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Genome Research Feb 2017Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or...
Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.
Topics: Carrier Proteins; Diabetes Mellitus, Type 2; Gene Expression Profiling; Gene Expression Regulation; Humans; Islets of Langerhans; Signal Transduction; Single-Cell Analysis; Transcriptome
PubMed: 27864352
DOI: 10.1101/gr.212720.116 -
Current Diabetes Reports Nov 2019Common genetic variants that associate with type 2 diabetes risk are markedly enriched in pancreatic islet transcriptional enhancers. This review discusses current... (Review)
Review
PURPOSE OF REVIEW
Common genetic variants that associate with type 2 diabetes risk are markedly enriched in pancreatic islet transcriptional enhancers. This review discusses current advances in the annotation of islet enhancer variants and their target genes.
RECENT FINDINGS
Recent methodological advances now allow genetic and functional mapping of diabetes causal variants at unprecedented resolution. Mapping of enhancer-promoter interactions in human islets has provided a unique appreciation of the complexity of islet gene regulatory processes and enabled direct association of noncoding diabetes risk variants to their target genes. The recently improved human islet enhancer annotations constitute a framework for the interpretation of diabetes genetic signals in the context of pancreatic islet gene regulation. In the future, integration of existing and yet to come regulatory maps with genetic fine-mapping efforts and in-depth functional characterization will foster the discovery of novel diabetes molecular risk mechanisms.
Topics: Diabetes Mellitus, Type 2; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Techniques; Genome-Wide Association Study; Humans; Islets of Langerhans; Promoter Regions, Genetic
PubMed: 31754873
DOI: 10.1007/s11892-019-1230-6 -
Islets Dec 2022The islets of Langerhans are highly organized structures that have species-specific, three-dimensional tissue architecture. Islet architecture is critical for proper... (Review)
Review
The islets of Langerhans are highly organized structures that have species-specific, three-dimensional tissue architecture. Islet architecture is critical for proper hormone secretion in response to nutritional stimuli. Islet architecture is disrupted in all types of diabetes mellitus and in cadaveric islets for transplantation during isolation, culture, and perfusion, limiting patient outcomes. Moreover, recapitulating native islet architecture remains a key challenge for generation of islets from stem cells. In this review, we discuss work that has led to the current understanding of determinants of pancreatic islet architecture, and how this architecture is maintained or disrupted during tissue remodeling in response to normal and pathological metabolic changes. We further discuss both empirical and modeling data that highlight the importance of islet architecture for islet function.
Topics: Cell Communication; Diabetes Mellitus; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Stem Cells
PubMed: 35258417
DOI: 10.1080/19382014.2022.2030649 -
Diabetologia Jul 2022The central and peripheral nervous systems play critical roles in regulating pancreatic islet function and glucose metabolism. Over the last century, in vitro and in... (Review)
Review
The central and peripheral nervous systems play critical roles in regulating pancreatic islet function and glucose metabolism. Over the last century, in vitro and in vivo studies along with examination of human pancreas samples have revealed the structure of islet innervation, investigated the contribution of sympathetic, parasympathetic and sensory neural pathways to glucose control, and begun to determine how the structure and function of pancreatic nerves are disrupted in metabolic disease. Now, state-of-the art techniques such as 3D imaging of pancreatic innervation and targeted in vivo neuromodulation provide further insights into the anatomy and physiological roles of islet innervation. Here, we provide a summary of the published work on the anatomy of pancreatic islet innervation, its roles, and evidence for disordered islet innervation in metabolic disease. Finally, we discuss the possibilities offered by new technologies to increase our knowledge of islet innervation and its contributions to metabolic regulation.
Topics: Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Pancreas
PubMed: 35348820
DOI: 10.1007/s00125-022-05691-9 -
Molecular Metabolism Sep 2018The sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy. (Review)
Review
BACKGROUND
The sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy.
SCOPE OF THE REVIEW
This review focuses on clinical and experimental sex differences in islet cell biology and dysfunction during development and in adulthood in human and animal models. We discuss sex differences in β-cell and α-cell function, heterogeneity, and dysfunction. We cover sex differences in communication between gonads and islets and islet-cell immune interactions. Finally, we discuss sex differences in β-cell programming by nutrition and other environmental factors during pregnancy.
MAJOR CONCLUSIONS
Important sex differences exist in islet cell function and susceptibility to failure. These differences represent sex-related biological factors that can be harnessed for gender-based prevention of and therapy for diabetes.
