Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘type 1 diabetes’


Clinical Trials Could Lead to FDA Approval for Artificial Pancreas

 Reported by: Irina Robu, PhD

Approximately 1.25 million American have type 1 diabetes accroding to the U.S. Centers for Disease Control and Prevention. A device that automatically monitors and regulates blood-sugar levels in people with type 1 diabetes developed by University of Virginia School of Medicine undergo two clinical trials starting early 2016.

The goal of the artificial pancreas is to eliminate the need for people with type 1 diabetes to stick their fingers multiple times daily to check their blood-sugar levels and to inject insulin manually.The artificial pancreas is designed to oversee and adjust insulin delivery as needed. At the center of the artificial pancreas platform is a reconfigured smartphone running advanced algorithms that is linked wirelessly to a blood-sugar monitor and an insulin pump, as well as a remote-monitoring site. People with the artificial pancreas can also access assistance via telemedicine.

Beneficial results from these long-term clinical trials examining how the artificial pancreas works in real-life settings could lead the U.S. Food and Drug Administration and other international regulatory groups to approve the device for use by people with type 1 diabetes, whose bodies do not produce enough insulin. The trials will conducted at nine locations in the U.S. and Europe sustained by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

The first study – the International Diabetes Closed-Loop trial – will test technology developed at UVA by a research team led by Boris Kovatchev, director of the UVA Center for Diabetes Technology. That technology has been refined for clinical use by TypeZero Technologies, a startup company in Charlottesville that has licensed the UVA system.
The second trial will examine a new control algorithm developed by the team of Dr. Francis Doyle III at the Harvard John A. Paulson School of Engineering and Applied Sciences to test whether it further improves control of blood-sugar levels.

Along with UVA, the artificial pancreas will be tested at eight additional sites: Harvard University, Mount Sinai School of Medicine, Mayo Clinic, University of Colorado, Stanford University, University of Montpellier in France, University of Padova in Italy and Academic Medical Center at the University of Amsterdam in The Netherlands.

Source
Advertisements

Read Full Post »


Reporter: Ritu Saxena, Ph.D.

Diabetes currently affects more than 336 million people worldwide, with healthcare costs by diabetes and its complications of up to $612 million per day in the US alone.  The islets of Langerhans, miniature endocrine organs within the pancreas, are essential regulators of blood glucose homeostasis and play a key role in the pathogenesis of diabetes.  Islets of Langerhans are composed of several types of endocrine cells.  The α- and β-cells are the most abundant and also the most important in that they secrete hormones (glucagon and insulin, respectively) crucial for glucose homeostasis (Bosco D, et al, Diabetes, May 2010;59(5):1202-10).

Diabetes is a ‘bihormonal’ disease, involving both insulin deficiency and excess glucagon.  For decades, insulin deficiency was considered to be the sole reason for diabetes; however, recent studies emphasize excess glucagon as an important part of diabetes etiology.  Thus, insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development.  Increasing the number of insulin-producing β cells while decreasing the number of glucagon-producing α cells, either in vitro in donor pancreatic islets before transplantation into type 1 diabetics or in vivo in type 2 diabetics, is a promising therapeutic avenue.  A huge leap has been taken in this direction by the researchers at the University of Pennsylvania (Philadelphia, PA) in collaboration with Oregon Health and Science University (Portland, OR), USA by demonstrating that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets.  In fact, the 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.  The research findings were published in the Journal of Clinical Investigation.

Study design: First step was to study and analyze the epigenetic and transcriptional landscape of human pancreatic human pancreatic α, β, and exocrine cells using ChIP and RNA sequencing.  Study design for determination of the transcriptome and differential histone marks included the dispersion and FACS to of human islets to obtain cell populations highly enriched for α, β, and exocrine (duct and acinar) cells.  Then, chromatin was prepared for ChIP analysis using antibodies for histone modifications, H3K4me3 (represents gene activation) and H3K27me3 (represents gene repression).  RNA-Sequencing analysis was then performed to determine mRNA and lncRNA.  Sample purity was confirmed using qRT-PCR of insulin and glucagon expression levels of the individual α and β cell population revealing high sample purity.

Results:

  • Long noncoding transcripts: Long noncoding RNA molecules have been implicated as important developmental regulators, cell lineage allocators, and contributors to disease development.  The authors discovered 12 cell–specific and 5 α cell–specific noncoding (lnc) transcripts, indicative of the valuable research resource represented from transcriptome data.  Recently discovered lncRNA molecules in islets are regulated during development and dysregulated in type 2 diabetic islets.
  • Monovalent histone modification landscapes shared among three cell types:  Monovalent H3K4me3-enriched regions, indicative of gene activation, were identified and compared in α, β, and exocrine cells.  Strikingly, the vast majority of monovalently H3K4me3-marked genes were shared among the 3 pancreatic cell lineages (83%–95%), reflecting both their related function in protein secretion and common embryonic descent. Similarly, a high degree of overlap was observed in H3K27me3 modification patterns in all the three cell types (73%–83%).
  • Bivalent histone modifications (H3K4me3 and H3K27me3) were high in α cells: Bernstein colleagues observed bivalent marks to be common in undifferentiated cells, such as ES cells and pluripotent progenitor cells, and in most cases, one of the histone modification marks was lost during differentiation, accompanying lineage specification (Bernstein BE, et al, Cell, 21 Apr 2006; 125(2):315-26).  α cells exhibited many more genes bivalently marked, followed by β cells and exocrine cells.  Bivalent state was remarkably similar to that of hESC, suggesting a more plastic epigenomic state for α cells.
  • Monovalent histone modifications were high in β cells: Thousands of the genes that were in bivalent state in α cells were in a monovalent state, carrying only the activating or repressing mark.
  • Inhibition of histone methyltransferases led to partial cell-fate conversion: Adenosine dialdehye (Adox), a drug that interferes with histone methylation and decreases H3K27me3, when administered in human islet tissue, led to decrease of H3K27me3 enrichment at the 3 gene loci that are originally expressed bivalently in α cells and monovalently in β cells:  MAFA, PDX1 and ARX.  Adox resulted in the occasional cooccurrence of glucagon and insulin granules within the same islet cell, which was not observed in untreated islets.  Thus, inhibition of histone methyltransferases leads to partial endocrine cell-fate conversion.

Conclusion:  α cells have been reprogrammed into β cell fate in various mouse models.  The reason, as proposed by the authors, might be the presence of more bivalently marked genes that confers a more plastic epigenomic state of the cells that probably drives them to the β cell fate.  Therefore, using epigenomic information of different cell types in pancreatic islets and harnessing it for subsequent manipulation of their epigenetic signature could be utilized to reprogram cells and hence provide a path for diabetes therapy.

Source: Bramswig NC, et al, Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest, 22 Feb 2013. pii: 66514.

Related reading on Pharmaceutical Intelligence:

Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes

Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reprogramming cell fate

CRACKING THE CODE OF HUMAN LIFE: Recent Advances in Genomic Analysis and Disease – Part IIC

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Genome-Wide Detection of Single-Nucleotide and Copy-Number Variation of a Single Human Cell

SNAP: Predict Effect of Non-synonymous Polymorphisms: How well Genome Interpretation Tools could Translate to the Clinic

Genomic Endocrinology and its Future

Read Full Post »