Non-alcoholic fatty pancreas disease and pancreatic exocrine insufficiency: pilot study and systematic review.

INTRODUCTION: The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is estimated as 2-46% among patients without known pancreatic diseases. An association between NAFPD and non-alcoholic fatty liver disease (NAFLD) has been proposed, as well as an association between NAFPD and pancreatic exocrine insufficiency (PEI). PATIENTS AND METHODS: Patients with histologically confirmed NAFLD were included in the study. The control group consisted of individuals included in a surveillance screening program. Magnetic resonance imaging (MRI) of the pancreas was performed in all patients and fat measurement was made using 2-point Dixon imaging. Fecal elastase-1 (FE-1) was performed to evaluate pancreatic exocrine function. Additionally, a 13C-mixed triglyceride breath test (13 C-MTG-BT) was performed in patients with FE-1 < 200 µg/g. RESULTS: Imaging signs of NAFPD were present in 17 (71%) patients; 11 (85%) from the NAFLD group and 6 (55%) from the control group. FE-1 < 200 µg/g was found in six (25%) patients (four in the NAFLD group and two in the control group); however, none of them had clinical symptoms of PEI. Therefore, in five out of six patients with low FE-1, a 13C-MTG-BT was performed, showing normal results (>20.9%) in all tested patients. Furthermore, the serum nutritional panel was normal in all patients with low FE-1. A systematic review identified five studies relevant to the topic. CONCLUSION: NAFPD was found in 85% of patients with NAFLD and in 55% of control patients. We did not diagnose PEI in either group. A literature review showed PEI in 9-56% of patients with NAFPD.

Low serum pancreatic amylase levels as a novel latent risk factor for colorectal adenoma in non-alcohol drinkers.

BACKGROUND AND AIM: Obesity, insulin resistance, and metabolic alterations increase the risk of colorectal cancer and adenoma (CRA). Non-alcoholic fatty liver disease (NAFLD) or pancreatic disease (NAFPD) shares many risk factors with CRA that may have significant roles in its development; however, the relationship between CRA and NAFLD/NAFPD remains unclear. METHODS: This cross-sectional study recruited 712 eligible participants without current drinking who had undergone total colonoscopy as part of a health checkup. These participants were classified into a CRA group (n = 236) and a control group (n = 439), which consisted of individuals without CRA and a history of polyp resection. NAFLD and NAFPD were diagnosed based on abdominal ultrasonography findings. RESULTS: Non-alcoholic fatty liver disease was observed more frequently in individuals with CRA than in the control group (55.9% vs 41.6%, P < 0.01). There was no significant association between NAFPD and CRA; however, serum pancreatic amylase (P-amylase) levels were significantly lower in individuals with CRA. Although NAFLD was one of the factors increasing the presence of CRA (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.07-2.10), low P-amylase levels were significantly associated with the presence of CRA (OR, 1.73; 95% CI, 1.04-2.88) independent of age, sex, current smoking, obesity, metabolic alterations including insulin resistance, and NAFLD. CONCLUSIONS: Low serum P-amylase levels were a possible independent risk factor for CRA in the present study. The latent pancreatic exocrine-endocrine-gut relationship was considered a novel pathway involved in obesity-related CRA development, in non-alcoholic individuals.

Nonalcoholic Fatty Pancreas Disease: Role in Metabolic Syndrome, "Prediabetes," Diabetes and Atherosclerosis.

