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Clinical Gems

Our clinical gems come from the top selling medical books, and text books because knowledge is everything when it comes to diabetes.

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #34: Beta-Cell biology of insulin secretion Part 4 of 5

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Gs-protein-coupled receptor: In pancreatic beta cells, various hormones, neurotransmitters, nucleotides, and fatty acids including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), adrenaline, ATP/ADP, lysophosphatidylcholine (LPC), and oleoylethanolamide (OEA) activate their specific receptors. These receptors when coupled with Gs-protein activate adenylate cyclase and increase cAMP production. These cAMP-increasing ligands potentiate both the 1st phase and 2nd phase of GIIS.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #33: Beta-Cell biology of insulin secretion Part 3 of 5

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Dynamics of insulin secretion: Biphasic insulin secretion -- insulin release from pancreatic beta cells in response to glucose is characterized by biphasic kinetics: an initial component (1st phase), which develops rapidly but lasts only a few minutes, followed by a sustained component (2nd phase). It has been thought that the biphasic response of insulin secretion reflects primarily the dynamics of spatially and functionally distinct insulin granules. The prevailing hypothesis is that the 1st phase of insulin secretion is attributable to fusion of predocked granules from a readily releasable pool (RRP) that accounts for less than 5% of total granules, while the 2nd phase involves recruitment of granules from a more distant reserve pool (RP) that accounts for the great majority of total granules.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #32: Beta-Cell biology of insulin secretion Part 2 of 5

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Metabolism-secretion coupling, triggering pathway: Glucose metabolism increases the cytosolic ATP concentration in pancreatic beta cells, this rise in ATP causing closure of the KATP channels and depolarization of the beta-cell membrane. Thus, KATP channels couple the cell’s metabolic state to electrical activity. The beta-cell KATP channel is composed of two subunits: Kir6.2 as a pore-forming subunit and the sulfonylurea receptor SUR1 as a regulatory subunit. Activity of the KATP channel is critical for GIIS. Membrane depolarization opens VDCCs, which allows Ca2+ influx into β cells, the resultant rise in intracellular Ca2+ triggering exocytosis of insulin granules. Thus, KATP channels and VDCCs are major ion channels required for metabolism-secretion coupling in insulin release.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #31: Beta-Cell Biology of Insulin Secretion Part 1 of 5

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In pancreatic beta cells, glucose metabolism is essential for the regulation of insulin secretion. Glucose is taken up by glucose transporters and metabolized to generate adenosine triphosphate (ATP), which is the main driver of glucose-induced insulin secretion (GIIS). Increased cytosolic ATP causes closure of ATP-sensitive K+ (KATP) channels, depolarizing the plasma membrane, leading to the opening of voltage-dependent Ca2+ channels (VDCCs), which allows Ca2+ influx. The resultant rise in intracellular Ca2+ concentration ([Ca2+]i) induces exocytosis of insulin granules in the triggering pathway of insulin secretion. In addition, other signals generated by glucose amplify insulin secretion. Lipid metabolism is also involved in GIIS by interacting with glucose metabolism.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #30: Insulin Gene Expression and Biosynthesis Part 6 of 6

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Regulation of proinsulin conversion: PC2 and PC1/3 are Ca2+-dependent enzyme activities with an acidic pH 5 – 5.5 optimum. Fortunately, the beta granule contains an intraorganellar environment of 1 – 10 mM free Ca2+ and acidic pH 5.5, which ideally suits the requirements for optimal PC2, PC1/3 and CP-H activities within this organelle.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #29: Insulin Gene Expression and Biosynthesis Part 5 of 6

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Transport of proinsulin from the ER to Golgi apparatus: After proinsulin is translocated into the lumen of the ER, it is then delivered in transport “COP-coated vesicles” to the cis-Golgi apparatus. Up until relatively recently, it was thought that newly synthesized proinsulin was passed from the cis-Golgi network “stack” via the medial- to the trans-stack of the Golgi apparatus stacks in “COP”-coated vesicles,

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #28: Insulin Gene Expression and Biosynthesis Part 4 of 6

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Insulin biosynthesis: the previous section outlines that insulin gene transcription is a highly controlled process. The product of this process, pre-proinsulin mRNA, is unusually stable in pancreatic beta cells and it is further stabilized as glucose concentrations increase. As such, there is normally an abundant source of preproinsulin mRNA in the beta-cell cytosol available for translation.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #27: Insulin Gene Expression and Biosynthesis Part 3 of 6

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Dysregulation of the insulin gene: There is convincing evidence that abnormalities in insulin gene sequence or function play a role in pancreatic beta-cell dysfunction in type 2 diabetes. Abnormalities in the insulin gene structure consist of rare control region mutations, while insulin gene expression appears to be reduced by metabolic conditions associated with the diabetic state.

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