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Abstract Purpose Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. Methods 26 adults from Children’s Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. Results Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. Conclusions In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK–eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.Understanding the mechanisms behind β-cell failure in diabetes mellitus is critical to prevent or revert disease. This Review highlights new findings from studies performed on human β-cells or on samples obtained from patients with type 1 or type 2 diabetes mellitus.

Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients. We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype, and treatments was obtained from responses to structured questionnaires. Physical and mental component summary (PCS and MCS, respectively) scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL. Mean PCS and MCS scores were 36.7±11.7 and 42.4±12.2, respectively. Significant (P<0.05) negative impact on PCS scores in multivariable analyses was noted owing to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points), and medical co-morbidities. Significant (P<0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points), and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency, and prior endotherapy/pancreatic surgery had no significant independent effect on QOL. Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses.

We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12–46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency.

Purpose of ReviewType 1 and type 2 diabetes are often accompanied by mostly mild forms of exocrine pancreatic insufficiency. Despite high prevalence, little is known about the clinical consequences of exocrine pancreatic insufficiency and its optimal (nutritional) treatment. Even less is known if and to what extent exocrine pancreas insufficiency also affects glycemic control in diabetes. This article aims for summarizing current clinical knowledge on screening, diagnosis, and treatment and gives an overview on the pathophysiology of exocrine pancreatic insufficiency in diabetes.Recent FindingsRecent studies reveal novel insights into the close interaction of acinar, ductal, and endocrine cells and the gut-pancreas axis.SummaryExocrine pancreatic insufficiency is a clinically relevant, frequent but poorly understood disorder in both type 1 and type 2 diabetes.

Cystic fibrosis (CF) is a disorder affecting the respiratory, digestive, reproductive systems and sweat glands. This lethal hereditary disease has known or suspected links to the dysbiosis gut microbiota. High-throughput meta-omics-based approaches may assist in unveiling this complex network of symbiosis modifications. The aim of this study was to provide a predictive and functional model of the gut microbiota enterophenotype of pediatric patients affected by CF under clinical stability. Thirty-one fecal samples were collected from CF patients and healthy children (HC) (age range, 1-6 years) and analysed using targeted-metagenomics and metabolomics to characterize the ecology and metabolism of CF-linked gut microbiota. The multidimensional data were low fused and processed by chemometric classification analysis. The fused metagenomics and metabolomics based gut microbiota profile was characterized by a high abundance of Propionibacterium, Staphylococcus and Clostridiaceae, including Clostridium difficile, and a low abundance of Eggerthella, Eubacterium, Ruminococcus, Dorea, Faecalibacterium prausnitzii, and Lachnospiraceae, associated with overexpression of 4-aminobutyrate (GABA), choline, ethanol, propylbutyrate, and pyridine and low levels of sarcosine, 4-methylphenol, uracil, glucose, acetate, phenol, benzaldehyde, and methylacetate. The CF gut microbiota pattern revealed an enterophenotype intrinsically linked to disease, regardless of age, and with dysbiosis uninduced by reduced pancreatic function and only partially related to oral antibiotic administration or lung colonization/infection. All together, the results obtained suggest that the gut microbiota enterophenotypes of CF, together with endogenous and bacterial CF biomarkers, are direct expression of functional alterations at the intestinal level. Hence, it's possible to infer that CFTR impairment causes the gut ecosystem imbalance.This new understanding of CF host-gut microbiota interactions may be helpful to rationalize novel clinical interventions to improve the affected children's nutritional status and intestinal function.

Objectives: To describe the results of nutritional and morphofunctional assessment in a cohort of adults with cystic fibrosis; to evaluate differences in nutritional status between patients with and without exocrine and/or endocrine pancreatic involvement. Methods: Cross-sectional study: A cohort of adults with cystic fibrosis evaluated in a multidisciplinary unit was analyzed. Pancreatic status was examined, and malnutrition was diagnosed according to GLIM criteria. Morphofunctional assessment consisted of nutritional ultrasound, bioelectrical impedance, handgrip dynamometry, and anthropometry. Qualitative variables are expressed as n (%), quantitative variables as median (IQR). For group comparisons, Fisher’s exact test was used for qualitative variables and the non-parametric median comparison test for quantitative variables. Results: n = 101 participants were recruited, of whom 44 (43.6%) were women. Median age was 33 (25–40.5) years. A total of 64 participants (63.4%) had exocrine pancreatic insufficiency (EPI), 44 (43.6%) had endocrine pancreatic insufficiency, and 28 (27.7%) had cystic fibrosis-related diabetes (CFRD). Median BMI was 23.4 (20.1–24.89) kg/m2. A total of 48 patients (47.5%) were malnourished. Males with EPI had a higher prevalence of undernourishment than those without (56.4% vs. 16.7%, p = 0.005), but not women. CFRD patients displayed no differences in morphofunctional assessment. Conclusions: Almost half the sample was undernourished using GLIM criteria. Males with exocrine pancreatic insufficiency had worse nutritional status. Endocrine pancreatic involvement did not affect nutritional status.

