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<blockquote data-quote="KenMacK" data-source="post: 2052594" data-attributes="member: 506757"><p>Sorry, the widespread myth that a T2D is not insulin deficient reflects the widespread misunderstanding of the hepatic-islets (i.e. portal) axis and its endocrinology, both in diabetes and in non-diabetes. This is WHY I emphasized that there is sustantial insulin deficiency in T2DM.</p><p>The basics of the endocinological defects of T1DM, T2DM, and almost all forms of MODY (excepting MODY2 or the glucokinase monogenic form) are underpinned by an insulin-secretion deficiency. Regardless of the specific form of diabetes, which is very different at the endocrine-pancreatic/cellular level, diabetes will not be diagnosed by conventional medical practice and guidelines until the overall beta-cell function drops to 20% (a loss of 80% in the acquired forms, T1DM and T2DM). In my form of MODY there is never any loss -- there is an underexpression of many proteins underpinning insulin production/secretion in the beta cells due to inherited mutations in the HNF1-alpha homeobox gene (HNF stands for "Hepatic Nuclear Factor" -- the gene is expressed in endocrine pancreas, liver, small intestine and kidneys).</p><p>In T1DM all of the loss of function is due to death/destruction of beta cells. The remaining beta cells are normal, but there are far too few present to balance the alpha cell population. In T2DM the loss of function comes from BOTH beta-cell apoptosis (i.e. death) and from beta-cell derangement (i.e. the remaining beta cells have abnormal and weak function, and are morphologically distorted and visibly inflamed).</p><p>However, regardless of type, the clinical manifestation (i.e. diagnosis) of diabetes does not occur until beta-cell function drops to 20% of normal. This takes years in either T1DM or T2DM. When the 20% threshold is crossed there is loss of insulin granulation (i.e. storage) in beta cells, and this results in the classic clinical symptoms of polyuria and polydipsia. The sudden appearance of these symptoms only occurs once insulin granulation is lost. It is very rare that diabetes is diagnosed until these symptoms appear.</p><p>IMO it is likely that a form of insulin resistance underpins T2DM (whereas this is not intrinsically true of T1DM or MODY), and that this insulin resistance is the earliest detectable defect of pre-diabetes, occuring in the alpha cells. Many independent diabetes basic research groups have detected the early defect in different ways, and it produces the hyperglucagonemia intrinsic to insulin deficiency of diabetes. However, at this early stage there is no insulin deficiency (yet) in animal models of T2DM. IR is one hypothesis that could explain the observed "early defect" of pre-diabetes (i.e. metabolic syndrome), but there are others and noone has yet been able to develop an experimental method to investigate the mechanism in alpha cells directly.</p><p>In the endocrine pancreas, or islets, insulin is the primary regulator of glucagon secretion by alpha cells. Islet BG is the secondary regulator. Glucagon is stimulated inversely to insulin. This is why insulin-deficient response to portal nutrients (i.e. glucose and amino acids) results in hyperglucagonemia for the entire absorptive/prandial period after a meal. It is the hyperglucagonemia itself that is responsible, almost entirely, for the hyperglycemia of diabetes. The liver exhibits excessive HGO (hepatic glucose output), but is correctly and normally responding to the hypoinsulinemic/hyperglucagonemic portal signaling.</p><p>This basic endocrinology has been verified by experiment continually since the 1970s. Roger Unger and colleagues did the original work, and Unger had to invent the first glucagon assay in order to accomplish this. I would recommend the work of Unger's current lab and also that of Alan Cherrington's lab for reference. And there are others that study the portal endocrinology in a quantitative fashion -- that is, they make measurements in vivo (usually in canine models).</p><p>The simplistic, and completely incorrect, notion that T2DM is a disease of whole-body IR and does not include insulin-secretion deficiency, beta-cell apoptosis, beta-cell derangement and lipotoxicity, etc. is absolutely tragic, especially for T2Ds. One need only read the massive body of islets research, including direct imaging of in-vivo islets in T2DM as well as extensive analysis of endocrine pancreas in autopsy, to understand this. The massive loss of beta cells in an overt T2D is not really subject to question, nor is the insulin deficiency at this stage of the condition.</p><p>Both pre-diabetics and overt T2Ds should practice strict ketogenic diets. These conditions are straightforwardly reversible, unlike other forms of diabetes, although full reversal and normalization of beta-cell population will take more than a decade for any overt T2D and is rarely accomplished. T2Ds should be using insulin to prevent the tissue death of diabetic complications that occur due to postprandial excursions. Other drugs such as metformin and GLP-1 agonists are simply impotent, especially during the most important hyperglycemic intervals of time following meals.</p><p>The process of tissue death, especially in certain tissues that do not express insulin, over many years due to diabetic hyperglycemia is INSIDIOUS. Later in life overt diabetics (excepting MODY2, in which complications do not occur because there is no insulin secretion defect) who do not practice insulin therapy to (albeit crudely) compensate for hyperglucagonemia and excessive HGO are likely to regret it. The excessive HGO (via hepatic glycogenolysis) of the diabetic cannot be prevented by any yet-known technology. However, exogenously-administred subcutaneous insulin flux (into circulation) can drive the excess glucose into "clearance" tissues -- mainly muscle -- to prevent large hyperglycemic transients.</p><p>Because a diabetic overproduces hepatic glycogen/glucose every day, and the substrates for this are gluconeogenic amino acids, the diabetic would be very wise to practice a diet rich in animal-source protein. So would the aging non-diabetic, for many reasons. But a diabetic definitely needs MORE high-quality protein on a daily basis due to the extra demand for hepatic gluconeogenic production.</p></blockquote><p></p>
