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xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article reviews key advances that have increased our understanding of the pathogenesis of diabetes.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EExclusive Article - For home page\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPrevention \u0026amp; Screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EDomenico Accili, MD, Columbia University, New York, New York, USA, delivered the Claude Bernard Lecture, reviewing key advances that have increased our understanding of the pathogenesis of diabetes.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EAccording to Dr Accili, in the 1980s diabetes researchers thought that the disease could be conquered if the paramount issues in its pathogenesis could be determined\u2014in particular,\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n            \u003Cp id=\u0022p-4\u0022\u003EWhy does glucose fail to promote glucose uptake?\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n            \u003Cp id=\u0022p-5\u0022\u003ECan a more durable insulin secretagogue be developed?\u003C\/p\u003E\n         \u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-6\u0022\u003EResearch consequently focused on developing tracer methods to evaluate glucose disposal and how insulin functioned to promote glucose uptake. Although it was thought that the subsequent cloning of numerous glucose transporters would provide clarification on these matters, decades later they remain unresolved. In fact, there has been a shift in focus.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EDr Accili discussed research performed in his laboratory in 1995 in which blocking the ability of insulin to promote glucose disposal in fat and muscle did not cause \u03b2-cell stress and hyperglycemia. This research led him to hypothesize that it was essential to focus on other sources of insulin resistance.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EIn what he refers to as \u201cthe new biology of diabetes,\u201d Dr Accili discussed the key pathophysiologic abnormalities involved in the progression of type 2 diabetes mellitus (T2DM), which are now known to include the following:\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-2\u0022\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n            \u003Cp id=\u0022p-9\u0022\u003EAbnormal hepatic lipid synthesis and lipoprotein production\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\n            \u003Cp id=\u0022p-10\u0022\u003EAltered endothelial response to vasoactive stressors\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-5\u0022\u003E\n            \u003Cp id=\u0022p-11\u0022\u003EAlterations in adipostatic hormones\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-6\u0022\u003E\n            \u003Cp id=\u0022p-12\u0022\u003ENumerous inflammatory changes\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-7\u0022\u003E\n            \u003Cp id=\u0022p-13\u0022\u003EPossible central nervous system involvement\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-8\u0022\u003E\n            \u003Cp id=\u0022p-14\u0022\u003ECellular biological changes that destroy pancreatic \u03b2 cells\u003C\/p\u003E\n         \u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-15\u0022\u003EDr Accili emphasized that understanding this complex set of interactions has tremendous potential for the development of novel therapies.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EIn the 1990s, a new protein, the FoxO (forkhead box O) transcription factor, was discovered to play a central role in hepatic gluconeogenesis\u2014one of the unsolved mysteries of diabetes. Of the many proteins in this family of transcription factors, FoxO1 is particularly important in the control of insulin-regulated gluconeogenesis in the liver through the enzyme glucose-6-phosphatase (G6Pase). G6Pase is required to allow the liver to release glucose. It is induced by glucagon during fasting and suppressed by insulin after a meal. If one genetically removes FoxO, Dr Accili noted, G6Pase is no longer induced by fasting nor suppressed by insulin. Moreover, if one blocks the ability of insulin to inhibit FoxO, the effect of insulin on G6Pase is also blocked\u2014indicating that it requires FoxO inactivation. FoxO therefore oversees the conversion of G6Pase to glucose that is necessary for hepatic glucose conversion, and insulin suppresses this step through FoxO. This discovery represents important progress, even though it has not resulted in complete understanding of how insulin controls hepatic glucose production (HGP).\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003ESince its discovery, FoxO has continued to be useful in furthering understanding of insulin action. Research has now shown that through FoxO, insulin also has roles in the following:\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-3\u0022\u003E\u003Cli id=\u0022list-item-9\u0022\u003E\n            \u003Cp id=\u0022p-18\u0022\u003EAppetite control\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-10\u0022\u003E\n            \u003Cp id=\u0022p-19\u0022\u003EEnergy efficiency\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-11\u0022\u003E\n            \u003Cp id=\u0022p-20\u0022\u003EHepatic glucose and lipid metabolism\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-12\u0022\u003E\n            \u003Cp id=\u0022p-21\u0022\u003EDifferentiation of endocrine progenitor cells\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-13\u0022\u003E\n            \u003Cp id=\u0022p-22\u0022\u003E\u03b2-cell function at various levels\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-14\u0022\u003E\n            \u003Cp id=\u0022p-23\u0022\u003EEndothelial response to atherogenic processes\u003C\/p\u003E\n         \u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-24\u0022\u003EDr Accili reviewed 2 areas of research with important implications for clinical decision making, highlighting the potential for them to give rise to new diabetes therapies.