Beta cells Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...

are heavily engaged in the synthesis and secretion of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

. They are therefore particularly sensitive to

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) stress and the subsequent

unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in resp ...

(UPR). Severe or prolonged episodes of ER stress can lead to the death of beta cells,Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42-61 which can contribute to the development of both Type I and Type II

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

. ER stress in beta cells links obesity to type 2 diabetes and inflammation to type 1 diabetes. ER stress in peripheral cells has also been linked to

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

, a precursor to

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

Activation of ER stress

ER stress can be activated by a variety of factors. In experimental conditions, excessive

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...

(which can happen following

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

, a common condition preceding

) and pro-inflammatory

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

(which can occur following an

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

, a common cause for

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

) can activate ER stress in beta cells. Causes such as defective protein processing and trafficking or inappropriate

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

regulation are likely in lipid-mediated ER stress. On the other hand, cytokines are likely to activate ER stress by decreasing the calcium pump ''Serca2b'' (also known as ''Atp2a2''), leading to subsequent depletion in the ER calcium stores.

ER Stress and Inflammation

All three of the pathways involved in the resolution of ER stress by the Unfolded Protein Response (UPR) are also related to inflammation. The two pathways are very connected and both have been shown to activate each other

Resolution of ER stress

Activation of ER stress by lipids results in a typical Unfolded Protein Response (UPR) to primarily restore ER function, whereas cytokine-activated ER stress leads to an atypical UPR that preferentially activate

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

in beta cells. The UPR is activated when

GRP78 Binding immunoglobulin protein (BiP) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the ''HSPA5'' gene. BiP is a HSP70 molecular chaperone located in the l ...

, a.k.a. BiP, a protein-folding chaperone, is recruited to assist in protein folding. In β-cells, insulin production is a major source of improperly folded protein. GRP78 is normally bound to the luminal domain of

ATF6 Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ''ATF6'' gene and is involved in the unfolded protein response. Function ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembra ...

IRE1 The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ''ERN1'' gene. Function The protein encoded by this gene is the ER to nucleus signalling 1 protein, a hu ...

, and PERK, which prevents them from initiating their respective pathways of the UPR. When GRP78 is recruited to assist in protein folding, unbound ATF6, IRE1 and PERK are able to initiate the UPR. The UPR is also activated by cytokines ER-stress activates Apoptosis through

C/EBP Homologous Protein DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the ''DDIT3'' gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding ...

(CHOP)

Measurement

ER Stress can be measured using Quantitative Real-Time

RT-PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase cha ...

to measure the rate at which XBP1 is cleaved by IRE1 when the UPR is activated. XBP1 mRNA cleavage leads to the translation of a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

for genes that resolve ER stress. Measuring the rate at which XBP1 is cleaved gives a quantitative measure of ER stress in real time.

References

{{Reflist Endoplasmic reticulum