**2. Pancreatic β cell and blood glucose regulation**

#### **2.1. Blood glucose regulation by pancreas**

The major cause of type 1 diabetes is loss of insulin-secreting pancreatic β cell and insu‐ lin inadequacy (3;4). For a better understanding of the pathogenesis of type 1 diabetes, the regulatory mechanisms of blood glucose by pancreaswill briefly introduced. Blood glucose level is closely regulated in order to provide a homeostatic microenvironment for tissues and organs. According to the American Diabetes Association, a normal fasting blood glucose level is between 70 to 100 mg/dL, and the recommended fasting level is to aim for 70 to 130 mg/dL and less than 180 mg/dL after meals (5). Blood glucose is moni‐ tored by the cells in the islets of Langerhans (6). Islets of Langerhans are clusters of pan‐ creatic cells that execute the endocrine function of pancreas. They contain the following 4 types of cells, in order of abundance: β cells, α cells, δ cells, and γ cells. Pancreatic β cells and α cells make up about 70% and 17% of islet cells respectively, and both of them are responsible for the blood glucose regulation by producing insulin (β cells) and glucagon (α cells) (6). Pancreatic δ cells produce somatostatin which has a major inhibitory effect, including on pancreatic juice production. Pancreatic γ cells secrete pancreatic polypeptide that is responsible for reducing appetite.

**Figure 1. Homeostatic regulation of blood glucose by pancreas**. Pancreas is the major organ responsible for main‐ taining the blood glucose homeostasis. Increase of blood glucose level can be sensed by GLUT2 on β cells, a glucose transporter. The metabolism of glucose in β cells promotes the secretion of insulin into circulation of blood. Circulat‐ ing insulin then increases the glucose uptake by a variety of tissues including liver, muscle, and fat. In liver, insulin sig‐ naling also stimulates the conversion of glucose into glycogen, a process called glycogenesis. Both glycogenesis and glucose uptake by peripheral tissues can lead to a decrease of glucose level in blood stream. In contrast, a drop of blood glucose level suppresses the secretion of insulin by β cells and stimulates α cells to release glucagon. Glucagon acts on liver and promotes glucose production by the breakdown of glycogen to glucose, a process called glycogenol‐

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Either insulin deficiency or insulin inefficiency can cause diabetes. As the only cell type pro‐ ducing insulin, β cell plays a critical role in the development of diabetes. In type 1 diabetes, autoimmune-mediated destruction of β cell leads to insufficient insulin production and in‐ ability of cells to take up glucose. In contrast, type 2 diabetes is caused by loss of insulin sen‐ sitivity. In response to insulin resistance, the body secretes more insulin to overcome the impaired insulin action. However, pancreatic β cells fail to secrete sufficient insulin to over‐ come insulin resistance in some individuals, resulting in type 2 diabetes (8;9). Therefore,

Pancreatic β cell is specialized for production of insulin to control blood glucose level. In re‐ sponse to hyperglycemia, insulin is secreted from a readily available pool in β cells. In the meantime, the secretion of insulin activates the biosynthesis of insulin (10). Insulin is first

ysis, and results in the increase of blood glucose.

**2.2. Pancreatic β cells and insulin biosynthesis**

dysfunction of β cell exists in both types of diabetes.

Insulin and glucagon have opposite functions on glucose regulation. They keep blood glu‐ cose level in a normal range by coordinating with each other (Figure 1). After a meal, the digestive system breaks down the carbohydrates to small sugar molecules, mainly glucose. The glucose is then absorbed across the intestinal wall and travel to the circulating blood‐ stream. Pancreatic β cells sense increased blood glucose level by taking up glucose through GLUT2, a glucose transporter. The metabolism of glucose in β cells leads to the increase of ATP/ADP ratio, which causes the closing of ATP-sensitive potassium channels and further leads to the open of calcium channels on membrane. The resulting increase of intracellular calcium concentration promotes the secretion of insulin into circulation of blood. Circulating insulin then acts on cells in a variety of tissues including liver, muscle, and fat through inter‐ acting with insulin receptor on the cell membrane. Insulin signaling induces the transloca‐ tion of glucose transporter GLUT4 to cell membrane of muscle cells and adipocytes, leading to the uptake of glucose into cells as an energy source. In addition, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis, in liver. Therefore, insulin lowers blood glucose level by promoting glycogenesis and glucose uptake by peripheral tissues (7). In contrast, a drop in blood glucose caused by starving or other sit‐ uations like extreme exercise suppresses the secretion of insulin by β cells and stimulates α cells of pancreas to release glucagon. Glucagon acts on liver and promotes glucose produc‐ tion by the breakdown of glycogen to glucose (called glycogenolysis), resulting in the in‐ crease of blood glucose.

