Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model.

BACKGROUND: Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS: The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS: The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION: benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.

Chronic Stress and Steatosis of Muscles, Bones, Liver, and Pancreas: A Review.

BACKGROUND: Chronic stress is a recognized risk factor for poor health, body composition disequilibrium, impaired mental health, and deterioration of quality of life. Chronic stress-related cortisol oversecretion and circadian dysregulation and associated systemic low grade, injurious inflammation ("para-inflammation") contribute to steatosis in various metabolically active solid organs, affecting both their structure and function. The aim of this review was to summarize current knowledge on the impact of chronic stress and associated para-inflammation on skeletal muscle, bone, liver, and pancreas, leading to their steatosis. Current management of these maladaptive conditions is also included and underscored in this review. SUMMARY: Steatosis of metabolically active solid organs is involved in various metabolic processes and considered a risk factor for chronic noncommunicable diseases, yet its role in chronic stress physiology and pathophysiology has been overlooked. KEY MESSAGES: Chronic stress-associated steatosis of several solid organs is generally disregarded in current clinical practice. Physicians should be alert for these steatoses and should address them adequately so as to provide appropriate medical care. New guidelines generated by learned societies are needed, along with large observational studies, to offer novel solutions to this old problem.

Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model

BACKGROUND: Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS: The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS: The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION: benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.

Ectopic fat deposition and its related abnormalities of lipid metabolism followed by nonalcoholic fatty pancreas.

Background and Objectives: The positive energy balance between caloric intake and caloric output increasing storage of triglycerides (TG) in adipocytes has made nonalcoholic fatty liver disease (NAFLD) one of the major public health problems in China. Excessive lipid deposition in the pancreas is referred to as nonalcoholic fatty pancreas disease (NAFPD). Early assessment of pancreatic fat infiltration will have an increasing role in the clinical management of the metabolic dysregulation and prevention pancreatic complications. Subjects and Methods: We retrospectively collected data of inpatients with NAFPD from EUS database between September 2012 and August 2020 at our endoscopic center. The prevalence of NAFPD and factors associated with its development were statistically analyzed. The echogenicity of the pancreas was compared to that of the left renal cortex during the EUS examination by using an existing criterion. Results: Four thousand, seven hundred and four consecutive individuals underwent EUS were enrolled. The prevalence of NAFPD was 1.2% (57/4704) . Factors independently associated with NAFPD on multivariate analysis were increasing TG (odds ratios [OR] 4.65, P = 0.014), NAFLD (OR 16.76, P = 0.005) and decreasing apolipoprotein A-1 (OR 0.002, P = 0.0127). We found no association between NAFPD and age, sex, total cholesterol or hypertension. Conclusions: We found a meaningful relationship between NAFLD, dyslipidemia, and NAFPD in Chinese. We hypothesized that NAFPD was strongly correlated with ectopic fat deposition and its related abnormalities of lipid metabolism. Early diagnosis of NAFLD provides opportunities to control the progression of NAFPD.

Impact of qualitative endoscopic ultrasonography on fatty pancreas at a referral medical center.

BACKGROUND: Taking advantage of the current advances in diagnostic imaging modalities, including endoscopic ultrasonography (EUS), and due to the increased attention to ectopic fat accumulation in the pancreas following the rising trend of metabolic syndrome, we qualitatively assessed the clinical implication of pancreatic steatosis by EUS in this study. METHODS: The study included 243 patients that were divided into four groups. The correlation between the average echogenicity of the pancreas and that of the control organs and the key clinical data of all study patients were collectively analyzed. The cut-off point of the pancreas-control (PC) ratio in EUS and liver-control (LC) ratio on abdominal ultrasound were determined from the population distribution and the obtained median values. RESULTS: With the cut-off point of 1.30 for the PC ratio and 1.20 for the LC ratio, sex, the Brinkman index, habitual alcohol drinkers, and fatty pancreas were significant factors. The associations between each relevant factor in fatty pancreas, metabolic syndrome in the fatty liver group, and age in the pancreatic cancer group were all significant in the analysis. In addition, we investigated whether the PC ratio differed according to age and staging in pancreatic cancer patients. Interestingly, the PC ratio was lower in the advanced stage group than in the early-stage group. CONCLUSION: Our results suggest that, irrespective of the degree, ectopic fat infiltration in the pancreas could be a specific clinical phenotype of serious pancreatic diseases, including pancreatic cancer, especially in high-risk patients.

