The Impact of Pancreatic Head Resection on Blood Glucose Homeostasis in Patients with Chronic Pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) often leads to recurrent pain as well as exocrine and/or endocrine pancreatic insufficiency. This study aimed to investigate the effect of pancreatic head resections on glucose metabolism in patients with CP. METHODS: Patients who underwent pylorus-preserving pancreaticoduodenectomy (PPPD), Whipple procedure (cPD), or duodenum-preserving pancreatic head resection (DPPHR) for CP between January 2011 and December 2020 were retrospectively analyzed with regard to markers of pancreatic endocrine function including steady-state beta cell function (%B), insulin resistance (IR), and insulin sensitivity (%S) according to the updated Homeostasis Model Assessment (HOMA2). RESULTS: Out of 141 pancreatic resections for CP, 43 cases including 31 PPPD, 2 cPD and 10 DPPHR, met the inclusion criteria. Preoperatively, six patients (14%) were normoglycemic (NG), 10 patients (23.2%) had impaired glucose tolerance (IGT) and 27 patients (62.8%) had diabetes mellitus (DM). In each subgroup, no significant changes were observed for HOMA2-%B (NG: p = 0.57; IGT: p = 0.38; DM: p = 0.1), HOMA2-IR (NG: p = 0.41; IGT: p = 0.61; DM: p = 0.18) or HOMA2-%S (NG: p = 0.44; IGT: p = 0.52; DM: p = 0.51) 3 and 12 months after surgery, respectively. CONCLUSION: Pancreatic head resections for CP, including DPPHR and pancreatoduodenectomies, do not significantly affect glucose metabolism within a follow-up period of 12 months.

[Open thoracic and thoracoabdominal aortic repair vs. f/bTEVAR - complementary or competitive?] / Offener thorakaler und thorakoabdominaler Aortenersatz vs. f/b(T)EVAR ­ komplementär oder kompetitiv?

The classical approach of open repair (OR) for thoracic and thoracoabdominal aortic pathologies, including aneurysms and dissection, has been outnumbered by the use of fenestrated/branched (thoracic) endovascular aortic repair (f/b[T]EVAR) in recent years. Providing OR for complex cases in an aortic service requires a dedicated surgical setup and a huge body of expertise in this particular field.In order to reduce specific complications, such as perioperative mortality, kidney failure, spinal cord ischemia, stroke or bowel ischemia, it is necessary to apply cerebrospinal-spinal fluid drainage, point-of-care coagulation therapy, distal and retrograde aortic perfusion and sequential clamping. Despite the predominance of endovascular solutions, the specific OR expertise is still needed for specific indications, such as young patients, connective tissue disorder or aortic graft infections.Currently, the short and mid term results for f/b(T)EVAR outweigh those for OR, including the shorter hospital stay and less invasive procedures. However, OR provides better long-term results for overall mortality, re-intervention rates and secondary complications.In conclusion, in our opinion OR is a service that is still necessary for dedicated aortic centres, but will most likely become more frequent again in the years to come.

Management and outcome of true visceral and renal artery aneurysm repair.

PURPOSE: Visceral and renal artery aneurysms (VAA, RAA) are very rare pathologies. Both surgical and endovascular therapies are discussed as therapeutic options for ruptured and non-ruptured aneurysm repair; we describe our experience in the open and endovascular management of these entities. METHODS: Retrospective database analysis of 60 treated VAA and RAA in 59 patients between 1994 and 2020. Outcome data was descriptively analyzed. RESULTS: Thirty-seven aneurysms were surgically treated and 23 interventionally. In the total study cohort, we observed a mortality of 1.7% and a morbidity of 18.6%. One major complication occurred. The morbidity was higher after surgical repair in ruptured and non-ruptured cases. The mean aneurysm diameter was 30.5 ± 15.6 mm. Patients with hepatic or pancreaticoduodenal artery aneurysms presented more often in the stage of rupture, without differences in aneurysm size. The length of hospital stay after endovascular repair was significantly shorter compared to open surgical treatment (7.2 ± 6.9 days versus 11.8 ± 6.7 days, p = 0.014), but only in elective cases. Primary technical success was significantly better in patients that underwent surgical repair in an intention to treat analysis (100% versus 79.3%). The mean follow-up of the cohort was 53.5 months (range 3-207 months). CONCLUSION: Elective endovascular therapy and open surgery of VAA and RAA are safe procedures with a good periprocedural and long-term outcome. Surgical revascularization showed a better primary technical success but was associated with longer length of hospital stays.

