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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv 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 discusses the controversies over insulin as an initial treatment of type 2 diabetes, the relationship between insulin sensitivity and exercise, portal insulin, as well as combination therapy with insulin and oral agents.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Einsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ediabetes mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EControversies over Insulin as Initial Treatment of Type 2 Diabetes\u003C\/h2\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Sweden.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-616651692\u0022 data-figure-caption=\u0022Sweden.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure1\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/10827\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n               \u003Cp id=\u0022p-2\u0022 class=\u0022first-child\u0022\u003ESweden.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EEarly insulin treatment may temporarily improve endogenous insulin secretion, which will result in better glycemic control, explained Michael Alvarsson, MD, PhD, Karolinska University Hospital, Stockholm, Sweden.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EThe possible benefits of early insulin treatment on insulin secretion are the effects of rapid normalization of blood glucose similar to other glucose-lowering agents (\u201cmore or less proven\u201d), and the potential benefit of \u201cbeta cell rest\u201d (not proven), according to Dr. Alvarsson.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EIneffective or inappropriate treatments expose patients to hyperglycemia and increase the risk of micro and macrovascular complications. The potential benefits of the early initiation of insulin are rapid glycemic control, possibly at lower insulin doses needed to achieve glycemic targets, lower risk of hypoglycemia and lower risk of weight gain due to smaller doses of insulin. The early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting weight gain or increased hypoglycemia (Wright A, et al. \u003Cem\u003EDiab Care\u003C\/em\u003E 2002). One study showed that when insulin was started in patients with newly-diagnosed type 2 diabetes and then stopped after near euglycemia was achieved, about 50% of individuals required oral drugs and a few required insulin within a year (\u003Cem\u003EDiab Care\u003C\/em\u003E 2004).\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003E\u201cWe need to start insulin treatment earlier than we do now, initiate insulin treatment more than we do now, and realize that quality of life is not affected in a negative way by insulin treatment,\u201d stated Dr. Alvarsson.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EShould insulin be the initial treatment for type 2 diabetes? Not according to Mayer B. Davidson, MD, UCLA School of Medicine, Los Angeles, CA. Dr. Mayer explained that the treatment of markedly symptomatic type 2 diabetic patients involves a number of therapeutic considerations: \u0026gt;90% can be successfully treated with sulfonylureas (max doses in patients \u0026lt;65; 1\/2 max dose in patients \u0026gt;65), and insulin should be used only if oral agents do not bring patients to target (Peters AL, et al. \u003Cem\u003EJ Clin Endocrinal Metab\u003C\/em\u003E 1996).\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe Mechanisms of Exercise\u003C\/h2\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EEnhanced insulin action on glucose uptake in the leg occurs 4 to 10 hours after exercise in humans (Richter et al. \u003Cem\u003EJ Appl Physiology\u003C\/em\u003E 1989). Exercise causes a prolonged reduction of malonyl coenzyme A (COA), which may increase insulin sensitivity, explained Erik A. Richter, MD, PhD, University of Copenhagen, Copenhagen, Denmark. Even in as little as four hours after exercise, there is a decrease in malonyl coA (p\u0026lt;0.05 rested versus exercise leg). Prior exercise does not alter insulin\u0027s effect on IR activity in vitro, IRS-1 associated P13K, and aPKC Thr410 phosphorylation; however, it does increase IRS-2 associated P13K activity in the resting state and during insulin stimulation, which could lead to increased production of PIP-3 (Roepstorff et al, unpublished).\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EThe STRRIDE study (Kraus et al. \u003Cem\u003EMSSE\u003C\/em\u003E 2001) found that a high-dose vigorous exercise group had a greater percentage of change in body mass compared to those who exercised at a moderate level. However, those in the moderate exercise group had a larger decrease in triglycerides, a larger percentage increase in insulin sensitivity index (ISI), and a larger percent increase in homeostasis model assessment (HOMA).\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EExercise can also alter where fat is deposited in the body. A study which compared women athletes and normal-weight controls between ages 18 and 70 found that visceral fat increased with age in both groups (Ryan et al. \u003Cem\u003EAJP\u003C\/em\u003E 1996). However, there was a reduction in visceral fat and increased glucose utilization when weight loss was combined with aerobic or resistive training. Adipokines, which are inflammatory markers that may have direct effects on liver and skeletal muscle, also decrease with aerobic training.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EAlice Smith Ryan, PhD, University of Maryland School of Medicine, Baltimore, MD, stated that weight loss in combination with exercise increases skeletal muscle lipoprotein lipase (LPL) activity and decreases adipose tissue LPL activity. LPL regulates the uptake and storage of triglycerides-fatty acids (TG-FA) by fat and muscle. Weight loss alone has no effect on basal skeletal muscle, nor does it change mean adipose tissue LDL activity in the abdomen or gluteal region. The combination of exercise and weight loss is vital for improving metabolic parameters.