Frequency of Nonalcoholic fatty pancreatic disease in patients with carcinoma pancreas presenting for upper abdominal Endoscopic Ultrasound in a tertiary care center.

OBJECTIVE: To determine the frequency of nonalcoholic fatty pancreatic disease in patients with carcinoma pancreas presenting for upper abdominal endoscopic ultrasound. METHODS: The prospective cross-sectional study was conducted in the Endoscopy Suite of Surgical Unit 4, Civil Hospital, Karachi, from October 2019 to September 2020, and comprised patients presenting for endoscopic ultrasound. Patients were divided into Group A comprising carcinoma pancreas patients, and Group B having non-carcinoma pancreas patients. Fatty pancreas was identified by hyperechogenicity on endoscopic ultrasound. Data was analysed using SPSS 19. RESULTS: Of the 68 patients, 44(64.7%) were male and 24(35.3%) were females. The overall mean age was 49.9±13.82 years (range: 16-80 years). There were 35(51.5%) patients in Group A and 33(48.5%) in Group B. The frequency of nonalcoholic fatty pancreatic disease was 18(26.5%) and 15(83.3%) of them were male subjects (p=0.04). Group A had 12(34.28%) subjects with nonalcoholic fatty pancreatic disease compared to 6(18%) in Group B (p=0.11). CONCLUSIONS: Nonalcoholic fatty pancreatic disease was frequently seen in carcinoma pancreas patients undergoing endoscopic ultrasound compared to non-carcinoma pancreas patients. Most of the patients affected were males.

Pancretic Fat Accummulation is Associated with Subclinical Atherosclerosis.

We investigated the relationship between pancreatic fat accumulation and markers of atherosclerosis among patients with nonalcoholic fatty liver disease (NAFLD). Patients with NAFLD have been reported to be at an increased risk of vascular events. We grouped 183 patients in whom we detected and graded hepatosteatosis (HS) on transabdominal ultrasonography into 2 groups based on the presence/absence of pancreatic fat. There were 85 participants (50 female; mean age: 53.6 ± 9.7 years) who were nonalcoholic fatty pancreas disease (NAFPD) positive and 98 participants (56 female; mean age: 51.4 ± 9.3 years) who were NAFPD negative. Carotid intima media thickness (cIMT) was significantly greater in the group where HS was accompanied by NAFPD (0.51 [0.40-0.62] vs 0.45 [0.35-0.55] mm; P < .001). Multivariable analyses showed that the independent predictors of increased cIMT were age (odds ratio [OR]: 1.108; 95% CI: 1.059-1.158, P = .001), hypertension (OR: 2.244; 95% CI: 1.099-4.579, P = .026), and the presence of NAFPD (OR: 3.078; CI 95% CI: 1.531-6.190, P = .0002). In the present study we demonstrated that, in patients with NAFLD, pancreatic fat accumulation was significantly associated with cIMT, a marker of early atherosclerosis. NAFPD may increase the risk of vascular events associated with NAFLD.

Environmental Factors Slightly Outweigh Genetic Influences in the Development of Pancreatic Lipid Accumulation: A Classical Twin Study.

