Beta cells Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vit ...

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 insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

. They are therefore particularly sensitive to

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

(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 mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...

(UPR). Severe or prolonged episodes of ER stress can lead to the death of beta cells, which can contribute to the development of both type I and type II

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

. 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 response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...

, a precursor to

type 2 diabetes Type 2 diabetes (T2D), 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 ...

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 organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

(which can happen following

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

, 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 produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

(which can occur following an

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

, a common cause for

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...

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

calcium Calcium is a chemical element; it has 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 it ...

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 ER calcium stores.

ER stress and inflammation

All three of the pathways involved in the resolution of ER stress by the

(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 ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

in beta cells. The UPR is activated when

GRP78 Binding immunoglobulin protein (BiPS) 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 ...

, 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 transmembr ...

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 (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 chain ...

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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

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 Pancreas Endocrine system