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-616651692\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure2\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure2\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/6\/2\/21\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/10829\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EType 2 Diabetes \u2014 Where Do We Go From Here?\u003C\/h2\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EMatthew C. Riddle, MD, Ohio State University, Columbus, OH, explained that portal insulin is the main regulator of glucose production. Systemic insulin suppresses free fatty acid (FFA) production and further reduces glucose production. Subcutaneously injected insulin augments both portal and systemic insulin and suppresses basal overproduction of glucose.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EBasal insulin controls basal glucose. Other favorable metabolic effects of basal insulin include reducing hypertriglyceridimia, improving high-density lipoprotein (HDL) levels, improving vasodilatory responses, and suppressing inflammatory markers. Endothelium-dependent vasodilation improves after starting basal insulin (Yki-Jarvinen H et al. \u003Cem\u003EArterioscler Throm Vase Biol\u003C\/em\u003E 2000).\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EThe \u201cproof of principle\u201d for basal insulin is the \u201cTreat to Target\u201d trial (Riddle M et al. \u003Cem\u003EDiab Care\u003C\/em\u003E 2003). The trial examined the use of bedtime glargine versus bedtime NPH added to 1 or 2 oral agents with a strict titration scale to lower fasting glucose levels. Fifty-eight percent of T2 patients reached the 7% A1C target (starting mean A1C 8.6%). Glargine caused less hypoglycemia than NPH. Dr. Riddle and colleagues concluded that the success of treatment was not affected by age or gender.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EDr. Riddle explained that ways to manage postprandial plasma glucose (PPG) after basal insulin titration are to switch to twice daily premixed or intermediate acting insulin; add the GLP-1 agonist exenatide, or add prandial injection in a step-wise fashion.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003E\u201cFive years ago we couldn\u0027t get anyone to 7%, and now 15% of our patients reach 7%. We have to use whatever means are available to reach that,\u201d said Dr. Riddle.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003ECombination therapy is another alternative. Reasons to consider using combination therapy with insulin and oral agents, according to Philip Raskin, CDE, MD, University of Texas, Southwestern Medical Center, Dallas, TX, are better glycemic control (drug synergy) and better patient acceptability.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EDr. Raskin went on to explain the effect of triple therapy in type 2 diabetes. Twenty-eight subjects with T2 were treated with insulin and metformin (2000 mg daily) or insulin and troglitazone (600 mg\/daily) for four months (Strowig et al. \u003Cem\u003EDiab Care\u003C\/em\u003E 2004). Troglitazone or metformin were added to the patients\u0027 therapy and titrated to the maximum dose. The insulin dose was decreased only to prevent hypoglycemia. The group receiving insulin and troglitazone plus metformin reached glycemic target (p\u0026lt;0.05 versus dual therapies). Triple therapy helped 100% of the subjects reach a target HbA1C of \u0026lt;7.0%, with 83% of them reaching \u0026lt;6.5% and 57% reaching \u0026lt;6.0%.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EThe combination of insulin and insulin sensitizers is a very effective means of achieving glycemic goals in patients with type 2 diabetes noted Dr. Raskin. Thiazolidinediones tend to have greater insulin sensitizing effects than metformin but can result in significant weight gain, he said.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EAdding exenatide to oral agents is another option. David Kendall MD and others conducted a study in which exenatide or placebo was added to maximum-effective doses of metformin and\/or sulfonylurea in patients with type 2 diabetes (Kendall, Diab Care 2005). Patients who received exenatide were more likely to achieve A1C \u22647% compared with patients who received placebo (\u003Cem\u003EP\u003C\/em\u003E\u0026lt; 0.0001).\u003C\/p\u003E\n         \u003Cdiv class=\u0022boxed-text\u0022 id=\u0022boxed-text-1\u0022\u003E\u003Cbr\/\u003E\u003Cdiv class=\u0022graphic\u0022 id=\u0022graphic-3\u0022\u003E\u003Cdiv class=\u0022graphic-inline anchor\u0022\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/highwire\/spmdc\/6\/2\/21\/embed\/graphic-3.gif\u0022\/\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-21\u0022\u003EWhy add on exenatide? Exenatide works, explained Robert E. Ratner, MD, MedStar Research Institute, Washington, DC:\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n                  \u003Cp id=\u0022p-22\u0022\u003EPatients can achieve A1C goals without weight gain and in many cases with weight loss\u003C\/p\u003E\n               \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n                  \u003Cp id=\u0022p-23\u0022\u003EExenatide is simple \u2014 \u0026gt;40% of patients reach goal after six months with minimum titration and no adjustments\u003C\/p\u003E\n               \u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n                  \u003Cp id=\u0022p-24\u0022\u003EExenatide is durable \u2014 providing A1C-lowering maintenance over 2 years\u003C\/p\u003E\n               \u003C\/li\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\n                  \u003Cp id=\u0022p-25\u0022\u003EExanatide is safe \u2014 low and progressively lower GI adverse events\u003C\/p\u003E\n               \u003C\/li\u003E\u003Cli id=\u0022list-item-5\u0022\u003E\n                  \u003Cp id=\u0022p-26\u0022\u003EExenatide causes minimal hypoglycemia when used in combination with metformin\u003C\/p\u003E\n               \u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2006 MD Conference Express\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\/6\/2\/21.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_figures.js?nzm5u2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzm5u2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}