takoyaki's popularity boomed in the Kanto region, the number of their stores increased.
But when the chain opened its first store in Osaka in 2000, some customers complained that it was "not takoyaki".
Gindako's takoyaki balls are grilled at high temperatures with cooking oil added at the final stage.
A HotLand spokesperson said: "This method is an effort to retain the shape and taste when they are delivered or customers take them home. But the texture, which makes the surface very crispy as if fried, is different from that of Osaka takoyaki, which led to negative reactions."
Despite the complaints, the company has not changed its cooking style — it has continued its expansion. Currently, the chain has as many as 10 stores in Osaka Prefecture.
Kita has a favourable opinion of Tsukiji Gindako's style, which has opened stores overseas and touts its desire to make takoyaki the soul food of Japan.
"It's great that more and more people are discovering takoyaki, isn't it? It's fine that both of us [Umaiya and Gindako] are trying to popularise our own versions of takoyaki at home and abroad, fueling the promotion of Japanese food culture," he said.
However, he added, "I'm not keen on having our takoyaki served elsewhere, if I can't see the expression on a customer's face when they say, 'This is Umaiya's takoyaki.'"
Therefore, Kita said, he has declined all offers to open other Umaiya outlets or sell frozen takoyaki under the Umaiya brand.
"For Osaka natives," Kumagai said, "it's like the dish is a part of our skin, so we didn't think it was worth talking about with others."
But now, these octopus balls are attracting attention from all over the world.
Kita said, "Ever since my store was included in the Michelin guidebook, I've wanted to offer much better takoyaki." The fourth-generation owner vowed, "My goal is to celebrate the 100th anniversary of this store's opening."
He keeps in mind the cautionary lesson his grandfather strictly taught him: "You must know this store's own taste, which is different from that of other stores."
With his grandfather's words in his heart, Kita prepares takoyaki on the custom-made grill that was built especially for use at Umaiya.


text:
BlackOut Design recently performed a complete website redesign for United Neighborhood Centers of Northeastern Pennsylvania (UNC). UNC was in need of a makeover to modernize their navigation and overall look. There was also plethora of information to organize due to the many facets surrounding such an active and positive organization. All of this was accomplished while working closely with the UNC team to ensure accuracy and approval.
UNC is pushing 90 years of community enrichment through their many programs and services. They even merged with the Scranton Council of Literacy Advance (SCOLA) in early 2011 to preserve this valuable literacy program. There are so many more wonderful accomplishments of this volunteer and non profit organization that you can now reference on their website.
BlackOut design was thrilled to work with yet another positive element of the Scranton community. At your leisure, read more about UNC here.


text: NextGen, MicroGaming, Netent and Betsoft slots continue our drive to diversify! Published on 2018-05-01 16:56 If Asian fantasy, medieval knights, tropical birds, cats and prehistoric themes is your cup of tea, then we've added five slots that will fit the bill nicely! 5 Knights NextGen invites you to a 'knight in' as it presents to you 5 Knights, which is a 5-reel, 3-row and 1 to 25 variable paylines slot with up to 500 coins... read more » Tags: 1 can 2 can bitcoin slot108 heroes bitcoin slot2 million b.c. bitcoin slot5 knights bitcoin slotcopy cats bitcoin slot


text:
Of all of the things we put on our body, jeans seem the most resistant to technological change. There is nothing close to as game-changing as Project Glass for the denim set, after all. Are blue jeans, black jeans and, um, all the other colored jeans doomed to stay the same forever and ever? Let me look at Crunchwear's trusty magic eight ball. Good news! It says "not likely," Thank you magic eight ball!
Italian denim designers, Replay, are trying their darnedest to bring jeans into the 21st century and beyond. To that end they have prepped a new line of jeans that is named "Social Denim." What's so social about this denim? Well, it's simple. These jeans come with Facebook and Twitter functionality built-in. You read that right. These jeans let you tweet.
It works via a special fifth pocket that contains a Bluetooth transmitter. Pair the device with a smartphone and you can use one of a series of buttons to broadcast your mood and/or current location in less time it takes you to zip up. I wonder if it has a button for "I ate too much last night and now I can't fit into these jeans."
The line will be available in December and prices will range from around $190 to $250. For high end denim with a high tech swagger, that doesn't seem like that bad of a price. Check a video and more images below.


