Cycling Alpha Cells in Regenerative Drug-Treated Human Pancreatic Islets Serve As Key Beta Cell Progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266427 | GEO | 2024/12/05
REPOSITORIES: GEO
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Project description:537 million people globally suffer from diabetes. Insulin-producing beta cells are reduced in number in most people with diabetes, but the majority still have some residual beta cells. Disappointingly, none of the many diabetes drugs in common use can increase human beta cell numbers. Recently, small molecules that inhibit the kinase, Dual Tyrosine-Regulated Kinase 1A (DYRK1A), have been shown to induce immunohistochemical markers of human beta cell replication, and this is enhanced by drugs that stimulate the GLP1 receptor (GLP1R) on beta cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human beta cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human beta cell survival. Here, we demonstrate for the first time that combination of a DYRK1A inhibitor with exendin-4 increases actual human beta cell mass in vivo by 400-700% in diabetic and non-diabetic mice over three months, reverses diabetes in vivo, without significant alteration in human alpha cell mass. The augmentation in human beta cell mass occurs through mechanisms that include enhanced human beta cell proliferation, function, and survival. The increase in human beta cell survival is mediated in part by the islet prohormone, VGF. Taken together, these findings demonstrate the remarkable therapeutic potential and safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.
2024-06-28 | GSE249310 | GEO
Project description:Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type–specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes. Pancreatic islets were collected post-mortem from 6 human donors and subjected to FACS to separate populations of alpha, beta, and exocrine cells. Depending on the availability of resulting material, sorted islet cell populations were used for H3K4me3, H3K27me3 ChIP-seq, or RNA-seq analysis. All ChIP-seq samples have a corresponding input from the same sample.
2013-08-28 | E-GEOD-50386 | biostudies-arrayexpress
Project description:Rodent models are widely used to study diabetes. Yet, significant gaps remain in our understanding of mouse islet physiology that reduce their accuracy as a model for human islet disease. We generated comprehensive transcriptomes of mouse beta and alpha cells using a novel bitransgenic mouse model generated for this purpose. This enables systematic comparison across thousands of genes between the two major endocrine cell types of the islets of Langerhans whose principal hormones are of cardinal importance for glucose homeostasis. Our data leveraged against similar data for human beta cells reveal a core common beta cell transcriptome of 9900+ genes and marked differences in the repertoire of receptors and long non-coding RNAs between mouse and human beta cells. The comprehensive comparison of the (dis)similarities between mouse and human beta cells represents an invaluable resource to boost the effectiveness by which rodent models offer guidance in finding cures for human diabetes. FACS purified alpha and beta cells from the same islets. Islets were isolated from bitransgenic offspring of a cross between mIns1-H2b-mCherry and S100b-eGFP transgenic reporter mice that mark beta and alpha cells, respectively. Islets from two replicate groups of 10 or 11 animals were pooled by sex to obtain sufficient material. Pooled islets were dissociated, sorted and collect in Trizol for RNA isolation and library construction.
2014-09-16 | E-GEOD-54973 | biostudies-arrayexpress
Project description:Rodent models are widely used to study diabetes. Yet, significant gaps remain in our understanding of mouse islet physiology. We generated comprehensive transcriptomes of mouse delta, beta and alpha cells using two separate triple transgenic mouse models generated for this purpose. This enables systematic comparison across thousands of genes between the three major endocrine cell types of the islets of Langerhans whose principal hormones control nutrient homeostasis. FACS purified delta or alpha cells and beta cells from the same islets. Islets were isolated from triple transgenic offspring of a cross between mIns1-H2b-mCherry (Jax # 028589) and either Sst-Cre (delta) or Gcg-cre (alpha) cells and a floxed YFP allele to label delta or alpha cells, respectively. Islets from replicate groups of 10 to 12 triple transgenic animals for each group were pooled by sex to obtain sufficient material. Pooled islets were dissociated, sorted and collect in Trizol for RNA isolation and library construction.