Fat accumulation in the pancreas associated with obesity and the metabolic syndrome (MetS) has been defined as "non-alcoholic fatty pancreas disease" (NAFPD). The aim of this review is to describe the association of NAFPD with obesity, MetS, type 2 diabetes mellitus (T2DM) and atherosclerosis and also increase awareness regarding NAFPD. Various methods are used for the detection and quantification of pancreatic fat accumulation that may play a significant role in the differences that have been observed in the prevalence of NAFPD. Endoscopic ultrasound provides detailed images of the pancreas and its use is expected to increase in the future. Obesity and MetS have been recognized as NAFPD risk factors. NAFPD is strongly associated with non-alcoholic fatty liver disease (NAFLD) and it seems that the presence of both may be related with aggravation of NAFLD. A role of NAFPD in the development of "prediabetes" and T2DM has also been suggested by most human studies. Accumulation of fat in pancreatic tissue possibly initiates a vicious cycle of beta-cell deterioration and further pancreatic fat accumulation. Additionally, some evidence indicates a correlation between NAFPD and atherosclerotic markers (e.g., carotid intima-media thickness). Weight loss and bariatric surgery decreases pancreatic triglyceride content but pharmacologic treatments for NAFPD have not been evaluated in specifically designed studies. Hence, NAFPD is a marker of local fat accumulation possibly associated with beta-cell function impairment, carbohydrate metabolism disorders and atherosclerosis.

Non-Alcoholic Fatty Pancreas Disease is Associated with SYNTAX Score in Acute Coronary Syndrome.

Background: Evidence that individuals with excess fat in the pancreas have an increased risk of cardiovascular disease has been growing recently. Risk evaluation in acute coronary syndrome (ACS) patients plays a crucial role for both prognosis prediction and decision-making. Aim: The main aim of this study was to investigate the relationship between non-alcoholic fatty pancreas disease (NAFPD) and the complexity and severity of coronary artery disease as assessed using the SYNTAX score (SXscore) in ACS patients. Methods: A total of 99 consecutive patients with a first-time diagnosis of ACS were recruited. NAFPD was evaluated using transabdominal ultrasonography (TUS). SXscore was calculated using the SXscore algorithm. Results: The patients with NAFPD had a significantly higher SXscore than those without NAFPD (12.3 ± 6.4 and 8.2 ± 4.3, p < 0.001). Univariable analysis showed that hypertension (p = 0.033) and presence of NAFPD (p = 0.001) were associated with increased SXscore. Moreover, multivariable analysis showed that the presence of NAFPD (p = 0.002) was associated with increased SXscore. Conclusions: NAFPD is easily detected by TUS. The presence of NAFPD in ACS patients may be a warning signal of complexity and severity of coronary artery disease.

The association between pancreas steatosis and metabolic syndrome: A systematic review and meta-analysis.

OBJECTIVES: Pancreas steatosis is the description of fat accumulation in the pancreatic gland. The prevalence and development mechanisms of pancreatic steatosis in patients with metabolic disorders still remain unclear. The aim of this study is to systematically review the association between pancreatic steatosis and metabolic co-morbidities. METHODS: We performed a systematic search strategy using three electronic databases (MEDLINE, Scopus, and Embase) for relevant studies concerning the associations of pancreatic steatosis with metabolic syndrome (MetS) and its clinical relevance from inception until 30 September 2018. RESULTS: One thousand three hundred fifty one references were identified in the initial search, and a total of 13 studies involving 49 329 subjects were included. This analyses elucidated the presence of non-alcoholic fatty pancreas disease (NAFPD) and was associated with a significant increased risk of metabolic syndrome (RR = 2.25; 95% CI, 2.00-2.53; P < 0.0001; I2  = 42.8%; eight studies included), hypertension (RR = 1.43; 95% CI, 1.08-1.90; P = 0.013; I2  = 94.7%; nine studies included), non-alcoholic fatty liver disease (NAFLD) (RR = 2.49; 95% CI, 2.06-3.02; P < 0.0001; I2  = 96.9%; nine studies included), diabetes mellitus (RR = 1.99; 95% CI, 1.18-3.35; P = 0.01; I2  = 97.6%; 10 studies included), and central obesity (RR = 1.91; 95% CI, 1.67-2.19; P < 0.0001; I2  = 95.9%; six studies included). The association between NAFPD and hyperlipidaemia was not statistically significant (RR = 1.33; 95% CI, 0.82-2.17; P = 0.249; I2  = 97%; five studies included). CONCLUSIONS: The existing evidence indicates that NAFPD is significantly associated with an increased risk of metabolic syndrome and its components. Well-designed prospective cohort studies between pancreatic steatosis and MetS are needed to elaborate the causality in the future.

Fatty pancreas disease: clinical impact.