text:
Thanks for the kind offer. The person being contacted to see if she has the status is the person who initiated the original email. The person doing the contacting is the person who forwarded the email to about four people. She also occasionally does transport for some of the SF ACC animals. If she does have the status and is willing to get them, then it's possible that she would need to pick them up and bring them to her rescue and then the transport person would deliver them to me. Again, the deadline is tomorrow per the person who is currently being contacted. She is the one who was alerted by SF ACC of the problem. Sorry for the vagueness and non-reference to names but they are purposefully being left out.If a non-profit can not be found. I'll pay the adoption fee.
I am to be at the shelter tomorrow at 11am. The shelter doesn't open until noon for adoptions but the person who is getting three of them is a volunteer there so we can get in early. Also, if you don't want the pregnant one, let me know. However, she would probably be one of the first to be put down. Even if the other person has to pick them up, I will check to see what is there if possible and what type of condition they are in. My understanding is that 19 came in and 7 were immediateley put down, for what reason I do not know. There are apparently some type of temporary cages that can be borrowed although I may not take them since I probably can come up with something with the male being placed this weekend.
Also, a FYI, the person who said that she probably could foster one or two for a short period has never had a guinea pig before. She's the one who rescues dogs and occasionally other critters.
As it stands now, kleenmama will take them if there is no charge? If there is a charge, Julian will cover the costs?
I will post more tomorrow, or sooner if need be; I will be leaving about 10am tomorrow to go to the city.


text:
I was recently investigating problematic inventory on one of Australia's busiest sites that used a nested player to override the playback controls of the actual video player in the page. The only way a user could mute or pause the player was to close the browser or tab.
Besides the obvious problems, namely that this is incredibly annoying to both the end user and the site owner, the fact that something like this could be permitted on a site or network is also indicative of even bigger issues in our industry.
Digging deeper, there were too many Digital Video Ad Serving Template (VAST) wrappers on the ad unit and a total of 11 impression trackers where you'd normally expect only two. These layers negatively impact viewability measurement and lead to major problems like degraded user experience, latency, or no ads playing at all.
What's even worse, this ad facilitated false completion data for that video campaign.
How is this happening?
The tip of the iceberg
Until new viewability measurement methods come into play, vendors are limited to measurement via Video Player Ad-Serving Interface Definition (VPAID). VPAID is open to exploitation because it is more accommodating than the more strict VAST method of video ad ingestion. This is especially true because a VPAID tag can be made up of JavaScript, which means room for creativity, as well as abuse.
It's not uncommon to have interactive video ad units or nested video players appear within video ad content as a result of allowing VPAID on a network, which is terrible for the industry as a whole. Simply put, the way we implement analytics to measure viewability is breaking things.
It's time to call for an end to Russian nesting doll hacks in video ads. Clean ads mean a better customer experience and better ratings, so there is nothing more important than yield and making the most of every ad opportunity. So what can we do about it?
Segregate video inventory: For direct, programmatic, Over The Top (OTT) television, Video On Demand (VOD), live streaming, desktop, and mobile web, segregate your video inventory to play up to the weaknesses and strengths of each.
Empower a good SSP: Reputable supply-side platforms are worth the investment to help maintain ad quality. SSP's can provide services to help teams create rules around file types that are allowed on sites or networks.
Enforce particular media types for devices: Manage the applications and sites that deliver nested hacks to the end user and define the rules that determine what ad media users get.
Don't use VPAID: Set up rules with the supply-side platform and run programmatic guaranteed campaigns, ensuring they don't carry nested players, tracking pixels, or unwarranted tracking.
Tool up and educate Ad-Ops: Educate Ad-Ops teams on how to read video ad tags for tell-tale signs of rogue code, tags, wrappers, and pixels. Give them tools like debugging consoles to add invaluable resources to their kits.
The way forward
In addition to the tips above, which can be applied to client side ad insertion, Brightcove's Server-Side Ad Insertion can solve many ad management issues and then some. Our technology mitigates both ad quality and ad blocking concerns. We are able to help customers reach and monetise audiences, regardless of platform, device, network or potential hurdle while still delivering a premium, TV-like experience across any device.
This Russian nesting doll issue isn't the only one we have to contend with in our industry, and Brightcove is focused on tackling the big problems in video ad quality and management head-on.
This post is the first in a series that will discuss how to rise above key challenges like header bidding, inspecting vast tags, and latency. Keep an eye out for the next installment.
See how we can help you


text:
In my former career as a classroom teacher, I spent at least $1000 of my own money each year on classroom supplies and instructional materials for the students in my first grade class. Out of pocket spending by teachers is so common that 92% of teachers report spending their earnings on materials for student use. Across our nation, teachers spend $1.3 billion dollars on classroom supplies each year.
As a former classroom teacher and a parent who advocates partnering with teachers to enhance our childrens' education, I am thrilled to be working with Office Depot REAL Change #TeachersChangeLives campaign. This campaign recognizes the contributions that teachers make each and every day to support their students by providing a chance for each and every one of us to help our kids' teachers. As a place where I shopped for classroom supplies and serves as THE place where our family shops for school essentials, I'm excited to be working with a national retailer that truly cares about teachers and their challenges and understands what they need in order to thrive.
Today I'm helping Office Depot kick off the first part of the campaign with a Pinterest Sweepstakes that is incredibly easy to enter in order to win Office Depot gift cards for you and the teacher of your choice. Here's a quick look at how to enter!
If you need to peek at an example, check out the Office Depot #TeachersChangeLives pin board!
Once you create your #TeachersChangeLives Pinterest board, be sure to report it using this form. Three winners whose boards meet the entry requirements will be randomly selected to win a $100 Office Depot gift card for themselves and a $50 Office Depot gift card for the teacher of their choice! Full sweepstakes rules can be found on Office Depot's Facebook page.
I am working as a consultant on the Office Depot REAL Change #TeachersChangeLives campaign and am being compensated for my involvement.