Dysfunction of Persisting ß Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis.

Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet ß cells. However, the role and sequence of ß cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of ß cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, ß cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained ß cell volume further declines. These results indicate that dysfunction of persisting ß cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy.

The pathohistological subtype strongly predicts survival in patients with ampullary carcinoma.

Ampullary cancer represents approximately 6% of the malignant periampullary tumors. An early occurrence of symptoms leads to a 5-year survival rate after curative surgery of 30 to 67%. In addition to the tumor stage, the immunohistological subtypes appear to be important for postoperative prognosis. The aim of this study was to analyze the different subtypes regarding their prognostic relevance. A total of 170 patients with ampullary cancer were retrospectively analyzed between 1999 until 2016 after pancreatic resection. Patients were grouped according to their pathohistological subtype of ampullary cancer (pancreatobiliary, intestinal, mixed). Characteristics among the groups were analyzed using univariate and multivariate models. Survival probability was analyzed by the Kaplan-Meier method. An exact subtyping was possible in 119 patients. A pancreatobiliary subtype was diagnosed in 69 patients (58%), intestinal in 41 patients (34.5%), and a mixed subtype in 9 patients (7.6%). Survival analysis showed a significantly worse 5-year survival rate for the pancreatobiliary subtype compared with the intestinal subtype (27.5% versus 61%, p < 0.001). The mean overall survival of patients with pancreatobiliary, intestinal, and mixed subtype was 52.5, 115 and 94.7 months, respectively (p < 0.001). The pathohistological subtypes of ampullary cancer allows a prediction of the postoperative prognosis.

Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes.

OBJECTIVE: Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. METHODS: Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs. RESULTS: After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10-24; PPP p-value = 3.64 × 10-24) and PSPH (OD p-value = 3.92 × 10-26; PPP p-value = 3.64 × 10-24). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples. CONCLUSIONS: eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone.

Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium ( www.imidia.org ) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). METHODS: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. RESULTS: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes. CONCLUSIONS/INTERPRETATION: These studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.

Blood Glucose Homeostasis in the Course of Partial Pancreatectomy--Evidence for Surgically Reversible Diabetes Induced by Cholestasis.

BACKGROUND AND AIM: Partial pancreatic resection is accompanied not only by a reduction in the islet cell mass but also by a variety of other factors that are likely to interfere with glucose metabolism. The aim of this work was to characterize the patient dynamics of blood glucose homeostasis during the course of partial pancreatic resection and to specify the associated clinico-pathological variables. METHODS: In total, 84 individuals undergoing elective partial pancreatic resection were consecutively recruited into this observational trial. The individuals were assigned based on their fasting glucose or oral glucose tolerance testing results into one of the following groups: (I) deteriorated, (II) stable or (III) improved glucose homeostasis three months after surgery. Co-variables associated with blood glucose dynamics were identified. RESULTS: Of the 84 participants, 25 (30%) displayed a normal oGTT, 17 (20%) showed impaired glucose tolerance, and 10 (12%) exhibited pathological glucose tolerance. Elevated fasting glucose was present in 32 (38%) individuals before partial pancreatic resection. Three months after partial pancreatic resection, 14 (17%) patients deteriorated, 16 (19%) improved, and 54 (64%) retained stable glucose homeostasis. Stability and improvement was associated with tumor resection and postoperative normalization of recently diagnosed glucose dysregulation, preoperatively elevated tumor markers and markers for common bile duct obstruction, acute pancreatitis and liver cell damage. Improvement was linked to preoperatively elevated insulin resistance, which normalized after resection and was accompanied by a decrease in fasting- and glucose-stimulated insulin secretion. CONCLUSIONS: Surgically reversible blood glucose dysregulation diagnosed concomitantly with a (peri-) pancreatic tumor appears secondary to compromised liver function due to tumor compression of the common bile duct and the subsequent increase in insulin resistance. It can be categorized as "cholestasis-induced diabetes" and thereby distinguished from other forms of hyperglycemic disorders.

Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology.

Studies on the cellular function of the pancreas are typically performed in vitro on its isolated functional units, the endocrine islets of Langerhans and the exocrine acini. However, these approaches are hampered by preparation-induced changes of cell physiology and the lack of an intact surrounding. We present here a detailed protocol for the preparation of pancreas tissue slices. This procedure is less damaging to the tissue and faster than alternative approaches, and it enables the in situ study of pancreatic endocrine and exocrine cell physiology in a conserved environment. Pancreas tissue slices facilitate the investigation of cellular mechanisms underlying the function, pathology and interaction of the endocrine and exocrine components of the pancreas. We provide examples for several experimental applications of pancreas tissue slices to study various aspects of pancreas cell biology. Furthermore, we describe the preparation of human and porcine pancreas tissue slices for the validation and translation of research findings obtained in the mouse model. Preparation of pancreas tissue slices according to the protocol described here takes less than 45 min from tissue preparation to receipt of the first slices.

Pathohistological subtype predicts survival in patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

OBJECTIVE: To investigate different subtypes of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and their prognostic value. BACKGROUND: IPMNs of the pancreas are estimated to have a better prognosis than pancreatic ductal adenocarcinomas (PDACs). In addition to the different growth types (ie, main duct vs. branch duct types), the histological subtypes of IPMNs (ie, intestinal, pancreatobiliary, gastric, and oncocytic type) are prognostically relevant. These subtypes can be characterized by different mucin (MUC) expression patterns. In this study, we analyzed the IPMNs from 2 pancreatic cancer referral centers by correlating the MUC expression, histological subtype, and clinical outcome. METHODS: We re-evaluated all resections due to a pancreatic tumor over a period of 15 years. Cases with IPMNs were identified, and the subtypes were distinguished using histopathological analysis, including the immunohistochemical analysis of MUC (ie, MUC1, MUC2, and MUC5AC) expression. Furthermore, we determined clinical characteristics and patient outcome. RESULTS: A total of 103 IPMNs were identified. On the basis of the MUC profile, histopathological subtypes were classified into the following categories: intestinal type [n = 45 (44%)], pancreatobiliary type [n = 41 (40%)], gastric type [n = 13 (12%)], and oncocytic type [n = 4 (4%)]. The following types of resections were performed: pancreatic head resections [n = 77 (75%)], tail resections [n = 16 (15%)], total pancreatectomies [n = 5 (5%)], and segment resections [n = 5 (5%)]. The 5-year survival of patients with intestinal IPMNs was significantly better than pancreatobiliary IPMNs (86.6% vs. 35.6%; P < 0.001). The pancreatobiliary subtype was strongly associated with malignancy [odds ratio (OR): 6.76], recurrence (P < 0.001), and long-term survival comparable with that of PDAC patients. CONCLUSIONS: Evaluation of IPMN subtypes supports postoperative patient prognosis prediction. Therefore, subtype differentiation could lead to improvements in clinical management. Potentially identifying subgroups with the need for adjuvant therapy may be possible.

Improved protocol for laser microdissection of human pancreatic islets from surgical specimens.