Pancreatic steatosis is the name for a state characterized by an increased accumulation of fat in the pancreas. It is most frequently due to obesity and the metabolic syndrome, other etiological factors may include some congenital syndromes, toxic substances or viral diseases. Diagnostics is based on non-invasive imaging methods. The most accessible is abdominal ultrasound, also endoscopic ultrasound, computed tomography or magnetic resonance imaging can be used. In clinical practice, pancreatic steatosis is in particular significant because of its close association with type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. The disorder may aggravate the burden of acute pancreatitis, examined is its relationship to pancreatic cancer. Significant are also surgical reports on complications after pancreatic surgeries on individuals with pancreatic steatosis. Key words: acute pancreatitis - dyslipidemia - fatty pancreas - non-alcoholic fatty pancreas disease - non-alcoholic steatopancreatitis - obesity - pancreatic carcinoma.

Correlation between Pancreatic Fat Deposition and Metabolic Syndrome: Relationships with Location in the Pancreas and Sex.

Objective To investigate the correlation between pancreatic fat deposition and metabolic syndrome (MetS) parameters, focusing on the locations of fat deposition in the pancreas and sex differences. Methods Degrees of fat deposition in the head, body, and tail of the pancreas were evaluated using computed tomography (CT). We examined the relationships between pancreatic fat deposition and the age, body mass index (BMI), visceral and subcutaneous fat, serum lipid profiles, hepatic steatosis, diabetes mellitus (DM), and hypertension (HTN). Results In this retrospective study, greater fat deposition was associated with a higher BMI, visceral and subcutaneous fat accumulation, and hepatic steatosis, with the pancreatic head showing the strongest correlation. Correlations of pancreatic fat deposition with the BMI and visceral and subcutaneous fat accumulation were stronger in females than in males, while correlations with hepatic steatosis were stronger in males than in females. In addition, a multivariate analysis did not suggest a direct causal relationship between pancreatic fat deposition and DM and HTN, but there was a significant correlation between pancreatic fat deposition in the pancreatic head and visceral fat area. Conclusion Pancreatic fat deposition, as evaluated by CT, especially in the part of the pancreatic head adjacent to the ampulla of Vater, is a sensitive indicator of MetS. The correlations between pancreatic fat deposition and MetS parameters tended to be stronger in females than in males. These results may help further elucidate the pathophysiology of MetS and provide opportunities for its diagnosis.

Pathophysiological Mechanisms and Clinical Associations of Non-Alcoholic Fatty Pancreas Disease.

Non-Alcoholic Fatty Pancreas disease (NAFPD), characterized by fat accumulation in pancreatic tissue, is an emerging clinical entity. However, the clinical associations, the underlying molecular drivers, and the pathophysiological mechanisms of NAFPD have not yet been characterized in detail. The NAFPD spectrum not only includes infiltration and accumulation of fat within and between pancreatic cells but also involves several inflammatory processes, dysregulation of physiological metabolic pathways, and hormonal defects. A deeper understanding of the underlying molecular mechanisms is key to correlate NAFPD with clinical entities including non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, atherosclerosis, as well as pancreatic cancer and pancreatitis. The aim of this review is to examine the pathophysiological mechanisms of NAFPD and to assess the possible causative/predictive risk factors of NAFPD-related clinical syndromes.

MRI-Measured Pancreatic Fat Correlates with Increased Arterial Stiffness in Patients Who are Overweight and Obese.

