Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
Acromegaly is a disease mainly caused by pituitary neuroendocrine tumor (PitNET) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogs (SSAs), that decrease tumor mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumor tissue from twelve patients with somatotropinomas, with half of the patients receiving SSA/DA treatment before surgery and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein–protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumor development promoting factors MUC16, MACC1, and GRHL2, were significantly downregulated in therapy administered PitNET tissue; this finding was supported by functional studies in GH3 cells. Protein–protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotropinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA significantly downregulated several factors involved in tumorigenesis, including MUC16, MACC1, and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumor suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumor effect of drug treatment.
Pituitary neuroendocrine tumours (PitNETs) are neoplasms of the pituitary that overproduce hormones or cause unspecific symptoms due to mass effect. Growth hormone overproducing GH-producing PitNETs cause acromegaly leading to connective tissue, metabolic or oncologic disorders. The medical treatment of acromegaly is somatostatin analogues (SSA) in specific cases combined with dopamine agonists (DA), but almost half of patients display partial or full SSA resistance and potential causes of this are unknown. In this study we investigated transcriptomic landscape of GH-producing PitNETs on several levels and functional models—tumour tissue of patients with and without SSA preoperative treatment, tumour derived pituispheres and GH3 cell line incubated with SSA to study effect of medication on gene expression. MGI sequencing platform was used to sequence total RNA from PitNET tissue, pituispheres, mesenchymal stromal stem-like cells (MSC), and GH3 cell cultures, and data were analysed with Salmon—DeSeq2 pipeline. We observed that the GH-producing PitNETs have distinct changes in growth hormone related pathways related to its functional status alongside inner cell signalling, ion transport, cell adhesion and extracellular matrix characteristic patterns. In pituispheres model, treatment regimens (octreotide and cabergoline) affect specific cell proliferation (MKI67) and core functionality pathways (RYR2, COL8A2, HLA-G, ARFGAP1, TGFBR2). In GH3 cells we observed that medication did not have transcriptomic effects similar to preoperative treatment in PitNET tissue or pituisphere model. This study highlights the importance of correct model system selection for cell transcriptomic profiling and data interpretation that could be achieved in future by incorporating NGS methods and detailed cell omics profiling in PitNET model research.
Группа препаратов, основанных на инкретиновых эффектах (аналоги глюкагоноподобного пептида-1 аГПП1) и ингибиторы дипептидилпептидазы-4, иДПП4), обладают способностью увеличивать репликацию β -клеток и ингибировать апоптоз. Инкретиномиметики способны влиять на функцию α-клеток, восстанавливая физиологическую регуляцию уровня глюкагона. При этом эффекты инкретиномиметиков на пролиферацию/апоптоз α-клеток изучены недостаточно. В единичных исследованиях отмечено увеличение пролиферации α-клеток, но факторы, определяющие выраженность этих изменений, не установлены. Цель - оценка влияния терапии инкретиномиметиками разной продолжительности на морфологические и функциональные особенности α- и β-клеток поджелудочной железы крыс (12 мес) с сахарным диабетом 2-го типа (СД 2-го типа). Методика. У крыс (возраст 12 мес), находящихся на высокожировой диете, моделировали стрептозотоцин-никотинамид-индуцированный СД 2-го типа. Животные получали инкретиномиметки: агонист рецепторов ГПП1 (лираглутид) или ингибитор ДПП4 (вилдаглиптин) в течение 4,10 и 24 нед. Макроскопически оценивали наличие/отсутствие видимых изменений поджелудочной железы. Парафиновые срезы поджелудочной железы окрашивали гематоксилином и эозином для оценки микроструктуры ткани. Проводили иммуногистохимическое (ИГХ) исследование с применением антител (Abcam) к глюкагону, инсулину в аппарате для ИГХ «Thermo Autostainer 720». После процедуры ИГХ ядра доокрашивали гематоксилином в аппарате для окраски гистологических микропрепаратов LeicaST5020. Результаты. Показано, что без лечения сахарный диабет приводил к снижению числа α- и β- клеток на всех сроках наблюдения. Лечение диабета лираглутидом и вилдаглиптином приводило к восстановлению пула как α-, так и β- клеток. При сравнении групп, получавших терапию и без терапии, с группой контроля значимые отличия сохранялись по количеству как α-, так и β-клеток во все сроки наблюдения. Через 4 нед в группах, получавших лираглутид, количество α-клеток стало сопоставимым с таковым в группе контроля, но количество β-клеток оставалось сниженным. После 10 и 24 нед терапии статистически