Background: Several studies showed that lipid accumulation in the pancreas (NAFPD: nonalcoholic fatty pancreas disease) may lead to different pancreatic disorders, including beta-cell dysfunction. The role of genetic and environmental factors in pancreatic lipid accumulation is unclear. We evaluated the magnitude of genetic and environmental impact on pancreatic lipid content within a cohort of adult twin pairs. Patients and Methods: We investigated 136 twin subjects [monozygotic (MZ, n = 86) and dizygotic (DZ, n = 50) same-gender twins (age 57.7 ± 9.1 years; body mass index [BMI] 28.0 ± 4.4 kg/m2; females 64.7%)] with a 256-slice computed tomography (CT)-scanner. Using nonenhanced CT images, we calculated the average value of pancreatic attenuation expressed in Hounsfield unit (HU) suggesting pancreatic lipid content. Crude data were adjusted to age, sex, BMI, and hemoglobinA1c values. Intrapair correlations were established, and structural equation models were used for quantifying the contribution of additive genetic (A), common environmental (C), and unique environmental (E) components to the investigated phenotype. Results: The study cohort represented a moderately overweight, middle-aged Caucasian population. Average pancreatic attenuation was 48.9 ± 11.9 HU in MZ and 49.0 ± 13.0 HU in DZ twins (P = 0.934). The intrapair correlation between HU values was stronger in MZ compared to DZ twins (rMZ = 0.536, P < 0.001; rDZ = 0.115, P = 0.580). Using the structural equation model, a greater unique environmental influence [E: 54%, 95% confidence interval (CI) 19%-66%] and a moderate additive genetic dependence (A: 46%, 95% CI 34%-81%) were found. Conclusions: The results of our classical twin study indicate that environmental (lifestyle) influences slightly outweigh genetic effects on the phenotypic appearance of pancreatic lipid accumulation known as NAFPD.

Nonalcoholic Fatty Pancreas Disease: Clinical Consequences.

Metabolic syndrome and its components such as obesity, hypertriglyceridemia, type-2 diabetes mellitus (DM-T2), and arterial hypertension are unequivocally serious problems for every society. This is especially true in economically developed countries where the imbalance in lifestyle between caloric intake and caloric output still gets greater and greater. This fact is not only a concern for the adult population but for children as well. However, metabolic syndrome does not only affect society and health in regards to cardiovascular diseases, it significantly concerns gastroenterology where it is classified as nonalcoholic fatty pancreas disease (NAFPD). The data gained from several trials show that the prevalence of NAFDP is 33% (95% CI 24-41%). When it comes to the diagnostic procedures concerning the presence of pancreatic fat, a whole spectrum of suitable methods are recommended. Probably, the most exact method is the use of magnetic resonance imaging. However, for common clinical practice, the abdominal sonographic examination based on the comparison of the pancreatic parenchymatous echogenity versus renal or hepatic echogenity is used. The clinical consequences of pancreatic steatosis and steatopancreatitis are significant. These diseases are connected with DM-T2 and insulin resistance. In recent years, changes of exocrine pancreatic function, particularly its decrease, have also been described. It is known that there is a close correlation between NAFPD and nonalcoholic hepatic steatosis and also with the increased thickness of aortic intima-media. There is also an important relationship between NAFPD and pancreatic carcinoma. Pancreatic steatosis, and especially its NAFPD form, is a serious state which can be treatable by the possible effective management of metabolic syndrome parameters, including obesity.

Beneficial Effects of n-3 Polyunsaturated Fatty Acids on Offspring's Pancreas of Gestational Diabetes Rats.

We studied the long-term influence of gestational diabetes mellitus (GDM) on the pancreas of offspring and the effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on offspring's pancreas. GDM offspring were divided into three groups: GDM offspring, n-3 PUFA-adequate-GDM offspring, and n-3 PUFA-deficient GDM offspring. All healthy and GDM offspring were fed up to 11 months old. The pancreas of GDM offspring exhibited fatty infiltration at 11 months old, whereas n-3 PUFA improved the pancreatic fatty infiltration. n-3 PUFA lowered the pancreatic oxidative stress and inflammation. Surprisingly, n-3 PUFA postponed pancreatic telomere shortening of GDM offspring at old age. Nontargeted metabolomics showed that many metabolites were altered in the pancreas of GDM offspring at old age, including l-valine, ceramide, acylcarnitines, tocotrienol, cholesteryl acetate, and biotin. n-3 PUFA modulated some altered metabolites and metabolic pathways. Therefore, GDM caused the long-term effects on offspring's pancreas, whereas n-3 PUFA played a beneficial role.

