Thursday, February 9, 2017

New Genes Predisposing to Type 2 Diabetes: Single Cell Transcriptome Analysis

Numerous studies have been carried out in the past 10-15 years utilizing a technology referred to as "genome-wide association study" (GWAS) to define subtle differences in the DNA sequences of genes in normal individuals and those with type 2 diabetes. These studies were/are aimed at determining if there are any correlations, at the level of the genome, with the likelihood of someone developing type 2 diabetes beyond the most obvious correlations of life style and diet. These GWAS data have indeed found numerous genes harboring nucleotide sequence differences (referred to as polymorphisms), many of which encode proteins critically involved in the overall processes of pancreatic endocrine (hormone) function and whole body metabolic regulation. Many of these genes can be found in the Diabetes page of my website:

http://themedicalbiochemistrypage.org/diabetes.php#type2genetics

It is important to understand that the pancreas is the endocrine organ that secretes insulin in response to increases in blood glucose (sugar) and glucagon in response to low blood glucose. These are not the only hormones secreted by this organ but are the most critical in the context of both type 1 and type 2 diabetes. Cells of the pancreas called alpha cells secrete glucagon and those called beta cells secrete insulin. The pancreas is not the only organ that can contribute to the disturbances in metabolism associated with type 2 diabetes, thus, many of the genes identified in GWAS studies do not participate in pancreatic function directly, but nonetheless the proteins encoded by these other genes are necessary for normal metabolic homeostasis. Several recent studies have focused on analyzing the transcriptional activity (what genes are turned on and at what level of activity and what genes are turned off) of the pancreas in both normal individuals and those with type 2 diabetes. However, the results these studies have provided only average transcriptional activity from all hormone secreting cell population.

A new study published in the prestigious journal, Cell Metabolism, has gone one step further and examined the differences in the patterns of genes that are expressed in single hormone secreting cells of the pancreas and made a comparison between these patterns in normal individuals and those with type 2 diabetes. Because the experiments are designed to analyze the transcription of genes into RNA, the data are examining what is termed the transcriptome of the single cells. 

RNA Sequencing of Single Human Islet Cells Reveals Type 2 Diabetes Genes

The results from this study demonstrate that there are at least 245 genes whose patterns of expression are significantly different when comparing the two groups of individuals: normal versus type 2 diabetic. Several genes were found to be expressed exclusively in the glucagon secreting alpha cells (GCG, DPP4, FAP, PLCE1, LOXL4, IRX2, TMEM236, IGFBP2, COTL1, SPOCK3, and ARRDC4) and several were found to be exclusively expressed in the insulin secreting beta cells (INS, ADCYAP1, IAPP, RGS16, DLK1, MEG3, INS-IGF2, and MAFA). The GCG gene encodes the hormone glucagon and the INS gene encodes the hormone insulin so it is not surprising that these genes are exclusively expressed in the cells known to secrete the encoded proteins. A total of 54 genes expressed in alpha cells and 48 genes expressed in beta cells were found to be differentially expressed in a comparison between normal and type 2 diabetic individuals. The other differentially expressed genes were identified in the two other types of pancreatic cells (delta cells and PP cells) but are not reviewed here. A striking finding from this study was that 28% of the identified differentially expressed genes from all four pancreatic cell populations have no known function.

Beyond the scope of this blog is a listing of all the differentially expressed genes, their functions, and an analysis of what the data mean in relation to the risk one may have for type 2 diabetes or whether there is any correlation to therapeutic intervention in individuals with the observed patterns of altered gene expression. However, I found it exciting that with respect pancreatic function and insulin secretion, there were four genes whose levels of expression were significantly lower in type 2 diabetic beta cells compared with normal pancreatic beta cells. These four genes are G6PC2, FFAR4, and SLC2A2. The protein encoded by the SLC2A2 gene is known as glucose transporter 2 (GLUT2). The function of this glucose transporter is to allow glucose entry into the pancreatic beta cell in order for it to be metabolized for energy (ATP) production. However, it is a relatively inefficient transporter so that glucose entry does not occur until blood glucose levels high in the post-feeding state. Since glucose metabolism is the primary metabolic mechanism stimulating insulin secretion it makes sense that reduced GLUT2 production would lead to reduced insulin secretion as is typical in type 2 diabetes.

To understand the mechanism of glucose-mediated insulin secretion go to the Insulin Functions page of my website:

http://themedicalbiochemistrypage.org/insulin.php

The FFAR4 gene encodes a cell surface receptor for certain types of lipids, particularly the omega-3 fatty acid, DHA (docosahexaenoic acid). The precise function of FFAR4 in the pancreatic beta cell is not yet well defined but it does participate in secretion of the hormone somatostatin from the delta cells. FFAR4 is also important in the regulation of adipose tissue function by enhancing insulin-mediated glucose uptake by adipocytes. Read more about the functions of FFAR4 in the Bioactive Lipids page of my website:

http://themedicalbiochemistrypage.org/bioactivelipids.php#gpr120

The G6PC2 gene encodes a catalytic subunit of the glucose 6-phosphatase enzyme, the enzyme that is responsible for the release of free glucose (from glucose-6-phosphate) from the liver, kidney, and small intestine in the context of the metabolic pathway of gluconeogenesis. Within the pancreas the G6PC2 encoded protein has no phosphate removal activity but it is a major target of cell-mediated autoimmunity in type 1 diabetes suggesting that there may be some component of immune function in the development of type 2 diabetes. Read more about this pathway in the Gluconeogenesis page of my website:

http://themedicalbiochemistrypage.org/gluconeogenesis.php

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