значимой разницы между группой контроля и животными, получавшими терапию лиралутидом, по количеству как β-, так и α- клеток не выявлено. Заключение. Полученные данные свидетельствуют в пользу того, что терапия инкретиномиметиками способствует восстановлению пула как α-, так и β-клеток поджелудочной железы. Drugs based on incretin effects, including analogs of glucagon-like peptide-1 (GLP1) and dipeptidyl peptidase-4 inhibitors (DPP4), increase replication and inhibit apoptosis of β-cells. Incretin mimetics can influence the function of α-cells thereby restoring physiological regulation of glucagon. However, effects of incretin mimetics on proliferation and apoptosis of α-cells are understudied. A few studies reported increased α-cell proliferation, but the factors determining the degree of these changes were not established. Aim. To evaluate the effect of incretin mimetic treatment of different duration on morphological and functional features of pancreatic α- and β-cells of 12-month-old rats with type 2 diabetes mellitus. Method. Streptozotocin-nicotinamide-induced type 2 diabetes mellitus was modeled in 12-month-old rats receiving a high-fat diet. The rats were treated with incretin mimetics, a GLP-1 receptor antagonist (Liraglutide) or a DPP-4 inhibitor (Vildagliptin) for 4, 10 or 24 weeks. Paraffin sections of the pancreas were stained with hematoxylin-eosin to evaluate the tissue microstructure. An immunohistochemical (IHC) study was performed using glucagon and insulin antibodies (Abcam) with a Thermo Autostainer 720 IHC instrument. After the IHC procedure, nuclei were additionally stained with hematoxylin using a Leica ST5020 stainer for histological micropreparations. Results. Untreated diabetes mellitus resulted in decreased numbers of α- and β-cells at all timepoints of observation. The treatments with Liraglutide and Vildagliptin recovered the pools of α- and β-cells. Significant differences of both treated and untreated diabetic groups from the control group in the number of α- and β-cells remained at all timepoints of observation. In the Liraglutide group at 4 weeks, the number of α-cells became comparable with the control group, but the number of β-cells remained lower. At 10 and 24 weeks of treatment, statistically significant differences between the control group and the Liraglutide or Vildagliptin treatment groups in the number of α- and β-cells were not observed. Conclusion. The results of the study suggested that the incretin mimetic therapy provided recovery of both α and β-cell pools in the pancreas.
Aim: to study the morphology of pancreatic islet cells in rats aged more than 1 year with experimental type 2 diabetes (T2D) that receive sulphonylureas for a long time.Patients and Methods: albino laboratory rats aged more than 1 year (equal to 40 years in humans) were enrolled in this experimental study. Streptozotocin and nicotinamide were administered to induce T2D (streptozotocin-nicotinamide-induced diabetic rats). The animals were divided into four groups, i.e., healthy controls, T2D with no treatment, T2D treated with glibenclamide, and T2D treated with gliclazide. After the experimental study, immunohistochemistry with the antibodies against insulin, glucagon, and Ki-67 was performed. Morphometric analysis was performed using microphotographs. Insulin-, glucagon- and Ki-67-positive cells in islets were calculated.Results: by the 24th week of the study, the ratio of the total volume of α-cells to islet area in rats receiving glibenclamide was similar compared to diabetic rats receiving no treatment (p=0.75). Meanwhile, the significant reduction in the number of α-cells was reported in rats receiving gliclazide compared to diabetic rats receiving no treatment (p=0.000004). Moreover, the number of α-cells was equal to healthy controls. The total volume of β-cells remained unchanged in rats receiving glibenclamide or gliclazide as compared with diabetic rats with no treatment.Conclusion: our findings demonstrate that older animals (>1 year of age) are characterized by the changes in the ratio of α- and β-cells that are similar to the adults with T2D, i.e., the reduction in the percentage of β-cells and the increase in the percentage of α-cells. Long-term treatment with sulphonylureas does not result in the additional changes in the number and total volume of β-cells (rats receiving sulphonylureas for 24 weeks are similar to T2D rats with no treatment in terms of the volume of β-cells). However, 24-week treatment with gliclazide results in the normalization of the total volume of α-cells, and their number is comparable to healthy controls.KEYWORDS: sulphonylureas, α-cells, β-cells, pancreas, type 2 diabetes. FOR CITATION: Tuchina T.P., Skotnikova K.P., Vtorushina A.A. et al. Morphology of pancreatic endocrine cells in rats with type 2 diabetes after the long-term treatment with sulphonylureas. Russian Medical Inquiry. 2020;4(6):329–333. DOI: 10.32364/2587-6821-2020-4-6-329-333.
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