**Figure 1. Homeostatic regulation of blood glucose by pancreas**. Pancreas is the major organ responsible for main‐ taining the blood glucose homeostasis. Increase of blood glucose level can be sensed by GLUT2 on β cells, a glucose transporter. The metabolism of glucose in β cells promotes the secretion of insulin into circulation of blood. Circulat‐ ing insulin then increases the glucose uptake by a variety of tissues including liver, muscle, and fat. In liver, insulin sig‐ naling also stimulates the conversion of glucose into glycogen, a process called glycogenesis. Both glycogenesis and glucose uptake by peripheral tissues can lead to a decrease of glucose level in blood stream. In contrast, a drop of blood glucose level suppresses the secretion of insulin by β cells and stimulates α cells to release glucagon. Glucagon acts on liver and promotes glucose production by the breakdown of glycogen to glucose, a process called glycogenol‐ ysis, and results in the increase of blood glucose.

### **2.2. Pancreatic β cells and insulin biosynthesis**

summarize the functional involvement of ER stress in the pathogenesis of type 1 diabetes

The major cause of type 1 diabetes is loss of insulin-secreting pancreatic β cell and insu‐ lin inadequacy (3;4). For a better understanding of the pathogenesis of type 1 diabetes, the regulatory mechanisms of blood glucose by pancreaswill briefly introduced. Blood glucose level is closely regulated in order to provide a homeostatic microenvironment for tissues and organs. According to the American Diabetes Association, a normal fasting blood glucose level is between 70 to 100 mg/dL, and the recommended fasting level is to aim for 70 to 130 mg/dL and less than 180 mg/dL after meals (5). Blood glucose is moni‐ tored by the cells in the islets of Langerhans (6). Islets of Langerhans are clusters of pan‐ creatic cells that execute the endocrine function of pancreas. They contain the following 4 types of cells, in order of abundance: β cells, α cells, δ cells, and γ cells. Pancreatic β cells and α cells make up about 70% and 17% of islet cells respectively, and both of them are responsible for the blood glucose regulation by producing insulin (β cells) and glucagon (α cells) (6). Pancreatic δ cells produce somatostatin which has a major inhibitory effect, including on pancreatic juice production. Pancreatic γ cells secrete pancreatic polypeptide

Insulin and glucagon have opposite functions on glucose regulation. They keep blood glu‐ cose level in a normal range by coordinating with each other (Figure 1). After a meal, the digestive system breaks down the carbohydrates to small sugar molecules, mainly glucose. The glucose is then absorbed across the intestinal wall and travel to the circulating blood‐ stream. Pancreatic β cells sense increased blood glucose level by taking up glucose through GLUT2, a glucose transporter. The metabolism of glucose in β cells leads to the increase of ATP/ADP ratio, which causes the closing of ATP-sensitive potassium channels and further leads to the open of calcium channels on membrane. The resulting increase of intracellular calcium concentration promotes the secretion of insulin into circulation of blood. Circulating insulin then acts on cells in a variety of tissues including liver, muscle, and fat through inter‐ acting with insulin receptor on the cell membrane. Insulin signaling induces the transloca‐ tion of glucose transporter GLUT4 to cell membrane of muscle cells and adipocytes, leading to the uptake of glucose into cells as an energy source. In addition, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis, in liver. Therefore, insulin lowers blood glucose level by promoting glycogenesis and glucose uptake by peripheral tissues (7). In contrast, a drop in blood glucose caused by starving or other sit‐ uations like extreme exercise suppresses the secretion of insulin by β cells and stimulates α cells of pancreas to release glucagon. Glucagon acts on liver and promotes glucose produc‐ tion by the breakdown of glycogen to glucose (called glycogenolysis), resulting in the in‐

and the potential underlying mechanisms.

196 Type 1 Diabetes

**2.1. Blood glucose regulation by pancreas**

that is responsible for reducing appetite.

crease of blood glucose.

**2. Pancreatic β cell and blood glucose regulation**

Either insulin deficiency or insulin inefficiency can cause diabetes. As the only cell type pro‐ ducing insulin, β cell plays a critical role in the development of diabetes. In type 1 diabetes, autoimmune-mediated destruction of β cell leads to insufficient insulin production and in‐ ability of cells to take up glucose. In contrast, type 2 diabetes is caused by loss of insulin sen‐ sitivity. In response to insulin resistance, the body secretes more insulin to overcome the impaired insulin action. However, pancreatic β cells fail to secrete sufficient insulin to over‐ come insulin resistance in some individuals, resulting in type 2 diabetes (8;9). Therefore, dysfunction of β cell exists in both types of diabetes.

Pancreatic β cell is specialized for production of insulin to control blood glucose level. In re‐ sponse to hyperglycemia, insulin is secreted from a readily available pool in β cells. In the meantime, the secretion of insulin activates the biosynthesis of insulin (10). Insulin is first synthesized as preproinsulin with a signal peptide in the ribosomes of the rough endoplas‐ mic reticulum. Preproinsulin is translocated into ER lumen by interaction of signal peptide with signal recognition particle on the ER membrane. Preproinsulin is converted to proinsu‐ lin by removing the signal peptide forming three disulfide bonds in the ER. Proinsulin is then translocated into Golgi apparatus and packaged into secretory granules that are close to the cell membrane. In the secretory granules, proinsulin is cleaved into equal amounts of insulin and C-peptide (Figure 2). Insulin is accumulated and stored in the secretory gran‐ ules. When the β cell is appropriately stimulated, insulin is secreted from the cell by exocy‐ tosis (11). As the major site for protein synthesis, ER plays an important role in insulin biosynthesis. To fulfill the requirement for secreting large amount of insulin, the pancreatic β cells are equipped with highly developed ER, leading to the vulnerability of β cell to ER stress (12). In type 1 diabetes, the loss of β cell increases the burden of insulin secretion on the residual β cells. On the on hand, this compensated action is beneficial for the control of blood glucose. On the other hand, it also increases the ER burden of residual β cells, which further exacerbates β cell death.

**3. Biological characterization of endoplasmic reticulum (ER) and ER**

in which large amounts of secretory proteins are synthesized.

**3.2. Unfolded protein response and ER stress**

Endoplasmic Reticulum (ER) is an organelle of eukaryotic cells that is responsible for the fa‐ cilitation of protein folding and assembly (13-15), manufacture of the membranes(16), bio‐ synthesis of lipid and sterol, storage of intracellular Ca2+, and transport of synthesized proteins in cisternae.It is a membranous network of tubules, vesicles, and cisternae that are interconnected by the cytoskeleton.The ER is well developed in endocrine cells such as β cell

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ER is categorized into two types: rough endoplasmic reticulum (RER) and smooth endoplas‐ mic reticulum (SER). As featured by its name, RER looks bumpy and rough under a micro‐ scope due to the ribosomes on the outer surfaces of the cisternae. RER is in charge for protein synthesis. The newly synthesized proteins are folded into 3-dimensional structure in RER and sent to Golgi complex or membrane via small vesicles. In contrast, SER appears to have a smooth surface under the microscope as it does not have ribosomes on its cisternae. SER is responsible for the synthesis of lipids and steroids, regulation of calcium concentra‐ tion, attachment of receptors on cell membrane proteins, and detoxification of drugs. It is found commonly in places such as in the liver and muscle. It is important for the liver to detoxify poisonous substances. Sarcoplasmic reticulum is a special type of SER. It is found in smooth and striated muscle, and is important for the regulation of calcium levels. It se‐ questers a large store of calcium and releases them when the muscle cell is stimulated.

ER stress is defined as the cellular responses to the disturbances of normal function of ER. The most common cause of ER stress is protein mis-folding. ER is the place where newly produced proteins fold into 3-dimensional conformation which is essential for their biologi‐ cal function. The sensitive folding environment could be disturbed by a variety of pathologi‐ cal insults like environmental toxins, viral infection, and inflammation. In addition to pathological insults, it can also be induce by many physiological processes such as overload‐ ed protein biosynthesis on ER, For example, in case of type 1 diabetes, increased insulin syn‐ thesis in residual β cell exceeds the folding capacity of ER, resulting in the accumulation of unfolded insulin. The accumulation of unfolded or mis-folded proteins in the ER leads a protective pathway to restore ER function, termed as unfolded protein response (UPR).

Protein folding requires a serial of ER-resident protein folding machinery. A special type of proteins called chaperones is used as a quality control mechanism in the ER. As the major mechanisms to promote protein folding, chaperones assist protein folding by interacting with the newly synthesized proteins.In addition,chaperones also help to break down un‐ folded or incorrectly folded proteins in the ER via a process called ER associated degrada‐ tion.The monitoring mechanism ensures the correct protein folding in the ER. The unfolded proteins usually have a higher number of hydrophobic surface patches than that of proteins

**stress**

**3.1. Endoplasmic reticulum**

**Figure 2. Biosynthesis of insulin in β cell.** In the ribosomes of rough endoplasmic reticulum, insulin is first synthe‐ sized as a precursor, preproinsulin. Preproinsulin has a signal peptide that directs it to translocate into ER lumen by interacting with signal recognition particle on the ER membrane. In ER lumen, preproinsulin is converted to proinsulin by removing the signal peptide and forming three disulfide bonds. Proinsulin is then translocated into Golgi apparatus and packaged into secretory granules where it is cleaved into equal amounts of insulin and C-peptide. After synthesis, insulin is stored in the secretory granules and secreted from the cell until the β cell is appropriately stimulated.