Purpose: Arterial stiffness is often increased in overweight or obese individuals before the development of hypertension (HT). This study aimed to determine the connection between pancreatic fat and atherosclerosis in overweight and obese people without HT. Patients and methods: We included 128 patients who were non-hypertensive and overweight or obese in a study between December 2019 and November 2022. Medical history was collected, and all participants underwent a physical examination and blood tests. Pancreatic fat content was measured by magnetic resonance imaging (MRI) and was grouped into quartiles based on pancreatic fat fraction (PFF). The upper three quartiles (PFF≥10.33%) were defined as non-alcoholic fatty pancreas disease (NAFPD) and the first quartile (PFF<10.33%) as non-NAFPD. High baPWV (H-baPWV) and low baPWV (L-baPWV) were classified according to the median baPWV (1159 cm/s). The effect of NAFPD on baPWV was examined using binary logistic regression. The study population consisted of 96 NAFPD and 32 non-NAFPD cases. Results: Participants with NAFPD had significantly higher levels of baPWV than people without. The rates of NAFPD and the PFF values varied significantly in the L-baPWV and H-baPWV groups. Logistic regression analysis suggested that the presence of NAFPD was independently correlated with increased baPWV after adjusting for age, smoking, body mass index, blood pressure, lipid profiles, and glycemic index. Conclusion: NAFPD is an independent risk factor for increased baPWV in individuals with overweight and obesity but no HT, suggesting that the presence of NAFPD may be a warning signal of early atherosclerosis.

Visual assessment of pancreatic fat deposition: useful grading system and the relation to BMI and diabetes.

PURPOSE: To establish a simple and clinically useful method for the visual assessment of pancreatic fat deposition using computed tomography (CT) images, and to evaluate the relationship of the pancreatic fat deposition with body mass index (BMI) and type 2 diabetes mellitus (DM). MATERIALS AND METHODS: We used a four-scale grading system as the visual assessment criteria for pancreatic fat deposition using CT images. Pancreatic fat deposition was assessed for 200 patients and the results were compared with the CT attenuation-based assessment. In addition, the relationships of pancreatic fat deposition with BMI and type 2 DM were investigated. RESULTS: The visual and CT attenuation-based assessments were considered consistent. The results of the visual assessment suggested that mild and moderate pancreatic fat deposition correlated with BMI and presence of type 2 DM while severe fat deposition did not correlate with them. No correlation between pancreatic fat deposition and HbA1c level was found. CONCLUSION: The visual assessment criteria we used were consistent with CT attenuation-based assessment and may be useful for clinical application of pancreatic fat deposition. According to the visually assessment, mild or moderate pancreatic fat deposition correlated with BMI and the presence of type 2 DM, but severe fat deposition did not correlate with them.

Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid.

Many breast cancer patients have both non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreas disease (NAFPD). Consequently, we hypothesized that NAFPD and NAFLD were associated with breast cancer, and aimed to build a novel risk-stratification scoring system based on it. In this study, a total of 961 patients with breast cancer and 1,006 non-cancer patients were recruited. The clinical characteristics were collected and analyzed using logistic analysis. Risk factors were assessed by a risk rating system. Univariate analysis showed that body mass index, triglyceride, total cholesterol, NAFLD, NAFPD, low-density lipoprotein, and uric acid (UA) were significantly related to breast cancer. Among them, NAFLD, NAFPD, and UA were independent risk factors related to breast cancer identified by multivariate analysis. The risk assessment model was established based on these factors and demonstrated that the odds ratio sharply increased with the rising scores. Compared with the low-risk group, the odds ratio in the intermediate- and high-risk groups were 1.662 (1.380-2.001) and 3.185 (2.145-4.728), respectively. In conclusion, the risk-stratification scoring system combining NAFLD, NAFPD, and UA can accurately predict the occurrence of breast cancer.

[Lipid accumulation in the pancreas: clinical significance of NAFPD (non-alcoholic fatty pancreas disease)] / A nem alkoholos hasnyálmirigy-elzsírosodás klinikai jelentosége