In New-Onset Diabetes Mellitus, Metformin Reduces Fat Accumulation in the Liver, But Not in the Pancreas or Pericardium.

Background: Nonalcoholic fatty pancreas and liver disease (NAFPD and NAFLD) and pericardial adipose tissue (PAT) are often associated with type 2 diabetes mellitus (T2DM). Our aim was to evaluate the incidence rate of NAFLD and NAFPD, PAT size, and the effect of metformin treatment on NAFLD, NAFPD, and PAT in new-onset T2DM (NODM). Methods: Seventeen patients with NODM and 10 subjects used as a control group were involved in the study. Computed tomography (CT) and laboratory tests were performed before the beginning of metformin therapy and 4 months afterward. PAT and the amount of fat in the pancreas and liver were determined by X-ray attenuation during unenhanced CT examination and compared with the values for the control subjects. Results: Metabolic parameters improved significantly after metformin therapy. NAFLD was diagnosed in 64.7% of the patients with NODM and in 10% of the control subjects. The radiation absorption of the liver was significantly lower in the patients with NODM compared with the control group and significantly higher after metformin therapy compared with the baseline values. Only six patients (35.3%) had NAFLD after metformin therapy. NAFPD was diagnosed in 82.3% of the patients with NODM and in 20% of the control subjects. The radiation absorption of the pancreas was significantly lower in the patients with NODM compared with the control group but did not change significantly after treatment. PAT size was significantly larger in the patients with NODM and did not change significantly after metformin treatment. Conclusions: NAFLD, NAFPD, and increased PAT were detected in the majority of patients with NODM. Metformin therapy decreased the amount of fat in the liver in parallel with an improvement in the metabolic parameters and may, thus, be beneficial for preventing the late consequences of NAFLD.

Prediabetes and type 2 diabetes are independent risk factors for computed tomography-estimated nonalcoholic fatty pancreas disease

OBJECTIVES: Nonalcoholic fatty pancreas disease (NAFPD) is characterized by excessive fat deposition in the pancreas in the absence of alcohol consumption. In this study, we aimed to detect a possible relationship between adipose tissue accumulation, prediabetes and diabetes. METHODS: This cross-sectional and retrospective study included 110 patients. Three groups were classified as controls, patients with prediabetes and patients with type 2 diabetes. The abdominal computed tomography (CT) attenuation measurement results of the pancreas were evaluated independently by two experienced radiologists. CT measurements and biochemical parameters were compared between study groups. The relationship between continuous variables was assessed by using one-way ANOVA. To determine the changes in the dependent variable for the effects on study groups, the independent variable was adjusted using ANCOVA. A p-value less than 0.05 was considered statistically significant. RESULTS: The presence of prediabetes and type 2 diabetes was correlated with a decrease in the mean Hounsfield Unit (HU) value of the pancreas (p=0.002). Age was determined to be an independent risk factor and was correlated with NAFPD (p=0.0001). When compared to the controls (p=0.041), 71% of patients with prediabetes and 67% of patients with type 2 diabetes were observed to have an increased incidence of NAFPD. Decreased serum amylase was found to be correlated with the mean HU value of the pancreas (p=0.043). CONCLUSION: NAFPD was independently correlated with both prediabetes and type 2 diabetes adjusted for age (p=0.0001) in this study. Additionally, age was determined to be an independent risk factor and was correlated with NAFPD.

Non-alcoholic fatty pancreas disease.