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EDIABETES AND ATHEROSCLEROSIS\u003C\/h2\u003E\n         \u003Cp id=\u0022p-25\u0022\u003EStatistics published by the American Heart Association have shown that heart disease and stroke are the major causes of death among patients with diabetes. A growing emphasis on helping patients achieve tight glycemic control has reduced the risk of microvascular complications associated with diabetes, but it remains a challenge to reduce the risk of macrovascular complications, which account for half of all diabetes-related health care costs. The liver is a key contributor to the atherogenic process, primarily because of the release of atherogenic lipoproteins.\u003C\/p\u003E\n         \u003Cp id=\u0022p-26\u0022\u003EInsulin affects hepatic lipid metabolism and may promote an atherogenic profile, Dr Accili noted. While FoxO is important in the control of glucose production through its regulation of G6Pase, FoxO also regulates its opposing enzyme, glucokinase (GCK). Under normal physiologic conditions, as glucose flows in and out of the liver, plasma glucose levels are maintained within a narrow range by the interplay of the GCK:G6Pase ratio. GCK also has the ability to promote lipogenesis. In the absence of FoxO, neither of these mechanisms functions appropriately. Consequently, instead of glucose being released by the liver for use by other tissues as an energy source, it is converted into fat. Additional experimental work has also confirmed the strong relationship between GCK levels and the amount of triglycerides in the liver [Peter A et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E. 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-27\u0022\u003EDr Accili explained that the intertwined nature of these processes has numerous implications. In patients with insulin resistance, as insulin levels increase to suppress HGP, they also promote GCK-dependent hepatic fat accumulation and triglyceride synthesis. Consequently, he proposed that an atherogenic lipoprotein profile is the price paid by the body to suppress HGP in the early stages of diabetes. He stressed that, at the clinical level, prevention of cardiovascular disease in T2DM must begin early, possibly even before the onset of fasting hyperglycemia. Trying to design a hepatic insulin sensitizer devoid of effects on lipoproteins will prove challenging.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EWHY \u03b2 CELLS FAIL\u003C\/h2\u003E\n         \u003Cp id=\u0022p-28\u0022\u003EThe intrinsic susceptibility for the functional exhaustion of \u03b2 cells differentiates individuals who go on to develop T2DM from those who do not. Although insulin resistance has been considered to be pivotal in the development of T2DM in recent decades, it does not lead to T2DM unless there is also \u03b2-cell dysfunction, because healthy \u03b2 cells can compensate for insulin resistance by increasing their number and the production of insulin [Kitamura T. \u003Cem\u003ENat Rev Endocrinol\u003C\/em\u003E. 2013]. \u03b2-cell failure is initially reversible, however, even after the onset of hyperglycemia. Dr Accili went on to emphasize 3 key islet abnormalities in T2DM:\u003C\/p\u003E\n         \u003Cul class=\u0022list-unord \u0022 id=\u0022list-4\u0022\u003E\u003Cli id=\u0022list-item-15\u0022\u003E\n               \u003Cp id=\u0022p-29\u0022\u003EAn impaired insulin response to a stimulus\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-16\u0022\u003E\n               \u003Cp id=\u0022p-30\u0022\u003EReduced \u03b2-cell mass\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-17\u0022\u003E\n               \u003Cp id=\u0022p-31\u0022\u003EAn inappropriate glucagon response\u003C\/p\u003E\n            \u003C\/li\u003E\u003C\/ul\u003E\n         \u003Cp id=\u0022p-32\u0022\u003EDr Accili discussed the changes in FoxO1 activity in the \u03b2 cell during the progression of diabetes, noting that, in early diabetes, FoxO1 is activated by moving into the nucleus, while in advanced stages of the disease, FoxO1 disappears from the \u03b2 cell along with insulin. Research has also now shown that dedifferentiation, not cell death, is the main cause of \u03b2-cell failure in diabetes and that dedifferentiated \u03b2 cells convert to non-\u03b2 endocrine cells. FoxO1 is implicated in these mechanisms [Talchai C et al. \u003Cem\u003ECell\u003C\/em\u003E. 2012]. According to Dr Accili, hyperglycemia-induced loss of FoxO1 alters \u03b2-cell metabolic flexibility, and this metabolic inflexibility sets the stage for \u03b2-cell failure. He noted that, since data from a recently completed study [Kim-Muller JY et al. \u003Cem\u003ECell Metab\u003C\/em\u003E. 2014] have also demonstrated the occurrence of \u03b2-cell dedifferentiation in people with T2DM, the paradigm for new therapeutic approaches to T2DM should shift to one that aims to restore \u03b2-cell differentiation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-33\u0022\u003EIn his concluding remarks, Dr Accili described another interesting discovery from his laboratory\u2014namely, that genetic removal of FoxO1 from endocrine progenitor cells in the gastrointestinal tract converts these gut cells into functional insulin-producing cells. Although this was initially seen in mice [Talchai C et al. \u003Cem\u003ENat Genet\u003C\/em\u003E. 2012], more recent work also demonstrated this mechanism in genetically engineered human cells [Bouchi R et al. \u003Cem\u003ENat Commun\u003C\/em\u003E. 2014]. Dr Accili added that, in addition to producing insulin, these cells release insulin in a physiologic-like manner. These findings highlight the potential to design drugs that can convert cells in the gut into insulin-producing cells, as a way to treat type 1 diabetes and possibly even T2DM.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/32\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzlwkp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}