Laser microdissection (LMD) is a technique that allows the recovery of selected cells and tissues from minute amounts of parenchyma. The dissected cells can be used for a variety of investigations, such as transcriptomic or proteomic studies, DNA assessment or chromosomal analysis. An especially challenging application of LMD is transcriptome analysis, which, due to the lability of RNA, can be particularly prominent when cells are dissected from tissues that are rich of RNases, such as the pancreas. A microdissection protocol that enables fast identification and collection of target cells is essential in this setting in order to shorten the tissue handling time and, consequently, to ensure RNA preservation. Here we describe a protocol for acquiring human pancreatic beta cells from surgical specimens to be used for transcriptomic studies. Small pieces of pancreas of about 0.5-1 cm(3) were cut from the healthy appearing margins of resected pancreas specimens, embedded in Tissue-Tek O.C.T. Compound, immediately frozen in chilled 2-Methylbutane, and stored at -80 °C until sectioning. Forty serial sections of 10 µm thickness were cut on a cryostat under a -20 °C setting, transferred individually to glass slides, dried inside the cryostat for 1-2 min, and stored at -80 °C. Immediately before the laser microdissection procedure, sections were fixed in ice cold, freshly prepared 70% ethanol for 30 sec, washed by 5-6 dips in ice cold DEPC-treated water, and dehydrated by two one-minute incubations in ice cold 100% ethanol followed by xylene (which is used for tissue dehydration) for 4 min; tissue sections were then air-dried afterwards for 3-5 min. Importantly, all steps, except the incubation in xylene, were performed using ice-cold reagents - a modification over a previously described protocol. utilization of ice cold reagents resulted in a pronounced increase of the intrinsic autofluorescence of beta cells, and facilitated their recognition. For microdissection, four sections were dehydrated each time: two were placed into a foil-wrapped 50 ml tube, to protect the tissue from moisture and bleaching; the remaining two were immediately microdissected. This procedure was performed using a PALM MicroBeam instrument (Zeiss) employing the Auto Laser Pressure Catapulting (AutoLPC) mode. The completion of beta cell/islet dissection from four cryosections required no longer than 40-60 min. Cells were collected into one AdhesiveCap and lysed with 10 µl lysis buffer. Each single RNA specimen for transcriptomic analysis was obtained by combining 10 cell microdissected samples, followed by RNA extraction using the Pico Pure RNA Isolation Kit (Arcturus). This protocol improves the intrinsic autofluorescence of human beta cells, thus facilitating their rapid and accurate recognition and collection. Further improvement of this procedure could enable the dissection of phenotypically different beta cells, with possible implications for better understanding the changes associated with type 2 diabetes.

Contrast-enhanced ultrasonography in pancreas transplantation.

BACKGROUND: Pancreas transplantation remains a major surgery with potential complications that require reliable imaging despite impaired kidney function. Contrast-enhanced ultrasonography (CEUS) has been proven to be an indispensable tool in the evaluation of the native pancreas. Here, CEUS studies are extended to pancreas transplants for the first time. METHODS: A total of 42 B-mode, duplex, and CEUS exams performed using 1 mL SonoVue (Bracco) on a Siemens Acuson Sequoia ultrasound machine were evaluated in 14 pancreas transplant recipients. Time-intensity curves and curve characteristics were calculated. The data were compared between normal pancreas transplants, grafts undergoing rejection, and grafts after successful treatment of the rejection episode. RESULTS: All of the grafts could be well visualized in all ultrasound exams. Although the arterial resistive index did not differentiate between rejection and the absence of rejection, in CEUS, the time-intensity curves showed a significantly slower ascent and diminished maximum intensity in pancreas grafts during rejection, with significantly reduced maximum intensity and time to reach peak intensity. After the successful treatment of rejection, these parameters were almost restored to initial values. DISCUSSION: CEUS displays the capillary perfusion of the tissue. Edema of the pancreas graft during rejection impairs capillary perfusion, reflected in the amount of contrast detected by CEUS and the dynamics of the influx of the contrast agent. CONCLUSION: CEUS yields useful information after pancreas transplantation and has been proven a sensitive tool in the surveillance of pancreas grafts. Further studies will be needed to differentiate rejection from other posttransplantation complications using CEUS.

Isolation of human islets from partially pancreatectomized patients.