Topics: Animals; Diabetes Mellitus; Gonadal Hormones; Humans; Islets of Langerhans; Sex Characteristics
PubMed: 29891438
DOI: 10.1016/j.molmet.2018.05.017 -
The Journal of Histochemistry and... Aug 2015
Topics: Animals; Histocytochemistry; Humans; Islets of Langerhans
PubMed: 26216132
DOI: 10.1369/0022155415586442 -
Journal of Molecular Medicine (Berlin,... Apr 2020The pancreatic islet is a dense cellular network comprised of several cell types with endocrine function vital in the control of glucose homeostasis, metabolism, and... (Review)
Review
The pancreatic islet is a dense cellular network comprised of several cell types with endocrine function vital in the control of glucose homeostasis, metabolism, and feeding behavior. Within the islet, endocrine hormones also form an intricate paracrine network with supportive cells (endothelial, neuronal, immune) and secondary signaling molecules regulating cellular function and survival. Modulation of these signals has potential consequences for diabetes development, progression, and therapeutic intervention. Beta cell loss, reduced endogenous insulin secretion, and dysregulated glucagon secretion are hallmark features of both type 1 and 2 diabetes that not only impact systemic regulation of glucose, but also contribute to the function and survival of cells within the islet. Advancing research and technology have revealed new islet biology (cellular identity and transcriptomes) and identified previously unrecognized paracrine signals and mechanisms (somatostatin and ghrelin paracrine actions), while shifting prior views of intraislet communication. This review will summarize the paracrine signals regulating islet endocrine function and survival, the disruption and dysfunction that occur in diabetes, and potential therapeutic targets to preserve beta cell mass and function.
Topics: Animals; Cell Survival; Ghrelin; Glucagon-Secreting Cells; Glucose; Glycogen; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Pancreatic Polypeptide; Paracrine Communication; Signal Transduction; Somatostatin; Somatostatin-Secreting Cells
PubMed: 32067063
DOI: 10.1007/s00109-020-01887-x -
Shock (Augusta, Ga.) Sep 2016Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of... (Review)
Review
Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of Langerhans. While typically representing only 1% to 2% of the total pancreatic mass, the islets have a remarkable ability to adapt to disparate situations demanding a change in hormone release, such as peripheral insulin resistance. There are many different routes to the onset of insulin resistance, including obesity, lipodystrophy, glucocorticoid excess, and the chronic usage of atypical antipsychotic drugs. All of these situations are coupled to an increase in pancreatic islet size, often with a corresponding increase in insulin production. These adaptive responses within the islets are ultimately intended to maintain glycemic control and to promote macronutrient homeostasis during times of stress. Herein, we review the consequences of specific metabolic trauma that lead to insulin resistance and the corresponding adaptive alterations within the pancreatic islets.
Topics: Animals; Antipsychotic Agents; Glucocorticoids; Humans; Insulin Resistance; Islets of Langerhans; Lipodystrophy; Obesity
PubMed: 26974425
DOI: 10.1097/SHK.0000000000000607 -
American Journal of Transplantation :... Sep 2018Pancreatic-islet transplantation is a safe and noninvasive therapy for type 1 diabetes. However, the currently applied site for transplantation, ie, the liver, is not... (Review)
Review
Pancreatic-islet transplantation is a safe and noninvasive therapy for type 1 diabetes. However, the currently applied site for transplantation, ie, the liver, is not the optimal site for islet survival. Because the human body has shortcomings in providing an optimal site, artificial transplantation sites have been proposed. Such an artificial site could consist of a polymeric scaffold that mimics the pancreatic microenvironment and supports islet function. Recently, remarkable progress has been made in the technology of engineering scaffolds. The polymer-islet interactions, the site of implantation, and scaffold prevascularization are critical factors for success or failure of the scaffolds. This article critically reviews these factors while also discussing translation of experimental studies to human application as well as the steps required to create a clinically applicable prevascularized, retrievable scaffold for implantation of insulin-producing cells for treatment of type 1 diabetes mellitus.
Topics: Animals; Diabetes Mellitus, Type 1; Graft Survival; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Polymers; Tissue Scaffolds
PubMed: 29790274
DOI: 10.1111/ajt.14942 -
Archives of Biochemistry and Biophysics Jan 2016Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of... (Review)
Review
Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to metabolic fuels, hormones, or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes gained from metabolomics studies.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Islets of Langerhans; Metabolomics
PubMed: 26116790
DOI: 10.1016/j.abb.2015.06.013