[QUOTE="KenMacK, post: 2052594, member: 506757"] Sorry, the widespread myth that a T2D is not insulin deficient reflects the widespread misunderstanding of the hepatic-islets (i.e. portal) axis and its endocrinology, both in diabetes and in non-diabetes. This is WHY I emphasized that there is sustantial insulin deficiency in T2DM. The basics of the endocinological defects of T1DM, T2DM, and almost all forms of MODY (excepting MODY2 or the glucokinase monogenic form) are underpinned by an insulin-secretion deficiency. Regardless of the specific form of diabetes, which is very different at the endocrine-pancreatic/cellular level, diabetes will not be diagnosed by conventional medical practice and guidelines until the overall beta-cell function drops to 20% (a loss of 80% in the acquired forms, T1DM and T2DM). In my form of MODY there is never any loss -- there is an underexpression of many proteins underpinning insulin production/secretion in the beta cells due to inherited mutations in the HNF1-alpha homeobox gene (HNF stands for "Hepatic Nuclear Factor" -- the gene is expressed in endocrine pancreas, liver, small intestine and kidneys). In T1DM all of the loss of function is due to death/destruction of beta cells. The remaining beta cells are normal, but there are far too few present to balance the alpha cell population. In T2DM the loss of function comes from BOTH beta-cell apoptosis (i.e. death) and from beta-cell derangement (i.e. the remaining beta cells have abnormal and weak function, and are morphologically distorted and visibly inflamed). However, regardless of type, the clinical manifestation (i.e. diagnosis) of diabetes does not occur until beta-cell function drops to 20% of normal. This takes years in either T1DM or T2DM. When the 20% threshold is crossed there is loss of insulin granulation (i.e. storage) in beta cells, and this results in the classic clinical symptoms of polyuria and polydipsia. The sudden appearance of these symptoms only occurs once insulin granulation is lost. It is very rare that diabetes is diagnosed until these symptoms appear. IMO it is likely that a form of insulin resistance underpins T2DM (whereas this is not intrinsically true of T1DM or MODY), and that this insulin resistance is the earliest detectable defect of pre-diabetes, occuring in the alpha cells. Many independent diabetes basic research groups have detected the early defect in different ways, and it produces the hyperglucagonemia intrinsic to insulin deficiency of diabetes. However, at this early stage there is no insulin deficiency (yet) in animal models of T2DM. IR is one hypothesis that could explain the observed "early defect" of pre-diabetes (i.e. metabolic syndrome), but there are others and noone has yet been able to develop an experimental method to investigate the mechanism in alpha cells directly. In the endocrine pancreas, or islets, insulin is the primary regulator of glucagon secretion by alpha cells. Islet BG is the secondary regulator. Glucagon is stimulated inversely to insulin. This is why insulin-deficient response to portal nutrients (i.e. glucose and amino acids) results in hyperglucagonemia for the entire absorptive/prandial period after a meal. It is the hyperglucagonemia itself that is responsible, almost entirely, for the hyperglycemia of diabetes. The liver exhibits excessive HGO (hepatic glucose output), but is correctly and normally responding to the hypoinsulinemic/hyperglucagonemic portal signaling. This basic endocrinology has been verified by experiment continually since the 1970s. Roger Unger and colleagues did the original work, and Unger had to invent the first glucagon assay in order to accomplish this. I would recommend the work of Unger's current lab and also that of Alan Cherrington's lab for reference. And there are others that study the portal endocrinology in a quantitative fashion -- that is, they make measurements in vivo (usually in canine models). The simplistic, and completely incorrect, notion that T2DM is a disease of whole-body IR and does not include insulin-secretion deficiency, beta-cell apoptosis, beta-cell derangement and lipotoxicity, etc. is absolutely tragic, especially for T2Ds. One need only read the massive body of islets research, including direct imaging of in-vivo islets in T2DM as well as extensive analysis of endocrine pancreas in autopsy, to understand this. The massive loss of beta cells in an overt T2D is not really subject to question, nor is the insulin deficiency at this stage of the condition. Both pre-diabetics and overt T2Ds should practice strict ketogenic diets. These conditions are straightforwardly reversible, unlike other forms of diabetes, although full reversal and normalization of beta-cell population will take more than a decade for any overt T2D and is rarely accomplished. T2Ds should be using insulin to prevent the tissue death of diabetic complications that occur due to postprandial excursions. Other drugs such as metformin and GLP-1 agonists are simply impotent, especially during the most important hyperglycemic intervals of time following meals. The process of tissue death, especially in certain tissues that do not express insulin, over many years due to diabetic hyperglycemia is INSIDIOUS. Later in life overt diabetics (excepting MODY2, in which complications do not occur because there is no insulin secretion defect) who do not practice insulin therapy to (albeit crudely) compensate for hyperglucagonemia and excessive HGO are likely to regret it. The excessive HGO (via hepatic glycogenolysis) of the diabetic cannot be prevented by any yet-known technology. However, exogenously-administred subcutaneous insulin flux (into circulation) can drive the excess glucose into "clearance" tissues -- mainly muscle -- to prevent large hyperglycemic transients. Because a diabetic overproduces hepatic glycogen/glucose every day, and the substrates for this are gluconeogenic amino acids, the diabetic would be very wise to practice a diet rich in animal-source protein. So would the aging non-diabetic, for many reasons. But a diabetic definitely needs MORE high-quality protein on a daily basis due to the extra demand for hepatic gluconeogenic production. [/QUOTE]
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