Investigations into the pathogenesis of type 2 diabetes and islets of Langerhans malfunction (1) have been hampered by the limited availability of type 2 diabetic islets from organ donors(2). Here we share our protocol for isolating islets from human pancreatic tissue obtained from type 2 diabetic and non-diabetic patients who have undergone partial pancreatectomy due to different pancreatic diseases (benign or malignant pancreatic tumors, chronic pancreatitis, and common bile duct or duodenal tumors). All patients involved gave their consent to this study, which had also been approved by the local ethics committee. The surgical specimens were immediately delivered to the pathologist who selected soft and healthy appearing pancreatic tissue for islet isolation, retaining the damaged tissue for diagnostic purposes. We found that to isolate more than 1,000 islets, we had to begin with at least 2 g of pancreatic tissue. Also essential to our protocol was to visibly distend the tissue when injecting the enzyme-containing media and subsequently mince it to aid digestion by increasing the surface area. To extend the applicability of our protocol to include the occasional case in which a large amount (>15g) of human pancreatic tissue is available , we used a Ricordi chamber (50 ml) to digest the tissue. During digestion, we manually shook the Ricordi chamber(3) at an intensity that varied by specimen according to its level of tissue fibrosis. A discontinous Ficoll gradient was then used to separate the islets from acinar tissue. We noted that the tissue pellet should be small enough to be homogenously resuspended in Ficoll medium with a density of 1.125 g/ml. After isolation, we cultured the islets under stress free conditions (no shaking or rotation) with 5% CO(2;) at 37 °C for at least 48 h in order to facilitate their functional recovery. Widespread application of our protocol and its future improvement could enable the timely harvesting of large quantities of human islets from diabetic and clinically matched non-diabetic subjects, greatly advancing type 2 diabetes research.

Hepatocyte nuclear factor (HNF) 4α expression distinguishes ampullary cancer subtypes and prognosis after resection.

OBJECTIVE: To investigate biological differences and prognostic indicators of different ampullary cancer (AC) subtypes. BACKGROUND: AC is associated with a favorable prognosis compared with other periampullary carcinomas. Aside from other prognostic factors, the histological origin of AC may determine survival. Specifically, the pancreatobiliary subtype of AC displays worse prognosis compared with the intestinal subtype. However, knowledge of inherent molecular characteristics of different periampullary tumors and their effects on prognosis has been limited. METHODS: Gene expression profiling was used to screen for differential gene expression between 6 PDAC cases and 12 AC cases. Among others, hepatocyte nuclear factor 4α (HNF4α) mRNA overexpression was observed in AC cases. Nuclear HNF4α protein expression was assessed using tissue microarrays consisting of 99 individual AC samples. The correlation of HNF4α expression with clinicopathological data (n = 99) and survival (n = 84) was assessed. RESULTS: HNF4α mRNA is 7.61-fold up-regulated in AC compared with that in PDAC. Bioinformatics analyses indicated its key role in dysregulated signaling pathways. Nuclear HNF4α expression correlates with histological subtype, grading, CDX2 positivity, MUC1 negativity and presence of adenomatous components in the carcinoma. The presence of HNF4α is a univariate predictor of survival in AC mean survival (50 months versus 119 months, P = 0.002). Multivariate analysis revealed that HNF4α negativity (HR = 17.95, 95% CI: 2.35-136.93, P = 0.005) and lymph node positivity (HR = 3.33, 95% CI: 1.36-8.18, P = 0.009) are independent negative predictors of survival. CONCLUSIONS: Immunohistochemical determination of HNF4α expression is an effective tool for distinguishing different AC subtypes. Similarly, HNF4α protein expression is an independent predictor of favorable prognosis in carcinoma of the papilla of Vater and may serve for risk stratification after curative resection.

Impaired insulin turnover in islets from type 2 diabetic patients.

Failure of pancreatic ß-cells contributes to the development of type 2 diabetes. Besides evidence of reduced glucose-stimulated insulin secretion and ß-cell mass, little information is available about the molecular deficits of human diabetic islets. Islets were isolated from macroscopically normal pancreatic tissue from 8 patients with type 2 diabetes and 17 matched non-diabetic patients who underwent pancreatic surgery. Insulin content and insulin secretion were measured before and after islet stimulation with 25 mM glucose for 2 hours. In parallel, we also investigated the subcellular localization of polypyrimidine tract-binding protein 1 (PTBP1), whose nucleocytoplasmic translocation is involved in the rapid posttranscriptional up-regulation of insulin biosynthesis following islet stimulation with glucose and GLP-1. Glucose stimulated insulin secretion was decreased, albeit not significantly, in type 2 diabetic islets compared to non-diabetic islets. Stimulation increased the total amount of insulin (islet insulin content + secreted insulin) in islet preparation from non-diabetic patients, but not from type 2 diabetic subjects. Furthermore, the nuclear levels of PTBP1 were decreased in stimulated non-diabetic islets, but not in type 2 diabetic islets. These results suggest that impairment of rapid insulin increase in response to glucose is a specific trait of type 2 diabetic islets. Nuclear retention of PTBP1 is likely to play a role in this deficit, which in turn can contribute to impaired insulin secretion in type 2 diabetes. Overall, these data highlight the importance of investigating mechanisms of insulin biosynthesis and degradation to gain insight into the pathogenesis of type 2 diabetes.