text:
Starfish story...
December 13, 2016
EVENT: Grandma's Marathon 2017
EVENT DATE: Jun 17, 2017
Questions? Please contact Ross Perko at firstname.lastname@example.com.
Get motivated, get fit and run for a cause! The Northern Lights Foundation is once again a proud partner of the Grandma's Marathon Charity Runner Program. The fundraising minimum to join our team is $500 and in 2016, every runner we had exceeded that goal!
Our overall goal for 2017 is to raise $15,000 in support of children facing life threatening illnesses. Be part of something bigger -- transform your life while helping support a fmaily who may live very near to the wonderful race course you wil be traversing in June!
The grants we give to families can be used for whatever they need. They can pay down medical bills, stay current on their mortgage or purchase healthier food options for their child's wellness or simply help to put gas in their car.
Know that your suport is immediate and felt so strongly by these deserving families!
Know you ARE MAKING AN INCREDIBLE DIFFERENCE!


text:
Our Grand Adventure today was for the folks and I to go to the Aullwood Apple Festival. Unlike the Troy Strawberry Festival, the featured fruit wasn't present in most of the booths, which was a bit of a surprise. But the various booths had interesting items and lots of food choices.
Dad and I decided to try the "fish boats" that one tent was selling. And while we waited for our food, mom held up the tent for the folks making our lunch - it was so blustery the tent kept threatening to fall over. The fish was excellent. Mom opted to try the lamb chili that another place was selling - that was tasty too. I also had a lemon shake-up, which was mighty tasty. And just because I could, I had the "hot waffle ice cream sandwich" which is just as described. Interesting.
As we were finishing our lunch, big black storm clouds crept over the festival, so we (and half of the folks there) headed to the inside bits. Thankfully, the clouds blew over without raining, so we returned outside to share an apple dumpling a la mode before heading back.
The rest of my day was spent cleaning house and listening to the latest Big Finish Sylv audio, Gods and Monsters. And halfway through that story, I got to watch the latest TV episode, "The Power of Three." Quite enjoyable. I'm gonna miss the Ponds!
Tomorrow is laundry day. And hopefully I get a nice walk in to enjoy our lovely weather.


text:
A new Oak Cliff middle school will bear the name of Zan Holmes Jr. The Dallas Independent School District board approved Zan Holmes Jr. Middle School Thursday. Holmes, a Dallas civil rights leader who served in the Texas House of Representatives from 1968 to 1972, is pastor emeritus at the St. Luke Community United Methodist Church. (I don't have any details on that school. I think the DISD press office must be in meetings or something because they're not answering the phones this morning.)
Kathlyn Joy Gilliam Collegiate Academy, in honor of the former school board trustee, will be the name of the early college academy that DISD is building on 5 acres adjacent to the University of North Texas at Dallas (by the way, that school changed its name from the University of North Texas Dallas campus). Gilliam served as a DISD board member from 1974 to 1997, and was school board president from 1980 to 1981.
The existing early college campus at Mountain View College will be named for Trini Garza, the first Hispanic to serve on the DISD board.


text:
It is our hope that this collection of humor will help make us laugh at ourselves, and hopefully live a more compassionate cruelty-free lifestyle.
(Photo - 189) Why are you interrupting us? - Photo submitted by Cherie Nickell
Previous | Humorous Animal Photos | Next
Return to: Humorous, Funny and Cute Animal Photos
Return to: Humor - Table of Contents


text:
Twice each year, up to100 young adults representing the ten nations around the Baltic Sea gather to work under the same conditions as the members of the European Parliament. Delegates prepare and debate relevant and vital European topics in 5 different committees.
The procedures in the General Assembly are very formal and in accordance with the European Parliament standards, and it is often hosted in the parliament building of the organizing country. Thus, after the committees have written their resolutions, the parliament assembles for the General Assembly, or plenary debate.
The approved resolutions are forwarded to the European Parliament as a summary of the week-long session. The youth of the Baltic Sea region have thus stated their opinions on the issues of European collaboration .


text: I was reading Havoc's post on past date film and when people started talking about freezing and condensation, I was reminded of some advice i was given by a sales person at the Eden Project.which is a glorified green house. I had forgotten to bring a camera(???) and had decided to purchase a Fuji Disposable, however before I entered the Tropical Biome, the sales assistant advised me to unwrap the camera and take it into the toilets and run it under a hot air hand dryer, the reasoning behind this was to heat up the camera so that when I entered the Tropical Biome condensation would not form inside the cam. The looks I had from people inside the toilet when I whipped out a camera and started "drying" it have put me off doing it again! :shock: Mind you it did take some cracking shots!