scholarly journals Ca2+ oscillations, waves, and networks in islets from human donors with and without type 2 diabetes

2021 ◽  
Author(s):  
Marko Gosak ◽  
Richard Yan-Do ◽  
Haopeng Lin ◽  
Patrick E Macdonald ◽  
Andraz Stozer
Keyword(s):  
Type 2 Diabetes ◽  
Calcium Imaging ◽  
Large Fraction ◽  
Human Islets ◽  
Calcium Oscillations ◽  
Calcium Waves ◽  
Intercellular Coupling ◽  
Reduced Activity ◽  
Glucose Dependence

Pancreatic islets are highly interconnected structures that produce pulses of insulin and other hormones, maintaining normal homeostasis of glucose and other nutrients. Normal stimulus-secretion and intercellular coupling are essential to regulated secretory responses and these hallmarks are known to be altered in diabetes. In the present study, we used calcium imaging of isolated human islets to assess their collective cell behavior. The activity occurred in the form of calcium oscillations, was synchronized across different regions of islets through calcium waves, and was glucose-dependent: higher glucose enhanced the activity, elicited a greater proportion of global calcium waves, and led to denser and less fragmented functional networks. Hub regions were identified in stimulatory conditions, and they represented the most active islet regions. Moreover, calcium waves were found to be initiated in different subregions and the roles of initiators and hubs did not overlap. In type 2 diabetes, glucose-dependence was retained, but a reduced activity, locally restricted waves, and more segregated networks were detected compared with control islets. Interestingly, hub regions seemed to suffer the most by losing a disproportionately large fraction of connections. These changes affected islets from donors with diabetes in a heterogeneous manner.

scholarly journals Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes

2020 ◽  
Vol 39 ◽  
pp. 101014 ◽  
Author(s):  
Scott A. Campbell ◽  
Dominic P. Golec ◽  
Matt Hubert ◽  
Janyne Johnson ◽  
Nicole Salamon ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Human Islets ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Matthias Thurner ◽  
Martijn van de Bunt ◽  
Jason M Torres ◽  
Anubha Mahajan ◽  
Vibe Nylander ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Human Islets ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Genome Wide Association Studies

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

scholarly journals Research-Focused Isolation of Human Islets From Donors With and Without Diabetes at the Alberta Diabetes Institute IsletCore

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 560-569 ◽  
Author(s):  
James Lyon ◽  
Jocelyn E. Manning Fox ◽  
Aliya F. Spigelman ◽  
Ryekjang Kim ◽  
Nancy Smith ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycated Hemoglobin ◽  
Organ Procurement ◽  
Human Islets ◽  
Human Islet ◽  
Islet Function ◽  
Small Contribution ◽  
Islet Isolation ◽  
Diabetes Status

Abstract Recent years have seen an increased focus on human islet biology, and exciting findings in the stem cell and genomic arenas highlight the need to define the key features of mature human islets and β-cells. Donor and organ procurement parameters impact human islet yield, although for research purposes islet yield may be secondary in importance to islet function. We examined the feasibility of a research-only human islet isolation, distribution, and biobanking program and whether key criteria such as cold ischemia time (CIT) and metabolic status may be relaxed and still allow successful research-focused isolations, including from donors with type 1 diabetes and type 2 diabetes. Through 142 isolations over approximately 5 years, we confirm that CIT and glycated hemoglobin each have a weak negative impacts on isolation purity and yield, and extending CIT beyond the typical clinical isolation cutoff of 12 hours (to ≥ 18 h) had only a modest impact on islet function. Age and glycated hemoglobin/type 2 diabetes status negatively impacted secretory function; however, these and other biological (sex, body mass index) and procurement/isolation variables (CIT, time in culture) appear to make only a small contribution to the heterogeneity of human islet function. This work demonstrates the feasibility of extending acceptable CIT for research-focused human islet isolation and highlights the biological variation in function of human islets from donors with and without diabetes.

scholarly journals A Systems Genetics Approach Identifies Genes and Pathways for Type 2 Diabetes in Human Islets

2012 ◽  
Vol 16 (1) ◽  
pp. 122-134 ◽  
Author(s):  
Jalal Taneera ◽  
Stefan Lang ◽  
Amitabh Sharma ◽  
Joao Fadista ◽  
Yuedan Zhou ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Human Islets ◽  
Systems Genetics

scholarly journals Insights Into the Molecular Mechanism for Type 2 Diabetes Susceptibility at the KCNQ1 Locus From Temporal Changes in Imprinting Status in Human Islets

Diabetes ◽  
2012 ◽  
Vol 62 (3) ◽  
pp. 987-992 ◽  
Author(s):  
M. E. Travers ◽  
D. J. G. Mackay ◽  
M. Dekker Nitert ◽  
A. P. Morris ◽  
C. M. Lindgren ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Mechanism ◽  
Human Islets ◽  
Temporal Changes ◽  
Diabetes Susceptibility

scholarly journals Amyloid precursor protein in pancreatic islets

2017 ◽  
Vol 235 (1) ◽  
pp. 49-67 ◽  
Author(s):  
Joshua A Kulas ◽  
Kendra L Puig ◽  
Colin K Combs
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Precursor Protein ◽  
Pancreatic Islets ◽  
Culture Media ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Precursor Protein ◽  
Protein Levels ◽  
Glucose Levels

The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP−/− and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion

2004 ◽  
Vol 286 (6) ◽  
pp. E1023-E1031 ◽  
Author(s):  
Isabelle Leclerc ◽  
Wolfram W. Woltersdorf ◽  
Gabriela da Silva Xavier ◽  
Rebecca L. Rowe ◽  
Sarah E. Cross ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Pancreatic Islets ◽  
Human Islets ◽  
Β Cells ◽  
Min6 Cells ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761–774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2–1 mM) activated AMPK in both human islets and MIN6 β-cells in parallel with an inhibition of insulin secretion, whereas leptin (10–100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal β-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.

scholarly journals Minireview: Intraislet Regulation of Insulin Secretion in Humans

2013 ◽  
Vol 27 (12) ◽  
pp. 1984-1995 ◽  
Author(s):  
Guy A. Rutter ◽  
David J. Hodson
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Activity ◽  
Cell Communication ◽  
Human Islets ◽  
Β Cells ◽  
Cell Cell

The higher organization of β-cells into spheroid structures termed islets of Langerhans is critical for the proper regulation of insulin secretion. Thus, rodent β-cells form a functional syncytium that integrates and propagates information encoded by secretagogues, producing a “gain-of-function” in hormone release through the generation of coordinated cell-cell activity. By contrast, human islets possess divergent topology, and this may have repercussions for the cell-cell communication pathways that mediate the population dynamics underlying the intraislet regulation of insulin secretion. This is pertinent for type 2 diabetes mellitus pathogenesis, and its study in rodent models, because environmental and genetic factors may converge on these processes in a species-specific manner to precipitate the defective insulin secretion associated with glucose intolerance. The aim of the present minireview is therefore to discuss the structural and functional underpinnings that influence insulin secretion from human islets, and the possibility that dyscoordination between individual β-cells may play an important role in some forms of type 2 diabetes mellitus.

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