2016-06-26 | E-GEOD-80673 | biostudies-arrayexpress
Project description:Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes a deterioration in beta cell function that disrupts glucose balance and signals the progression to diabetes 1. Glucagon like Peptide 1 (GLP1) agonists improve glucose tolerance in insulin resistance, although some individuals are unresponsive to treatment. Here we show that increases in GLP1 during feeding promote beta cell function in part through the PKA-mediated activation of CREB and its coactivator CRTC2 2. Mice with a knockout of CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia associated with high fat or high carbohydrate diet feeding disrupted cAMP signaling in pancreatic islets. Indeed, prolonged elevations in circulating glucose concentrations interfered with CREB signaling by activating the mTOR pathway and triggering the hypoxia inducible factor (HIF1)-dependent induction of the Protein Kinase A Inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity 3. As disruption of the PKIB gene restored glucose tolerance and insulin secretion in obesity, our results demonstrate how cross-talk between nutrient and hormonal pathways contributes to loss of pancreatic islet function in insulin resistance. Rat insulinoma cells were used to interrogate the impact of glucose exposure and CREB activity on cAMP dependent gene regulation in the pancreatic beta cells
2015-02-23 | E-GEOD-60158 | biostudies-arrayexpress
Project description:Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type–specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.
2013-08-28 | GSE50386 | GEO
Project description:Dedifferentiation of pancreatic beta cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. We employed single-cell RNAseq to detail the maturation program of alpha and beta cells during human ontogeny. We show that although both alpha and beta cells mature in part by repressing non-endocrine genes, alpha-cells retain hallmarks of an immature state, while beta-cells attain a full beta-cell specific gene expression program. In islets from T2D donors, both alpha- and beta-cells return to a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes while increasing expression of exocytosis, inflammation and stress response signaling pathways. These changes support the increased proportion of beta-cells displaying suboptimal function observed in T2D islets. These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.
2020-10-01 | GSE154126 | GEO
Project description:Many patients with type 1 diabetes (T1D) have residual beta cells producing small amounts of C-peptide long after disease onset, but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual beta cells and alpha cells persisting in the islet endocrine compartment are largely unknown due to difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant beta cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D alpha cells was markedly reduced and these cells had alterations in transcription factors constituting and alpha and beta cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of alpha-to-beta cell conversion. These results suggest a new explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
2017-12-12 | GSE106148 | GEO
Project description:The activity of pancreatic islets’ insulin-producing β-cells is closely regulated by systemic cues and, locally, by adjacent islet hormone-producing “non-β-cells” (namely α-, δ- and γ-cells). Still, it is unclear whether the presence of the non-β-cells is a requirement for accurate insulin secretion. Here, we generated and studied a mouse model in which adult islets are exclusively composed of β-cells, and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation. They exhibited enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was like in intact islets, both in homeostatic conditions and upon extreme insulin demand. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of human islets comprising all four cell types. Together, the findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. This is particularly relevant in diabetes, where non-β-cells become dysfunctional and worsen the disease’s pathophysiology. These results support efforts aimed at developing diabetes treatments by generating β-like cell clusters devoid of non-β-cells, as for example from human embryonic stem cells and/or by in situ conversion of non-β-cells into insulin producers.
2024-07-19 | GSE226479 | GEO
Project description:Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes a deterioration in beta cell function that disrupts glucose balance and signals the progression to diabetes 1. Glucagon like Peptide 1 (GLP1) agonists improve glucose tolerance in insulin resistance, although some individuals are unresponsive to treatment. Here we show that increases in GLP1 during feeding promote beta cell function in part through the PKA-mediated activation of CREB and its coactivator CRTC2 2. Mice with a knockout of CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia associated with high fat or high carbohydrate diet feeding disrupted cAMP signaling in pancreatic islets. Indeed, prolonged elevations in circulating glucose concentrations interfered with CREB signaling by activating the mTOR pathway and triggering the hypoxia inducible factor (HIF1)-dependent induction of the Protein Kinase A Inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity 3. As disruption of the PKIB gene restored glucose tolerance and insulin secretion in obesity, our results demonstrate how cross-talk between nutrient and hormonal pathways contributes to loss of pancreatic islet function in insulin resistance.
2015-02-23 | GSE60158 | GEO