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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 #38: Normal Beta-cell Function Part 3 of 6

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Beta-Cell response to nonglucose secretagogues: Proteins and amino acids -- The insulinotropic effect of oral proteins was first described almost 50 years ago and recently confirmed. After the ingestion of a small amount of proteins (30–50 g) or a larger amount of proteins (2 g kg−1), plasma insulin was raised two- to threefold over baseline and remained persistently elevated for 90 or 240 minutes, respectively. In either case, blood glucose did not change, whereas both GLP-1 and GIP levels were raised threefold over fasting values.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #37: Normal Beta-cell Function Part 2 of 6

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Beta-Cell response to intravenous glucose: Although in normal living conditions beta cells are stimulated by hyperglycemia that follows glucose ingestion, the study of the response to intravenous glucose is of fundamental importance for understanding the physiology of beta cells. Several tests have been developed for this purpose and this section describes the most relevant and the characteristics of insulin secretion that they reveal.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #36: Normal Beta-cell Function Part 1 of 6

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Insulin is an ancient hormone; it emerged early in evolution since the most primitive forms of vertebrates (extant lamprey and hagfish) evolving from insulin-like peptide genes, which are expressed in all multicellular animals. From an evolutionary point of view insulin facilitates survival in an environment where access to nutrients is discontinuous, erratic, and difficult, requiring the function of highly specialized tissues necessary to allow movement and appropriate reactions to external stimuli (i.e., skeletal muscle and nervous system). Insulin, in the fed state is secreted to stimulate glucose and amino acids uptake allowing the build-up of depots of glycogen, proteins and lipids, which are necessary to sustain the energy requirements during successive fasting.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #35: Beta-Cell biology of insulin secretion Part 5 of 5

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Autocrine effect of insulin on insulin secretion: Rodent and human pancreatic beta cells possess the various components of the insulin signaling system, including insulin receptor, insulin-like growth factor-1 (IGF-1) receptor, insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), and protein kinase B (PKB)/Akt. It has been shown that insulin binds to the insulin receptors on the surface of beta cells and induces phosphorylation of the insulin receptors and IRSs,modulating its own secretion. This effect of insulin is involved especially in the 1st phase of GIIS in mice.

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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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