Molecular pathogenesis of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are rare primary neoplasms of the pancreas and arise sporadically or in the context of genetically determined syndromes. Depending on hormone production and sensing, PNETs clinically manifest due to a hormone-related syndrome (functional PNET) or by symptoms related to tumor bulk effects (non-functional PNET). So far, radical surgical excision is the only therapy to cure the disease. Development of tailored non-surgical approaches has been impeded by the lack of experimental laboratory models and there is, therefore, a limited understanding of the complex cellular and molecular biology of this heterogeneous group of neoplasm. This review aims to summarize current knowledge of tumorigenesis of familial and sporadic PNETs on a cellular and molecular level. Open questions in the field of PNET research are discussed with specific emphasis on the relevance of disease management.

Neuroendocrine tumors of the pancreas.

This literature review briefly summarizes the epidemiology, pathophysiology, clinical management, and outcomes of patients with pancreatic neuroendocrine tumors (PNETs) and highlights recent advances in PNET research. PNETs are rare neoplasms, compared with carcinomas arising from pancreatic exocrine tissue. They, like other neuroendocrine tumor types, display variable malignant potential, hormone-related syndromes (functionality), localization, and genetic background. Although tumor origin and molecular pathogenesis remain poorly understood, recently established grading and staging systems facilitate patient risk stratification, and thereby directly impact clinical decision making. Although the optimal clinical management of PNETs involves a multidisciplinary approach, surgery remains the only curative treatment for early-stage disease. Surgery may also have a role in patients with advanced-stage disease, including those with hepatic metastases. Alternative therapeutic approaches applied to PNETs, including chemotherapy, radiofrequency ablation, transarterial chemoembolization, biotherapy, polypeptide radionuclide receptor therapy, antiangiogenic therapy, and selective internal radiotherapy, have failed to demonstrate a long-term survival benefit. Surgery remains the primary therapeutic option for patients with PNETs. Research on PNETs is desperately needed to improve the therapeutic options for patients with this disease.

ICA512 signaling enhances pancreatic beta-cell proliferation by regulating cyclins D through STATs.

Changes in metabolic demands dynamically regulate the total mass of adult pancreatic beta-cells to adjust insulin secretion and preserve glucose homeostasis. Glucose itself is a major regulator of beta-cell proliferation by inducing insulin secretion and activating beta-cell insulin receptors. Here, we show that islet cell autoantigen 512 (ICA512)/IA-2, an intrinsic tyrosine phosphatase-like protein of the secretory granules, activates a complementary pathway for beta-cell proliferation. On granule exocytosis, the ICA512 cytoplasmic domain is cleaved and the resulting cytosolic fragment (ICA512-CCF) moves into the nucleus where it enhances the levels of phosphorylated STAT5 and STAT3, thereby inducing insulin gene transcription and granule biogenesis. We now show that knockdown of ICA512 decreases cyclin D1 levels and proliferation of insulinoma INS-1 cells, whereas beta-cell regeneration is reduced in partially pancreatectomized ICA512-/- mice. Conversely, overexpression of ICA512-CCF increases both cyclin D1 and D2 levels and INS-1 cell proliferation. Up-regulation of cyclin D1 and D2 by ICA512-CCF is affected by knockdown of STAT3 and STAT5, respectively, whereas it does not require insulin signaling. These results identify ICA512 as a regulator of cyclins D and beta-cell proliferation through STATs and may have implication for diabetes therapy.