Purpose Pancreatic cancer is a fatal cancer with a median survival from diagnosis of around 5 months Speer et al. (Med J Aust 196(8):511–515, 2012 ). Given the short survival time for people with pancreatic cancer, effective supportive care is imperative to enable best quality of life. This article presents an unexpected finding from research into the psychosocial supportive care needs of people affected by pancreatic cancer that management of pancreatic exocrine insufficiency is an area of unmet need that severely impacts on quality of life and increases carer burden in people affected by pancreatic cancer. Methods A qualitative inquiry framework was used to explore participants’ perspectives and experience. Two groups of participants ( N  = 35) were recruited across Australia from people accessing the Cancer Helpline or direct referral from clinicians/nurses: patients diagnosed with pancreatic cancer ( N  = 12) and carers/family ( N  = 23) including a subgroup of bereaved participants ( N  = 14). Sampling continued until saturation. A thematic content analysis was conducted. Results The findings revealed that the major quality of life theme was difficulty in managing gut symptoms and complex dietary issues . Issues were related to lack of information about malabsorption and managing symptoms of pancreatic exocrine insufficiency. This was compounded by a lack of routine dietary consultation: perceived reluctance of clinicians to prescribe enzyme supplements and poor understanding of dose to diet guidelines. Conclusion Participants expressed distress relating to the effects of pancreatic exocrine insufficiency. Pancreatic enzyme supplement therapy with clear dosage guidelines and associated dietary advice could resolve symptoms of malabsorption and markedly improve quality of life. For people affected by pancreatic cancer, this is an essential supportive care.

Background Patients with pancreatic insufficient cystic fibrosis (PI‐CF) meeting standard criteria for normal glucose tolerance display impaired β‐cell secretory capacity and early‐phase insulin secretion defects. We sought evidence of impaired β‐cell secretory capacity, a measure of functional β‐cell mass, among those with early glucose intolerance (EGI), defined as 1‐hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L). Methods A cross‐sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI‐CF categorized by OGTT as normal (PI‐NGT: 1‐hour glucose <155 mg/dL and 2‐hour <140 mg/dL [7.8 mmol/L]; n = 13), PI‐EGI (1‐hour ≥155 mg/dL and 2‐hour <140 mg/dL; n = 13), impaired (PI‐IGT: 2‐hour ≥140 and <200 mg/dL [11.1 mmol/L]; n = 8), and diabetic (cystic fibrosis‐related diabetes, CFRD: 2‐hour ≥200 mg/dL; n = 8) participated. Post‐prandial glucose tolerance and insulin secretion, and β‐cell secretory capacity and demand were derived from mixed‐meal tolerance tests (MMTTs), and glucose‐potentiated arginine (GPA) tests, respectively. Results PI‐EGI had elevated post‐prandial glucose with reduced early‐phase insulin secretion during MMTT compared to PI‐NGT (P < .05). PI‐EGI also exhibited impaired acute insulin and C‐peptide responses to GPA (P < .01 vs PI‐NGT), measures of β‐cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI‐IGT and CFRD (P < .05 vs PI‐NGT), and correlated with 1‐hour glucose in PI‐CF (P < .01). Conclusions PI‐CF patients with 1‐hour OGTT glucose ≥155 mg/dL already manifest impaired β‐cell secretory capacity with associated early‐phase insulin secretion defects. Avoiding hyperglycemia in patients with EGI may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion.

Appetite loss is one complication of chronic heart failure (CHF), and its association with pancreatic exocrine insufficiency (PEI) is not well investigated in CHF. We attempted to detect the association between PEI and CHF-induced appetite. Patients with CHF were enrolled, and body mass index (BMI), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) cardiac function grading, B-type natriuretic peptide (BNP), serum albumin, pro-albumin and hemoglobin were evaluated. The pancreatic exocrine function was measured by fecal elastase-1 (FE-1) levels in the enrolled patients. Appetite assessment was tested by completing the simplified nutritional appetite questionnaire (SNAQ). The improvement of appetite loss by supplemented pancreatic enzymes was also researched in this study. The decrease of FE-1 levels was found in patients with CHF, as well as SNAQ scores. A positive correlation was observed between SNAQ scores and FE-1 levels (r = 0.694, p < 0.001). Pancreatic enzymes supplement could attenuate the decrease of SNAQ scores in CHF patients with FE-1 levels <200 μg/g stool and SNAQ < 14. Appetite loss is commonly seen in CHF, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a possible pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms.