This is in contrast to the glucagon-producing alpha cells and other islet cell types in the islets that are well equipped with these H 2 O 2 -inactivating enzymes. On the other hand the membranes of the pancreatic beta cells are well protected against lipid peroxidation and ferroptosis through high level expression of glutathione peroxidase 4 GPx4 and this again is at variance from the situation in the non-beta cells of the islets with a low expression level of GPx4.

The weak antioxidative defence equipment of the pancreatic beta cells, in particular in states of disease, is very dangerous because the resulting particular vulnerability endangers the functionality of the beta cells, making people prone to the development of a diabetic metabolic state.

Graham Rena, D. Roman Abrosimov, Marius W. Baeken, … Bernd Moosmann. The peptide hormone insulin 51 amino acids; molecular weight 5. Lack of insulin causes severe hyperglycaemia, which results in a life-threatening diabetic metabolic state.

It is synthesised in the beta cells of the islets of Langerhans of the pancreas. The physiological regulator of insulin biosynthesis is the blood glucose concentration. An increase in its concentration stimulates insulin biosynthesis.

Insulin consists of two peptide chains, the A-chain with 21 amino acids and the B-chain with 30 amino acids. The two chains are linked by two disulfide bridges. A third disulfide bridge within the A-chain is important for stabilising the spatial structure of insulin.

A number of genetically modified human insulins with shorter or longer half-lives are nowadays available for the therapy of patients with diabetes.

Proinsulin, the precursor of insulin, is synthesised via the peptide preproinsulin in the rough endoplasmic reticulum of pancreatic beta cells as a single-stranded polypeptide chain. The A- and B-chains are linked by oxidation of SH groups via disulfide bridges and thereafter the connecting C-peptide, which connects the two chains, is cut out by proteolysis [ 1 ].

Insulin and C-peptide are stored in an equimolar ratio in the insulin secretory granules formed in the Golgi complex until their content is released from the beta cells by exocytosis. During this process, the membrane of the granule and that of the cell surface fuse, so that insulin and C-peptide enter the extracellular space.

From there, insulin is transported via the bloodstream to the target organs. No biological function is known for the C-peptide. The signal for the physiological insulin secretion induced by glucose is generated in the metabolism of glucose [ 2 ]. Thus, ATP produced in the metabolism of glucose is not only an energy source for the beta cells but also the signal for initiation of insulin secretion.

Four biological structures are crucial for the generation of the signal for glucose-induced insulin secretion Fig. When the blood glucose concentration increases after ingestion of food, the glucose concentration in the extracellular space of the beta cells is raised. The glucose molecules are transported into the cytoplasm of the beta cells by facilitated diffusion by means of a low-affinity glucose transporter especially the GLUT2 in the plasma membrane, so that the intracellular concentration always corresponds approximately to the glucose concentration in the extracellular space Fig.

In addition to high-affinity hexokinase isoenzymes with K m values in the micromolar concentration range, which are found in all organs, the pancreas beta cells is virtually the only organ besides the liver that possesses a low-affinity glucose phosphorylating enzyme, namely the hexokinase IV, better known as glucokinase.

In pancreatic beta cells, glucokinase is the signal recognition enzyme responsible for mediating glucose-induced insulin secretion, known as the glucose sensor. By phosphorylating the glucose in the physiological millimolar concentration range 4—8 mM , the glucokinase generates an increased metabolic flow rate, resulting in an increase in the concentration of ATP and a simultaneous decrease in ADP.

ATP thus acts as a second messenger in the beta cells Fig. ATP binds to a specific potassium channel, the ATP-sensitive potassium channel in the cell membrane of the pancreatic beta cells, thereby causing depolarisation of the beta cells [ 2 ].

This channel protein is associated with a second protein, the so-called sulfonylurea receptor, which is the site of action of the blood sugar-lowering sulfonylureas Fig. The beta cells have in addition a voltage-dependent calcium channel.

As a result of the depolarisation of the beta cells, this channel opens and allows calcium to flow in from the extracellular space. The increase in the free calcium concentration in the cytoplasm of the beta cells is then responsible for triggering glucose-induced insulin secretion by exocytosis [ 2 ], which is characterised by a biphasic kinetic profile Fig.

A scheme of the cellular structures important for physiological regulation of insulin secretion in pancreatic beta cells. Depicted are the nucleus, the mitochondria Mito , the peroxisomes P , the lysosomes L , the endoplasmic reticulum ER , the Golgi apparatus G and the secretory granules SV.

Elevated postprandial blood glucose increases the glucose concentration within beta cells via rapid equilibration through the glucose transporters in the plasma membrane.

Glucose is phosphorylated by glucokinase GK. This leads to the production of glucosephosphate G6P and determines the rate of glycolysis. The elevated glycolytic flux and the mitochondrial metabolism stimulate the ATP production. This is called the initiating pathway red arrow.

The K ATP channel is a complex of four pore-forming Kir6. The SUR1 subunit can react with blood glucose-lowering sulfonylurea drugs SU to initiate insulin secretion.

This stimulates exocytosis of insulin-containing secretory granules. The second mechanism enabling glucose-induced insulin secretion potentiation is called the amplifying pathway green arrow. This mechanism is based on the anaplerosis providing intermediates of tricarboxylic acid cycle without involvement of the K ATP channel.

Many hormones, small peptides and extracellular messengers can also potentiate glucose-induced insulin secretion through binding to their plasma membrane receptors and activation of intracellular signalling cascades, typically G-protein-mediated not depicted here.

These four structures together form the apparatus for the recognition of the glucose stimulus and exocytosis of insulin in the beta cells of the islets of Langerhans in the pancreas Fig. In healthy people, they ensure that the stored insulin is released as needed when the blood sugar concentration increases after food intake typically from about 4 to about 8 mM.

Different pathomechanisms are responsible for impaired insulin secretion in type 1 and type 2 diabetes [ 1 , 2 , 3 ]. Furthermore, various amino and keto acids, as well as glucose, can increase insulin secretion by means of ATP. In addition, there are other second messengers that can also increase the cytoplasmic calcium concentration and thus increase insulin secretion.

For example, for many peptides e. the incretin hormones glucagon-like peptide 1 [GLP-1] and gastric inhibitory polypeptide [GIP] , cyclic AMP cAMP and in the case of vagal stimulation with acetylcholine inositol trisphosphate are the responsible second messengers.

The concentrations of these intracellular second messengers are increased in the beta cell when the respective agonist binds to its plasma membrane receptor. In contrast to glucose, these mechanisms cannot trigger insulin secretion.

However, glucose-induced insulin secretion can be increased during food intake and thus optimally adapted to the respective metabolic situation, so that the organism is supplied with insulin as needed.

The amplifying metabolic signals are most likely generated in the tricarboxylic acid cycle [ 2 ]. In quantitative terms the amplifying pathway provides at least as much insulin to the organism as the triggering pathway [ 2 ].

The insulin-producing beta cells as well as the other hormone-producing cells are arranged in the form of endocrine micro-organs, the so-called islets of Langerhans or pancreatic islets.

The islets are embedded in the exocrine tissue of the pancreas total number of islets 0. The average islet has a diameter of — μm and consists of — endocrine cells.

The islets of Langerhans are composed of different endocrine cell types. The last two hormones have no crucial function in the organism. In rodents the beta cells are located in the centre of the islet, surrounded by a rim of the non-beta cells so-called mantle islets , while the non-beta cells are scattered around throughout the islets in-between the beta cells in the human islets.

The pancreatic beta cell is very sensitive to oxidative stress, explaining its particular vulnerability in states of disease [ 1 ]. It is the imbalance between H 2 O 2 generation and its decomposition that easily causes damage to the beta cells [ 3 ]. In virtually all cell types and organs such as liver, kidney and other major organs of the body, the balance between H 2 O 2 generation and decomposition is maintained by a battery of H 2 O 2 -inactivating enzymes [ 5 , 6 , 7 , 8 ].

They prevent oxidative stress that is an imbalance between the generation of reactive oxygen species and the capacity to detoxify these reactive species. All the protective enzymes generate H 2 O through reduction of H 2 O 2 and are not inducible.

The great number of these decomposing enzymes expressed in virtually all major subcellular compartments is an indication of their importance in providing efficient protection against oxidative stress-mediated cellular toxicity.

The effective inactivation systems limit the lifetime and restrict the movements of H 2 O 2 over large distances and thus provide protection against oxidative stress.

This has favourable consequences for the cell: a oxidative stress and the resultant cell death are counteracted and b localized oxidation of reactive thiol proteins within the cell as the basis for thiol-based cellular signalling is favoured.

This restricts H 2 O 2 distribution in the cell. This is general thinking in the research community [ 7 , 8 ]. View Metrics. Share X Facebook Email LinkedIn. Jennifer Couper, MD 1,2. visual abstract icon Visual Abstract.

Original Investigation. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes. Gregory P.

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