Pancreatic lipid accumulation - which is known as NAFPD (non-alcoholic fatty pancreas disease) - has gained an increasing attention in the last couple of years. Previously, this alteration was mentioned using different names. Undoubtedly, the term of NAFPD is still rarely used in the Hungarian scientific literature, even the proper translation should be considered difficult. Pancreatic lipid accumulation is a clinical manifestation of ectopic occurrence of adipose tissue. NAFPD can be diagnosed by different imaging modalities. Although proper quantification of pancreatic lipid accumulation is challenging, ultrasonography and computed tomography are used in clinical practice. The prevalence of NAFPD was about 30-35% in different adult populations but a relatively higher frequency might also be observed in children and adolescents with obesity. NAFPD may influence both endocrine and exocrine functions of the pancreas. Clinical studies documented a close correlation between NAFPD and type 2 diabetes/metabolic syndrome. Local consequences of pancreatic lipid accumulation are less recognized but clinical observations suggested that NAFPD might play a role in the development of acute and chronic pancreatitis, pancreatic cancer, and pancreatic exocrine dysfunction. Therapeutically, weight loss in patients with obesity, due to life-style modification, pharmacological intervention or bariatric surgery, may reduce pancreatic lipid accumulation. Importantly, antihyperglycemic treatment of patients with type 2 diabetes should be performed by using antidiabetic drugs providing not only proper glycaemic control but even weight loss. NAFPD is a relatively new clinical entity which is rather common and probably underdiagnosed. Basic and new data about NAFPD are of importance for clinicians working in the field of different specialties and sub-specialties (internal medicine, gastroenterology, diabetology, lipidology, obesitology, surgery). Orv Hetil. 2022; 163(44): 1735-1742.

Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals.

CONTEXT: Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis. OBJECTIVE: We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype × pancreatic fat interactions on insulin secretion. DESIGN: Two observational studies. SETTING: University hospital. PATIENTS OR PARTICIPANTS: A total of 360 nondiabetic individuals with elevated risk for T2D (Tuebingen Family Study [TUEF]), and 64 patients undergoing pancreatectomy (Pancreas Biobank [PB], HbA1c <9%, no insulin therapy). MAIN OUTCOME MEASURES: Insulin secretion calculated from 5-point oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms. RESULTS: Pancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (P = 0.003), which was similar in the replication cohort with histological measurements (P = 0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, whereas individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin resistance-specific and a liver/lipid-specific polygenic scores. CONCLUSIONS: The associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.

Metabolic Syndrome and Abnormal Peri-Organ or Intra-Organ Fat (APIFat) Deposition in Chronic Obstructive Pulmonary Disease: An Overview.

Chronic obstructive pulmonary disease (COPD) is a common disorder with an increasing prevalence, characterised by persistent respiratory symptoms and airflow limitation. Systemic inflammation is involved in the pathogenesis of COPD and can also predispose to metabolic disorders (e.g., metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD)). Such comorbidities can negatively affect COPD outcomes, cardiovascular risk, and quality of life. Apart from NAFLD, abnormal peri-organ or intra-organ fat (APIFat) could be considered as markers for cardiometabolic diseases and even for COPD. The present narrative review considers the associations of COPD with MetS, NAFLD, and other APIFat, including epicardial, perirenal, peripancreatic, and intramuscular adipose tissue. Further research is needed to define these relationships and identify any potential clinical implications.

Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report.

INTRODUCTION: Diabetes patients with Prader-Willi syndrome (PWS) are obese because of hyperphagia; weight control by dietary modification and medicine is required for glycemic control. There are several recent reports showing the effectiveness of GLP-1 receptor agonists (GLP-1RAs) for diabetes treatment in PWS. CASE REPORT: A 36-year-old Japanese male patient was diagnosed with PWS at 10 years of age. At age 16 years, he was diagnosed with diabetes and began to take several kinds of oral hypoglycemic agents. At age 29 years, his BMI was 39.1 kg/m2 and he was referred to our department for diabetes and obesity treatment. In the present case, the HbA1c was not improved by GLP-1RAs despite a 28-kg BW reduction, which included a 9-kg loss of muscle. Apprehensive of further loss of muscle mass, basal insulin of insulin glargine was administered in addition to GLP-1RAs. Immediately after the addition of tofogliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, the patient's HbA1c decreased dramatically with only about an additional 3% BW reduction. We note an improvement in our case of lipid deposition in the pancreas confirmed by abdominal CT after the improvement of HbA1c. It is unknown whether this improvement of fatty pancreas was a cause or an effect of the improved glycemic control in the present case. CONCLUSION: This finding clearly supports the effectiveness of combining SGLT2 inhibitors with GLP-1RAs for treatment of patients with PWS and non-alcoholic fatty pancreas disease.

Impact of non-alcoholic fatty pancreas disease on glucose metabolism.

With the increasing global epidemic of obesity, the clinical importance of non-alcoholic fatty pancreas disease (NAFPD) has grown. Even though the pancreas might be more susceptible to ectopic fat deposition compared with the liver, NAFPD is rarely discussed because of the limitation of detection techniques. In the past, NAFPD was considered as an innocent condition or just part of clinical manifestations during the course of obesity. Recently, a growing body of research suggests that NAFPD might be associated with ß-cell dysfunction, insulin resistance and inflammation, which possibly lead to the development of diabetes and metabolic syndrome. The present review summarized the current literature on the epidemiology, potential pathophysiology, diagnostic techniques, impact of NAFPD on ß-cell function and insulin resistance, and the clinical relevance of the interplay between NAFPD and glucometabolic disorders.

Ectopic fat accumulation in the pancreas and its clinical relevance: A systematic review, meta-analysis, and meta-regression.

OBJECTIVE: Growing evidence suggests that individuals with excessive fat in the pancreas are at an increased risk of chronic metabolic disorders. The aim was to systematically review studies on non-alcoholic fatty pancreas disease (NAFPD) with a view to determine its prevalence, associations with metabolic co-morbidities, and to suggest normal pancreatic fat percentage threshold. METHODS: Three electronic databases (MEDLINE, Scopus, and Embase) were queried. Studies in humans were eligible for inclusion if they provided data on NAFPD and/or pancreatic fat percentage. Where possible, data were pooled using random-effects meta-analysis and the effect of covariates analysed using meta-regression. RESULTS: Pooling data on pancreatic fat percentage from nine studies (1209 healthy individuals who underwent magnetic resonance imaging), yielded the weighted mean and weighted standard deviation of 4.48% and 0.87%, respectively. Pooling data on NAFPD from eleven studies (12,675 individuals), yielded the pooled prevalence of 33% (95% confidence interval, 24% - 41%). Meta-regression analysis showed that the prevalence of NAFPD was independent of age and sex. The presence of NAFPD was associated with a significantly increased risk of arterial hypertension (risk ratio 1.67; 95% confidence interval, 1.32-2.10; p<0.0001), diabetes mellitus (risk ratio 2.08; 95% confidence interval, 1.44-3.00; p=0.0001), and metabolic syndrome (risk ratio 2.37; 95% confidence interval, 2.07-2.71; p<0.0001). CONCLUSION: The findings indicate that NAFPD is a frequent clinical entity, associated with significantly increased risk of metabolic syndrome and its components. The normal pancreatic fat cut-off point of 6.2% may be recommended for use in future prospective studies.

Protein kinase STK25 aggravates the severity of non-alcoholic fatty pancreas disease in mice.

Characterising the molecular networks that negatively regulate pancreatic ß-cell function is essential for understanding the underlying pathogenesis and developing new treatment strategies for type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic fat storage, meta-inflammation, and fibrosis in liver and skeletal muscle. Here, we assessed the role of STK25 in control of progression of non-alcoholic fatty pancreas disease in the context of chronic exposure to dietary lipids in mice. We found that overexpression of STK25 in high-fat-fed transgenic mice aggravated diet-induced lipid storage in the pancreas compared with that of wild-type controls, which was accompanied by exacerbated pancreatic inflammatory cell infiltration, stellate cell activation, fibrosis and apoptosis. Pancreas of Stk25 transgenic mice also displayed a marked decrease in islet ß/α-cell ratio and alteration in the islet architecture with an increased presence of α-cells within the islet core, whereas islet size remained similar between genotypes. After a continued challenge with a high-fat diet, lower levels of fasting plasma insulin and C-peptide, and higher levels of plasma leptin, were detected in Stk25 transgenic vs wild-type mice. Furthermore, the glucose-stimulated insulin secretion was impaired in high-fat-fed Stk25 transgenic mice during glucose tolerance test, in spite of higher net change in blood glucose concentrations compared with wild-type controls, suggesting islet ß-cell dysfunction. In summary, this study unravels a role for STK25 in determining the susceptibility to diet-induced non-alcoholic fatty pancreas disease in mice in connection to obesity. Our findings highlight STK25 as a potential drug target for metabolic disease.

