Pancreatic Endocrine Dysfunction Research Articles

Image J as the quantification tool in endosonography strain elastography may be reflected in the disturbance of endocrine pancreatic dysfunction.

Pancreatic fibrosis is one of the main pathological features of chronic pancreatitis (CP), suggesting a strong relationship between CP and pancreatic ductal cancer. There was no available data about pancreatic fibrosis and pancreatic dysfunction in the early CP (ECP) using endosonography (EUS). Asymptomatic patients with pancreatic enzyme abnormalities (AP-P; n = 56) and patients with ECP (n = 21) were determined by the absence of abnormal findings on upper gastrointestinal endoscopy, abdominal ultrasonography, and abdominal computed tomography. An Olympus EUS (GF-UCT 260; Olympus) was used to perform EUS. Open software "Image J", developed by NIH, was used to measure the surface area fraction of the designated elastic blue region. The maximum value among the pancreatic head, pancreatic body, and pancreatic tail was defined as the ELST-blue score. The exocrine and endocrine pancreatic functions were evaluated using the N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA) test and homeostasis model assessment of β-cell function (HOMA-β) value, respectively. EUS score, lobularity, and hyperechoic foci/strands in patients with ECP were significantly (p < 0.001) higher than those in patients with AP-P. In addition, there were no significant differences in the BT-PABA test (73.1 ± 25.5, 68.5 ± 15.6) and HOMA-β (93.1 ± 67.4, 73.5 ± 139.7) between patients with ECP and AP-P. The ELST-blue score measured by image J as the quantification tool in EUS strain elastography in patients with ECP was significantly higher (p = 0.002) than that in patients with AP-P. Interestingly, the ELST-blue score was significantly associated with HOMA-β in patients with ECP. The ELST-blue score may be a useful tool for the evaluation of endocrine pancreatic dysfunction in the ECP.

Pancreatic volume and endocrine function changes following pancreaticoduodenectomy for peri-ampullary neoplasms: A retrospective single-center study utilizing pancreas volumetry.

We evaluated long-term pancreatic functional outcomes, including pancreatic volumetry after pancreaticoduodenectomy (PD) for peri-ampullary neoplasm. We retrospectively reviewed 353 patients with a 12-month follow-up who underwent elective pancreaticoduodenectomies for peri-ampullary neoplasms at a single university hospital between January 2011 and December 2020. Perioperative and postoperative outcomes, long-term pancreatic endocrine functions, and pancreatic volume changes 12 month postoperatively were evaluated. The mean age was 65.4 years, and the sex ratio was 1.38. The patients with prediagnosed diabetes mellitus (DM) comprised 31.4%. The peri-ampullary neoplasm origins were: the pancreas (49.0%), common bile duct (27.2%), ampulla of Vater (18.4%), and duodenum (5.4%). The 1-week, and 3-, 6-, and 12-month postoperative proportions of patients with DM diagnosed before surgery combined with new-onset postoperative DM were 39.7%, 42.8%, 43.9%, and 49.6%, respectively. The preoperative and postoperative 1-week, and 3-, 6-, and 12-month mean pancreatic volumes were 82.3, 38.7, 28.1, 24.9, and 25.5 mL, respectively. Univariate risk factor analyses for new-onset DM after PD observed no significant difference between the 'No DM after PD' and 'New-onset DM after PD' groups. Following PD for peri-ampullary neoplasms, pancreatic endocrine functions and volumes continued to decrease for a minimum of 12 months. The current study did not identify any causal relationship between pancreatic endocrine dysfunction and pancreatic atrophy following PD.

Intrapancreatic fat deposition is unrelated to liver steatosis in metabolic dysfunction-associated steatotic liver disease