Obesity is a growing problem worldwide and disorders associated with excess body fat including the metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular disease and malignant neoplasms are becoming a major cause of morbidity and mortality. Over the past decade, a vast amount of research has furthered our understanding of non-alcoholic fatty liver disease; however, only recently pancreatic fat infiltration is coming to the forefront of investigation. Termed non-alcoholic fatty pancreas disease (NAFPD), it is becoming evident that it has important associations with other diseases of obesity. It appears to arise as obesity progresses and after an initial phase of pancreatic hypertrophy and hyperplasia, fatty infiltration becomes apparent. Various studies have demonstrated that NAFPD may exacerbate the severity of acute pancreatitis, promote pancreatic dysfunction associated with insulin resistance and T2DM, and even have links to the development of pancreatic carcinoma, and therefore, it must be investigated in further detail.

Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

Is a fatty pancreas a banal lesion?

So far, a fatty pancreas has been related to obesity and the ageing processes in the body. The current list of pathogenetic factors of the condition is clearly extended with genetically conditioned diseases (cystic fibrosis, Shwachman-Diamond syndrome and Johanson-Blizzard syndrome), pancreatitis, especially hereditary and obstructive, metabolic and hormonal disorders (hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hypercortisolemia), alcohol overuse, taking some medicines (especially adrenal cortex hormones), disease of the liver and visceral adiposis. As regards lipomatosis of that organ resulting mainly from dyslipidemia and hyperglycemia, the term "nonalcoholic fatty pancreas disease" was introduced. Experimental studies on animals and histological preparations of the pancreatic fragments show that the lipotoxicity of the collected adipocytes collected ion the organ release a cascade of proinflammatory phenomena, and even induces the processes of carcinogenesis. Pancreas adiposis is best defined in Computed Tomography and Magnetic Resonance Imaging. However, a series of works proved the usefulness in the diagnostics of that pathology of transabdominal and endoscopic ultrasonography. In that method, the degree of adiposis was based on the comparison of echogenicity of the pancreas and the liver, renal parenchyma, spleen and/or retroperitoneal adipose. Recently, the evaluation was expanded by the evaluation of the degree of pancreatic adipose with the pancreas-to-liver index, utilizing to that end a special computer program. According to our experience, the simplest solution is the method utilized by us. On one crosssection of the body of the pancreas, its echogenicity is assessed in comparison to retroperitoneal adipose and the visibility of the splenic vein, pancreatic duct and the major retroperitoneal vessels. Depending on the visualization of these structures, it is possible to determine the degree of pancreas adiposis. Such a study applies to 250 people, in whom the adiposis was detected in 16.5%, which is close to other cohort US examinations results.

Enigmatic ectopic fat: prevalence of nonalcoholic fatty pancreas disease and its associated factors in a Chinese population.

BACKGROUND: Fatty infiltration of the pancreas is an enigmatic manifestation of ectopic fat deposition in obesity. Studies have shown that pancreatic lipid accumulation interferes with insulin secretion in humans. However, the prevalence of fatty pancreas and its associated factors in the general population remain unclear. The aim of this study was to investigate the prevalence of fatty pancreas and its association with diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiometabolic risk factors in a Chinese population. METHODS AND RESULTS: This was a cross-sectional study. A total of 8097 subjects with or without fatty pancreas (n=1297 and 6800, respectively) were recruited. Each subject was assessed by using abdominal sonography to diagnose NAFLD and fatty pancreas. Clinical and metabolic parameters were compared between groups, and their associations with fatty pancreas were examined. The prevalence of fatty pancreas was 16%. The fatty pancreas group had a significantly greater proportion of subjects with diabetes (12.6% versus 5.2%) and NAFLD (67.2% versus 35.1%) than did the non-fatty pancreas group (P<0.001). In the logistic regression analysis, age (P<0.001), general or central obesity (P<0.001), diabetes (P<0.001), and NAFLD (P<0.001) were independently associated with fatty pancreas after adjustment for sex, lipid profile, alanine transaminase/aspartate transaminase ratio, hypertension, smoking, alcohol drinking, and exercise. CONCLUSIONS: The prevalence of fatty pancreas is high in the general population. Both diabetes and NAFLD are important associated factors of fatty pancreas, independent of age, sex, adiposity, and other cardiometabolic risk factors.