Remodelamento do fígado, pâncreas e tecido adiposo em modelo experimental de 'síndrome metabólica' tratado com telmisartana, sitagliptina e metformina / Remodeling of the liver, pancreas and adipose tissue in an experimental model of metabolic syndrome treated with telmisartan, sitagliptin and metformin

A intervenção farmacológica pode minimizar ou até mesmo reverter o remodelamento adverso em órgãos num modelo de síndrome metabólica. Este trabalho teve como objetivo avaliar os efeitos das monoterapias e associações medicamentosas sobre a morfologia do tecido adiposo, remodelamento hepático e pancreático em camundongos C57b1/6 alimentados com dieta very high-fat. Camundongos C57b1/6 machos foram alimentados com dieta very high-fat (HF, 60% de lipídios) ou dieta padrão (SC, 10% de lipídios) por 10 semanas, quando foram iniciados os tratamentos: HF-T (HF + Telmisartana, 5.2mg/Kg/dia), HF-S (HF + Sitagliptina, 1.08g/Kg/dia), HF-M (HF + Metformina, 310.0mg/Kg/dia) e as associações medicamentosas HF-TM, HF-TS e HF-SM. Os grupos tratados também tiveram livre acesso à dieta high fat e os tratamentos duraram 6 semanas. Técnicas morfométricas, estereológicas, imunohistoquímicas, ELISA, western blotting e microscopia eletrônica foram utilizadas. A dieta high-fat causou sobrepeso, intolerância oral à glucose, hiperinsulinemia, hipertrofia de ilhotas e adipócitos, grau 2 de esteatose hepatica (<33%) redução da expressão de PPAR-alfa e de GLUT-2, concomitante com aumento da expressão de SREBP-1 no grupo HF (P<0.0001). Por outro lado, todos os tratamentos resultaram resultaram em perda de peso significativa, reversão da resistência à insulina, hipertrofia de ilhotas e adipócitos e alívio da esteatose hepática. Somente os grupos HF-T e HF-TS apresentaram massa corporal similar ao grupo SC ao final do experimento, sendo que o último também apresentou reversão da esteatose hepática. O aumento da expressão do PPAR-alfa paralelamente ao decréscimo da expressão do SREBP-1 explica os achados favoráveis para o fígado. A normalização do tamanho do adipócito foi consistente com os níveis maiores de adiponectina e com a redução dos níveis de TNT-alfa (P<0.0001) nos grupos tratados. Todos os tratamentos foram eficazes para controlar a síndrome metabólica. Os melhores resultados ...

Pharmacological intervention can minimize or even reverse remodeling due to metabolic syndrome. This work sought to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, pancreatic and hepatic remodeling in C57BL/6 mice fed a high-fat diet. Male C57BL/6 mice were fed a very high-fat diet (HF, 60% lipids) or standard chow (SC, 10% lipids) over 10 weeks, after which drug treatments began: HF-T (HF + Telmisartan, 5.2mg/Kg/day), HF-S (HF + Sitagliptin, 1.08g/Kg/day), HF-M (HF + Metformin, 310.0mg/Kg/day) and the drug combinations HF-TM, HF-TS and HF-SM. Treated groups also had free access to HF diet and treatments lasted 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blotting and electron microscopy were used. The HF diet yielded an overweight phenotype, oral glucose intolerance, hyperinsulinemia, hypertrophied islets and adipocytes, stage 2 steatosis (<33%) and reduced liver PPAR-alpha and GLUT-2, concomitant with enhanced SREBP-1 expression, in the HF group (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, reversed insulin resistance, islet and adipocyte hypertrophy and alleviated hepatic steatosis. Only HF-T and HF-TS presented body weights similar to SC mice at the end of the experiment and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining parallel to higher GLUT-2 and reduced SREBP-1 expression explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha levels (P<0.0001) in treated groups. In conclusion, all treatments were effective in controlling metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action