Individuals with obesity may develop intrapancreatic fat deposition (IPFD) and fatty pancreas disease (FPD). Whether this causes inflammation and fibrosis and leads to pancreatic dysfunction is less established than for liver damage in metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, the interrelations of FPD and MASLD are poorly understood. Therefore, we aimed to assess IPFD and fibro-inflammation in relation to pancreatic function and liver disease severity in individuals with MASLD. Seventy-six participants from the Amsterdam MASLD-MASH cohort (ANCHOR) study underwent liver biopsy and multiparametric MRI of the liver and pancreas, consisting of proton-density fat fraction sequences, T1 mapping and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). The prevalence of FPD was 37.3%. There was a clear correlation between pancreatic T1 relaxation time, which indicates fibro-inflammation, and parameters of glycemic dysregulation, namely HbA1c (R= 0.59; p <0.001), fasting glucose (R= 0.51; p <0.001) and the presence of type 2 diabetes (mean 802.0ms vs. 733.6ms; p <0.05). In contrast, there was no relation between IPFD and hepatic fat content (R= 0.03; p=0.80). Pancreatic IVIM diffusion (IVIM-D) was lower in advanced liver fibrosis (p <0.05) and pancreatic perfusion (IVIM-f), reflecting vessel density, inversely correlated to histological MASLD activity (p <0.05). Consistent relations exist between pancreatic fibro-inflammation on MRI and endocrine function in individuals with MASLD. However, despite shared dysmetabolic drivers, our study suggests IPFD is a separate pathophysiological process from MASLD. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and 68% of people with type 2 diabetes have MASLD. However, fat infiltration and inflammation in the pancreas are understudied in individuals with MASLD. In this cross-sectional MRI study, we found no relationship between fat accumulation in the pancreas and liver in a cohort of patients with MASLD. However, our results show that inflammatory and fibrotic processes in the pancreas may be interrelated to features of type 2 diabetes and to the severity of liver disease in patients with MASLD. Overall, the results suggest that pancreatic endocrine dysfunction in individuals with MASLD may be more related to glucotoxicity than to lipotoxicity. NTR7191 (Dutch Trial Register).

A narrative review on the role of genetics in children with acute recurrent pancreatitis and chronic pancreatitis.

The incidence of pancreatitis in children has increased over the past two decades. With advances in molecular biological techniques and clinical research, genetic variations have emerged as a pivotal etiological factor in pediatric pancreatitis. This review aims to summarize recent clinical research advancements in understanding pediatric pancreatitis caused by various gene mutations. As of the year 2020, researchers had identified 12 genes implicated in the pathogenesis of pancreatitis. These genes primarily contributed to the development of pancreatitis through three mechanisms. Pancreatitis resulting from these gene mutations exhibits several distinct characteristics, including early onset, a heightened risk of developing pancreatic duct stones, rapid disease progression, and a significantly increased risk of pancreatic endocrine and exocrine dysfunction, as well as pancreatic cancer in the future. Genetic sequencing is recommended for children with pancreatitis based on six indications. The sequencing not only assists in the clinical diagnosis but also enhances our understanding of the pathophysiology of pancreatitis.

SAT079 A Novel Variant In The Carboxyl Ester Lipase (CEL) Gene Causing MODY

Abstract Disclosure: C.R. Medavarapu: None. M. McNutt: None. Introduction: Maturity-onset diabetes of the young (MODY) is a group of autosomal dominantly inherited disorders of non-autoimmune diabetes mellitus. Here, we report a patient initially diagnosed with type 2 DM and later found to have carboxyl ester lipase (CEL)-MODY. Case: A 51 year-old female was diagnosed with DM at the age of 44 and initially categorized as having type 2 DM based on normal GAD-65 antibodies. The patient’s DM was well controlled on semaglutide. The patient, however, reported chronic diarrhea/steatorrhea and intermittent dull abdominal pain which was not associated with semaglutide. The patient continued to have GI symptoms despite stopping the semaglutide. Abdominal imaging was unremarkable with a normal-appearing pancreas. Interestingly, the patient's daughter had similar gastric inflammatory symptoms and multiple members of the family have early-onset DM. Due to this symptom complex and similar presentation in the family, an inflammatory pathologic syndrome was suspected. A monogenetic auto-inflammatory syndrome was also considered in differential and the whole exome was analyzed. Genetic testing identified a novel, likely pathogenic heterozygous variant in CEL(NM_001807.5): c.1875del. Pathogenic variants in CEL are associated with MODY, type VIII. Discussion: Single-base deletions in the CEL gene can cause exocrine and endocrine pancreatic dysfunction. Our patient presented with a novel c.1875del variant in CEL that has not been reported in the literature as causative of disease nor as a variant in the general population. This variant lies in the variable number of tandem repeats (VNTR)-containing exon 11 of CEL. Two other single nucleotide deletions in this exon were described in the original report of CEL-MODY. The c.1875del variant results in the deletion of one nucleotide at position c.1875 of the CEL gene, causing a frameshift in the protein reading frame. Loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay is expected. The c.1875del CEL variant is classified as likely pathogenic, and it correlated with our patient's clinical and biochemical findings. Typically, patients with CEL-MODY develop pancreatic exocrine dysfunction in early childhood and later develop DM in their 40s. A genetic diagnosis helps in determining the choice of treatment, managing associated complications, and the need for further genetic counseling for the family. Insulin is the most appropriate treatment in CEL-MODY; however, other anti-DM drugs can also be used as seen in our patient. The risk of DM complications from CEL-MODY is unknown but patients can develop pancreatic cysts and clinicians should watch for these complications. Our case highlights the need for high suspicion for possible CEL-MODY and considering genetic testing in the setting of coexistent endocrine and exocrine pancreatic insufficiency. Presentation: Saturday, June 17, 2023

Image or scope: Magnetic resonance imaging and endoscopic testing for exocrine and endocrine pancreatic insufficiency in children

ObjectivesWe sought to evaluate associations between Magnetic Resonance Imaging (MRI) findings, exocrine pancreatic insufficiency (EPI) and endocrine insufficiency (prediabetes or diabetes) in children. MethodsThis was a retrospective study that included patients<21 years of age who underwent MRI and endoscopic pancreatic function testing (ePFT; reference standard for pancreatic exocrine function) within 3 months. MRI variables included pancreas parenchymal volume, secreted fluid volume in response to secretin, and T1 relaxation time. Data were analyzed for the full sample as well as the subset without acute pancreatitis (AP) at the time of imaging. ResultsOf 72 patients, 56% (40/72) were female with median age 11.4 years. A 5 mL decrease in pancreas parenchymal volume was associated with increased odds of exocrine pancreatic dysfunction by both ePFT (OR = 1.16, p = 0.02 full sample; OR = 1.29, p = 0.01 no-AP subset), and fecal elastase (OR = 1.16, p = 0.04 full sample; OR = 1.23, p = 0.02 no-AP subset). Pancreas parenchymal volume had an AUC 0.71 (95% CI: 0.59, 0.83) for predicting exocrine pancreatic dysfunction by ePFT and when combined with sex and presence of AP had an AUC of 0.82 (95% CI: 0.72, 0.92).Regarding endocrine function, decreased pancreas parenchymal volume was associated with increased odds of diabetes (OR = 1.16, p = 0.03), and T1 relaxation time predicted glycemic outcomes with an AUC 0.78 (95% CI: 0.55–1), 91% specificity and 73% sensitivity. ConclusionsPancreas parenchymal volume is an MRI marker of exocrine and endocrine pancreatic dysfunction in children. A model including sex, AP, and pancreas volume best predicted exocrine status. T1 relaxation time is also an MRI marker of endocrine insufficiency.

PSUN236 Previously Undiagnosed Hereditary Pancreatitis Presenting as New Onset Type 3c Diabetes Mellitus

Abstract Background Type 3c Diabetes Mellitus (DM3c) or Pancreatogenic Diabetes is defined as diabetes secondary to pancreatic disease. The most common cause of Type 3c Diabetes is chronic pancreatitis, accounting for 80% of cases.1 Hereditary pancreatitis, with mutations such as SPINK1, CFTR, CTRC, is an underdiagnosed cause of chronic pancreatitis leading to Type 3c Diabetes Mellitus.1 The typical disease course for hereditary pancreatitis is recurrent episodes of acute pancreatitis that leads to chronic pancreatitis.1 The average time between hereditary pancreatitis diagnosis and development of DM3c has been shown to be 80 +/- 24 months.1 We present a case of previously undiagnosed hereditary pancreatitis presenting as new onset Type 3c Diabetes Mellitus. Clinical Case A 33-year-old male presents with a two month history of diarrhea, epigastric pain, and weight loss. Vital signs on presentation were blood pressure 105/74, heart rate 59, BMI 13. Physical exam revealed a cachectic appearing male with epigastric tenderness. Lab-work showed blood glucose 819 mg/dL, SOsm 313 mOsm/kg, lipase 21 U/L, bicarbonate 33 mmol/L. A computed tomography (CT) of the abdomen revealed punctate pancreatic parenchymal calcifications, suggestive of chronic pancreatitis. He was admitted to general medicine for management of HHS, where he was treated with IV hydration and insulin therapy. Workup for new onset diabetes revealed a negative anti-GAD Ab &amp;lt;5.0 U/mL, and C peptide level 0.5 ng/mL which suggested β cell dysfunction and decreased endogenous insulin secretion. With these lab values, along with radiographic findings consistent with chronic pancreatitis, the likely driving factor for his diabetes was pancreatic disease and he was diagnosed with DM3c. Severe pancreatic disease was further shown by a reduced fecal elastase level of &amp;lt;50, suggesting exocrine pancreatic insufficiency. Investigating the etiology of his chronic pancreatitis, history revealed no prior episodes of acute pancreatitis or abdominal pain, and no family history of pancreatitis. Workup for common causes of pancreatitis, including alcohol use, hypertriglyceridemia, and gallstones was negative, and genetic workup was pursued. The patient was found to be heterozygous for a SPINK1 mutation, which is a known mutation in hereditary pancreatitis.1 Therefore, hereditary pancreatitis was determined to be the likely cause of his chronic pancreatitis which led to Type 3c Diabetes Mellitus. He was started on daily insulin therapy and pancreatic enzymes for his endocrine and exocrine pancreatic dysfunction respectively, with improvement in symptoms. Conclusion This is a unique case of hereditary pancreatitis presenting as new onset Type 3c Diabetes Mellitus with no prior episodes of acute pancreatitis or established diagnosis of chronic pancreatitis. References Ramalho, G. X., &amp; Dytz, M. G. (2020). Diabetes of the exocrine pancreas related to hereditary pancreatitis, an update. Current Diabetes Reports, 20(6). Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSUN138 Demonstration of Progressive Beta-Cell Failure in Familial Partial Lipodystrophy

Abstract Background Familial Partial Lipodystrophy Type 2 (FPLD2) is an autosomal dominant disorder caused by inherited mutations on the LMNA gene, typically on exon 8 and 11. Insulin resistance and diabetes mellitus are common clinical manifestations in patients with partial lipodystrophy. Despite aggressive treatment aiming reduction in insulin resistance, patients usually require insulin treatment, highlighting the presence of insulin secretion defects. The sequence of events to develop metabolic derangement is not well studied. This study aims to compare the metabolic changes and insulin secretion in two generations of patients with FPLD2. Methods In a longitudinal study, we are studying the metabolic and morphometric changes in younger patients carrying the mutation who have not fully expressed the phenotype and comparing their findings to their affected older relatives. In the first year of the study, six affected young patients (age: 17±4 years, 4F/2M) and four affected older relatives (age: 46±7 years, all-female) have completed a 5-hour OGTT with 75g of glucose to determine the metabolic parameters at 30-minute intervals as well as the area under the curve (AUC) for these parameters. Results Patients in the younger group did not have a clinical diagnosis of diabetes (mean HbA1c of 5.3±0.3%), while all patients in the older generation had the diagnosis of diabetes mellitus with higher HbA1c (7.9±3.1%, p=0.05). Younger patients showed a lower AUC for glucose (28703±12037 mg/dL/min), triglycerides (38820±15305 mg/dL/min, p&amp;lt;0.05)) and free fatty acids (FFA) (78±29mmol/L/min) compared to older affected patients (glucose AUC: 67563±39089 mg/dL/min; triglycerides AUC: 96461±39989 mg/dL/min; FFA AUC: 159±125 mmol/L/min). However, insulin and C-peptide AUC were higher in the younger group compared to the older generation (insulin AUC: 60664±66802 vs. 29331±23341 mcU/mL/min; C-peptide AUC: 3466±1646 vs. 2548±1391 mg/L/min). The change in C-Peptide in the first 30 min post glucose was significantly higher in the younger group compared to the older group (12±1.8 vs. 5±4 mg/L; p&amp;lt;0.05). Insulin secretion during the first 30 min of the test was numerically higher in the younger group versus the older group (213±90 vs. 90±115 mcU/mL). Conclusion Our data (albeit limited) show that the clinical manifestation of diabetes mellitus in older patients with FPLD2 is associated with impairments in insulin secretion, therefore highlighting the importance of beta-cell failure in the development of diabetes mellitus in this population. These data draw attention to the need for further investigation of the pancreatic endocrine dysfunction to treat and better understand diabetes mellitus in this population. Strategies to address just insulin resistance may not be sufficient to prevent the development of diabetes in the long run. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Timing, approach, and treatment strategies for infected pancreatic necrosis: a narrative review

Timing, approach, and treatment strategies for infected pancreatic necrosis: a narrative review

Characterisation of an Atrx Conditional Knockout Mouse Model: Atrx Loss Causes Endocrine Dysfunction Rather Than Pancreatic Neuroendocrine Tumour.

Simple SummaryATRX and DAXX mutations occur in 30–40% of pancreatic neuroendocrine tumours (PanNETs), and there are no reports in the literature of any genetically engineered mouse model (GEMM) evaluating the effect of Atrx disruption as a putative driver event on PanNET initiation. We created a novel GEMM with Atrx conditional disruption in β cells. We observed that this genetic alteration, per se, was not tumourigenic, but we reported novel roles of Atrx on endocrine function, which resulted in dysglycaemia and the exacerbation of inflammageing (increased pancreatic inflammation and hepatic steatosis).ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.

Transcription Factors in Deriving β Cell Regeneration: A Potential Novel Therapeutic Target.

Recently, remarkable advances have been achieved in the molecular biopathology field and researchers turned to evaluate the role, molecular mechanisms, and clinical value of transcription factors in curing a variety of parenchymal degenerative pathologies. Special agents have the capability to cell lineage reprogramming termed transcription factors with a capacity for gene expression modification. Therefore, whatever niche factor may modify gene expression is termed as a transcription factor. A variety of transcription factors have been identified to participate in the regulation of pancreatic stem cell maturation, differentiation, and proliferation; primarily, not only Pdx1, NeuroG3, and MafA, but transcription factors can also transdifferentiate somatic cells in between, liver and gallbladder cells into insulin-producing cells. These heterogenic capabilities of the transcription factors are of clinical significance since they can control cells' regeneration capacity. Physiologically, the pancreatic cells are subdivided into exocrine and endocrine cells. Pancreatic endocrine dysfunction is clinically more common and of more clinical relevance. The paper will illustrate the role and possible mechanisms of transcription factors in the transdifferentiation of endodermderived somatic cells into pancreatic beta-like cells. Clinically, understanding the potential mechanisms in generating physiologic beta cells is extremely crucial to optimize current therapies and evaluate new therapeutic targets via recruiting specific transcription factors. The transcription factors can be applied to both types of diabetes and chronic pancreatitis.

The effect of zinc deficiency and iron overload on endocrine and exocrine pancreatic function in children with transfusion-dependent thalassemia: a cross-sectional study

BackgroundChildren with transfusion-dependent thalassemia (TDT) suffer from secondary hemosiderosis and the delirious effects this iron overload has on their different body organs, including the pancreas. They are also more prone to develop zinc deficiency than the general pediatric population. This study aimed to determine the effect of zinc deficiency and iron overload on the endocrine and exocrine pancreas in TDT children.MethodsEighty children, already diagnosed with TDT, were included in this study. We assessed the following in the participant children: serum ferritin, serum zinc, endocrine pancreatic function (oral glucose tolerance test (OGTT), fasting insulin level and from them, HOMA-IR was calculated), and exocrine pancreatic function (serum lipase and serum amylase).ResultsForty-four TDT children had a subnormal zinc level, while 36 of them had a normal serum zinc level. TDT children with low serum zinc had significantly more impaired endocrine pancreatic function and an abnormally high serum lipase than children with normal serum zinc, p < 0.05 in all. Serum zinc was significantly lower in TDT children with serum ferritin above the ferritin threshold (≥2500 ng/ml) than those below (59.1 ± 20.2 vs. 77.5 ± 28.13), p = 0.02. TDT children, having a serum ferritin ≥2500 ng/ml, had significantly more frequently impaired endocrine pancreatic function and abnormally high serum lipase than TDT children below the ferritin threshold, p < 0.05 in all.ConclusionIn children with transfusion-dependent thalassemia, zinc deficiency aggravates iron-induced pancreatic exocrine and endocrine dysfunction.

Ovariectomy Increases Pancreatic Endoplasmic Reticulum Stress Genes in Simian Immunodeficiency Virus Infection

Background Antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Older PLWH, especially menopausal women, experience complex interactions of HIV, ART, hormonal status, and lifestyle behaviors such as at-risk alcohol use, increasing the risk of metabolic comorbidities. Our studies have demonstrated that chronic binge alcohol (CBA) significantly decreases acute insulin response to a glucose challenge in Simian Immunodeficiency Virus (SIV)-infected macaques, suggesting pathophysiological changes in pancreatic endocrine function. Endoplasmic Reticulum (ER) stress is one of the major mechanisms associated with alcoholic pancreatitis and endocrine pancreatic dysfunction. The objective of this study was to examine the effects of CBA administration and gonadal hormone loss, resulting from ovariectomy (OVX), on pancreatic mechanisms that contribute to impaired glucose-insulin dynamics in SIV-infected female macaques. Hypothesis Chronic binge alcohol and ovariectomy increase pancreatic ER stress and decrease expression of regulators of insulin synthesis. Methods CBA or isovolumetric water (VEH) was administered through an intragastric catheter for 30 minutes, 5 days a week. Three months after initiation of CBA/VEH administration, macaques were infected with SIVMac251 and 2.5 months later initiated on ART. After 1 month of ART, macaques underwent sham surgery or ovariectomy and euthanized 9 months post-SIV-infection. Total RNA was isolated from pancreas collected from macaques (VEH/SHAM= 8, CBA/SHAM= 7, VEH/OVX= 7, CBA/OVX n=7). cDNA was synthesized and qPCR was used to analyze gene expression of markers for ER stress (X-Box Binding Protein 1, XBP1; Activating Transcription Factor 4, ATF4; and C/EBP Homologous Protein, CHOP) and regulators of insulin synthesis (Homeobox Protein Nkx-2.2, NKX2.2; insulin promoter factor 1, PDX1; Transcription factor MafA, MAFA; Glucose transporter 2, GLUT2; and Glucokinase). Results There was a main effect of OVX to increase mRNA expression of ATF4 and XBP1 (p<0.05) in SIV-infected macaques. There was not a statistically significant effect of CBA or OVX to alter gene expression of CHOP, or insulin synthesis markers, NKX2.2, PDX1, MAFA, GLUT2 and Glucokinase. Conclusions OVX increased pancreatic expression of ER stress markers without significantly altering expression of regulators of insulin synthesis. We speculate that the increased expression of ER stress markers may result in increased beta cell apoptosis. These findings provide evidence for pancreatic mechanisms that can contribute to the observed impairment of glucose insulin dynamics in SIV infection.

Chronic binge alcohol impairs glucose‐insulin dynamics in SIV‐infected female rhesus macaques

Background Antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Older PLWH, especially post-menopausal women, experience complex interactions of HIV, ART, hormonal status, and lifestyle behaviors such as at-risk alcohol use, increasing the risk of metabolic comorbidities. We have previously shown that chronic binge alcohol (CBA) reduces the acute insulin response to a glucose challenge in SIV-infected male macaques and that at-risk alcohol use decreases HOMA-β (a marker for pancreatic beta cell function) in PLWH. Meanwhile, the role of estrogen in pancreatic health maintenance is not fully understood. The objective of this study was to determine the effect of CBA and ovarian hormone loss, resulting from ovariectomy (OVX), on glucose-insulin dynamics and pancreatic integrity in SIV-infected female rhesus macaques. Hypothesis We hypothesized that chronic binge alcohol and ovariectomy would decrease insulin response to a glucose challenge and impair insulin and glucagon expression in pancreatic islets. Methods 28 adult female macaques were used in the study. CBA or isovolumetric water (VEH) was administered through an intragastric catheter for 30 minutes, 5 days a week, with blood alcohol concentrations reaching 50-60 mM. Three months after initiation of CBA/VEH administration, macaques were infected with SIVMac251 and 2.5 months later initiated on ART. After 1 month of ART, macaques underwent sham surgery or ovariectomy. Using a modified frequently sampled intravenous glucose tolerance test (FSIVGTT), blood glucose and serum insulin values were measured. Glucose and insulin dynamic measures including the acute insulin response to glucose (AIRg), insulin sensitivity (Si), disposition index (DI), and glucose effectiveness (Sg) were determined using minimal model software. Insulin and glucagon expression was determined in formalin-fixed, paraffin-embedded pancreatic tissue collected at study endpoint. Corrected total cell fluorescence for insulin and glucagon were calculated using ImageJ software. To confirm these results, total RNA was isolated from pancreas and mRNA expression of insulin and glucagon determined using quantitative PCR. Results There was a main effect of CBA to decrease AIRg (p=0.02) and increase Si (p=0.01). There were no statistically significant effects of OVX on AIRg (p=0.06) or Si (p=0.4). There were also no statistically significant effects of CBA or OVX on DI or Sg. Neither CBA nor OVX altered the protein or mRNA expression of insulin and glucagon in pancreatic islets. Conclusion CBA decreased the acute endogenous insulin release in response to a glucose challenge without significantly altering basal pancreatic islet expression of insulin and glucagon, while OVX did not significantly alter any of these measures. These results indicate that CBA impairs the immediate release of insulin from beta cell insulin secretory vesicles, and we speculate that CBA dysregulates the metabolic signaling pathway of insulin secretion. Determining mechanisms of pancreatic endocrine dysfunction will inform therapeutic strategies to improve alcohol-mediated impaired glucose insulin dynamics in the context of SIV/HIV.

Use of hemoglobin A1c to identify dysglycemia in cystic fibrosis.

BackgroundCystic fibrosis (CF) leads to pancreatic endocrine dysfunction with progressive glycemic disturbance. Approximately 30%–50% of people with CF eventually develop CF–related diabetes (CFRD). Pre-CFRD states progress from indeterminant glycemia (INDET) to impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Screening guidelines recommend inconvenient annual 2-hour oral glucose tolerance tests (OGTTs), beginning at age 10 years. More efficient methods, such as hemoglobin A1C (HbA1c), have been evaluated, but only limited, relatively small studies have evaluated the association between HbA1c and pre-CFRD dysglycemic states.ObjectiveTo determine whether HbA1c is an appropriate screening tool for identifying patients with pre-CFRD dysglycemia to minimize the burden of annual OGTTs.MethodsThis retrospective review evaluated medical records data of all University of Massachusetts Memorial Health System CF patients with an HbA1c result within 90 days of an OGTT between 1997 and 2019. Exclusion criteria were uncertain CF diagnosis, other forms of diabetes, or incomplete OGTT. In total, 56 patients were included and categorized according to OGTT results (American Diabetes Association criteria): normal glucose tolerance, INDET, IFG, or IGT. Associations were evaluated between HbA1c and OGTT results and between HbA1c and pre-CFRD dysglycemic states.ResultsMean HbA1c was not significantly different between patients with normal glucose tolerance and those in the INDET (p = 0.987), IFG (p = 0.690), and IGT (p = 0.874) groups. Analysis of variance confirmed the lack of association between HbA1c and glycemia, as mean HbA1c was not significantly different amongst the four categories (p = 0.250).ConclusionThere is increasing awareness of the impact of pre-CFRD states, including reduced pulmonary function and nutritional status. Unfortunately, our results do not support using HbA1c as a screening tool for pre-CFRD dysglycemia, specifically INDET, IFG, and IGT. Further studies are warranted to evaluate more efficient screening methods to reduce the burden of annual OGTTs.

The Effects of Non-Nutritive Sweetener Consumption in the Pediatric Populations: What We Know, What We Don't, and What We Need to Learn.

Childhood obesity is increasing at an alarming rate in the United States. This trend carries serious risk of children developing obesity-related diseases including Type 2 diabetes and cardiovascular disease. Non-nutritive sweeteners (NNS) are used as substitution for table sugar as a way to prevent weight gain. Their consumption is ubiquitous in adults and children; however the long-term health outcomes of chronic NNS consumption in children are unclear. Conflicting observational studies suggest that children consuming NNS are at risk of obesity and development of type 2 diabetes, while others concluded some benefits in weight reduction. Here, we review the physiological mechanisms that can contribute to the negative metabolic effects of NNS. We will focus on how NNS alters the sweet perception leading to increase caloric consumption, how NNs alters the gut microbiota, and how NNS may disrupt glucose homeostasis and initiate a vicious cycle of pancreatic endocrine dysfunction. Studies focused on the pediatric population are limited but necessary to determine whether the potential weight loss benefits outweigh the potential negative metabolic outcomes during this critical development period.

CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation.

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF-related diabetes (CFRD) is one of the most prevalent comorbidities of CF. Altered glucose homeostasis has been reported in CF patients. The mechanism has not been fully elucidated. Besides the consequence of pancreatic endocrine dysfunction, we focus on insulin-responsive tissues and glucose transportation to explain glucose homeostasis alteration in CFRD. Herein, we found that CFTR knockout mice exhibited insulin resistance and glucose tolerance. Furthermore, we demonstrated insulin-induced glucose transporter 4 (GLUT4) translocation to the cell membrane was abnormal in the CFTR knockout mice muscle fibers, suggesting that defective intracellular GLUT4 transportation may be the cause of impaired insulin responses and glucose homeostasis. We further demonstrated that PI(4,5)P2 could rescue CFTR related defective intracellular GLUT4 transportation, and CFTR could regulate PI(4,5)P2 cellular level through PIP5KA, suggesting PI(4,5)P2 is a down-stream signal of CFTR. Our results revealed a new signal mechanism of CFTR in GLUT4 translocation regulation, which helps explain glucose homeostasis alteration in CF patients.

Taurine treatment reverses protein malnutrition-induced endothelial dysfunction of the pancreatic vasculature: The role of hydrogen sulfide

BackgroundProtein malnutrition in childhood predisposes individuals to vascular and pancreatic endocrine dysfunction, thus increasing the risk of diabetes and hypertension. Because taurine may reduce cardiometabolic risk, we hypothesized that taurine treatment has a beneficial effect on the pancreatic vasculature during protein restriction. Methods and resultsWeaned mice were fed a normal or a low-protein diet and were treated with or without taurine for 3 months. The lieno-pancreatic artery (LPA) from low-protein diet-treated mice exhibited impaired endothelium-dependent relaxation to acetylcholine that was associated with decreased endothelium-derived hyperpolarization (EDH), hydrogen sulfide (H2S) production, and H2S-synthesizing CBS expression and impaired vasorelaxation to an H2S-donor, NaHS. These changes were prevented by taurine treatment. We compared the effects of taurine with the effects of the direct vasodilator hydralazine and found that both normalized blood pressure and the endothelial vasodilator function of the LPA in the mice fed a protein-restricted diet. However, only taurine restored the CBS expression in the LPA and insulin secretion in response to high glucose. The LPA supplies the pancreas and shares morphometry with the mesenteric resistance artery (MRA). However, in the MRA, low-protein diet-induced endothelial dysfunction is driven by impaired NOS-derived NO with no changes in H2S signaling. ConclusionsThe results suggest that taurine protects against protein malnutrition-induced endothelial dysfunction in the LPA by upregulating the CBS-H2S pathway. Considering the importance of the pancreatic vasculature for endocrine islet activity, taurine may be a potential therapy for the vascular and metabolic dysfunction associated with malnutrition and comorbidities.

MiR-34a-5p and miR-452-5p: The Novel Regulators of Pancreatic Endocrine Dysfunction in Diabetic Zucker Rats?

Objective: The pancreatic endocrinal system dominates the regulation of blood glucose levels in vivo, and the dysfunction of pancreatic endocrine β-cells is a major cause of the occurrence and development of Type 2 diabetes (T2D). Although microRNA (miRNA) have been found to be key regulators of pancreatic β-cells proliferation, differentiation and apoptosis, the underlying mechanism remains enigmatic. The aim of this study was to identify several novel miRNAs which might be involved in the etiopathogenesis of diabetic β-cells dysfunction.Methods: The miRNA expression profiles in the pancreas of high-fat diet (HFD) fed Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats feed with normal-fat diet (NFD) were detected by using miRNA microarray chip, and individually verified the most significant factors by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the target genes related to each of the identified miRNAs and the functions of these target genes in different metabolic signaling pathways.Results: Compared with the ZL rats, a total of 24 differentially expressed miRNAs were detected in ZDF rats. Among which miR-34a-5p and miR-452-5p were the most significantly up-regulated and down-regulated respectively. These miRNAs have not been reported in rats' pancreas before. By GO and KEGG enrichment analyses, we found that miR-34a-5p could negatively regulate pancreatic β-cell proliferation through the involvement of Wnt signaling pathway. In addition, it was also found to regulate insulin secretion through the insulin signaling pathway to modulate blood glucose levels. At the same time, miR-452-5p was found to positively regulate the activity of the key rate-limiting enzyme branched-chain α-keto acid dehydrogenase-β (BCKDHB) in the catabolism of branched chain amino acids (BCAA), leading to mitochondrial dysfunction in pancreatic β-cells.Conclusions: miR-34a-5p and miR-452-5p were identified as the novel regulators of pancreatic endocrine dysfunction. These miRNAs might have the potential to be utilized as the new predictive biomarkers for the diagnosis of the occurrence and development of T2D, as well as the therapeutic targets for T2D treatment.

Date palm fruit extract ameliorated pancreatic apoptosis, endocrine dysfunction and regulatory inflammatory cytokines in Streptozotocin-induced diabetes in rats.

The current work studied the mechanism(s) and ability by which date palm (Phoenix dactylifera L.) fruit extract (DPE) inspired a glucose-lowering impact in rats suffering from diabetes. Forty-eight albino rats were divided into six various experimental treatments after induction of diabetes by intraperitoneal infusion of streptozotocin (45mg/kg bwt) as follows: normal control, DPE, diabetic control, diabetic glibenclamide (GLI), diabetic DPE, and diabetic GLI plus DPE-treated groups. In animals euthanized after 8weeks, blood and pancreatic tissue samples were assembled to assess different biochemical and histopathological changes. The expressions of insulin, B cell lymphoma-2 (Bcl-2), and cysteine aspartate-specific protease-3 (caspase-3) in islet β cells were also evaluated using immunohistochemical assessment. Diabetic rats exhibited hyperglycemia; increment of pancreatic malondialdehyde (lipid peroxidation biomarker), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β); and decrement of plasma insulin and pancreatic antioxidants: glutathione, superoxide dismutase, and catalase values. Also, the pancreatic islets exhibited histopathological and morphometric alternations associated with weak positive insulin and Bcl-2 immunoreactivity and strong positive caspase-3 immunoreactivity. DPE and/or GLI, an anti-diabetic drug, improved the pancreatic histoarchitecture and improved β cell function and structure, which increased insulin levels and improved the insulin, Bcl-2, and caspase-3 immunoreactivity in diabetic rats. Nevertheless, the combined DPE and GLI therapy revealed a significant recovery and restoration of β cells' structure and function. The date palm fruit has anti-apoptotic, anti-inflammatory, and antioxidant activities and hypoglycemic effects, which in turn play a pivotal role in avoiding the progression of diabetes mellitus. Moreover, it could potentiate the glucose-lowering activity of anti-diabetic drugs.