From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus
TLDR
Eight players comprise the ominous octet and dictate that treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects.Abstract:
Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.
The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …read more
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Journal Article
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
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TL;DR: In this article, the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.
Journal ArticleDOI
Role of Insulin Resistance in Human Disease
TL;DR: The possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
Journal Article
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
R C Turner,C Fox,Matthews,H McElroy,Carole A. Cull,Rury R. Holman,P. A. Neil,D R Hadden,D Wright,E Manley,Irene M Stratton,UK Prospective Diabetes,E M Kohner,Frighi,Michael Gnant +14 more
TL;DR: The effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.
Journal ArticleDOI
PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
Vamsi K. Mootha,Cecilia M. Lindgren,Cecilia M. Lindgren,Karl-Fredrik Eriksson,Aravind Subramanian,Smita Sihag,J. Lehar,Pere Puigserver,Emma Carlsson,Martin Ridderstråle,Esa Laurila,Nicholas E. Houstis,Mark J. Daly,Nick Patterson,Jill P. Mesirov,Todd R. Golub,Todd R. Golub,Pablo Tamayo,Bruce M. Spiegelman,Eric S. Lander,Joel N. Hirschhorn,Joel N. Hirschhorn,Joel N. Hirschhorn,David Altshuler,Leif Groop +24 more
TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
Journal Article
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
R C Turner,Rury R. Holman,Irene M Stratton,Carole A. Cull,David R Matthews,Susan E. Manley,V Frighi,D Wright,Andrew Neil,E M Kohner,H McElroy,C Fox,D R Hadden,Grp Ukpds. +13 more
TL;DR: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.
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R C Turner,Rury R. Holman,Carole A. Cull,Irene M Stratton,David R Matthews,V Frighi,Susan E. Manley,Andrew Neil,K McElroy,D Wright,E. M. Kohner,Caroline S. Fox,D R Hadden,Z Mehta,Albert V. Smith,Z Nugent,Richard Peto,A I Adlel,Jim Mann,P A Bassett,S. Oakes,Tim Dornan,Stephen J Aldington,H Lipinski,R Collum,K Harrison,C MacIntyre,S Skinner,A Mortemore,D Nelson,S Cockley,S Levien,L Bodsworth,R Willox,T Biggs,S Dove,E Beattie,M Gradwell,S Staples,R Lam,F Taylor,L Leung,R D Carter,S M Brownlee,K E Fisher,K Islam,R. Jelfs,P A Williams,F A Williams,P J Sutton,A Ayres,Lisa Logie,C Lovatt,M A Evans,L A Stowell,I Ross,I A Kennedy,D. J. Croft,A H Keen,C Rose,M Raikou,A E Fletcher,Christopher J. Bulpitt,Clare Battersby,J S Yudkin,Richard Stevens,M R Stearn,S L Palmer,M S Hammersley,S L Franklin,R S Spivey,Jonathan C. Levy,C R Tidy,N J Bell,J Steemson,B A Barrow,R Coster,K Waring,L Nolan,E Truscott,N Walravens,L Cook,H Lampard,C Merle,P Parker,J McVittie,I Draisey,L E Murchison,Brunt Ahe.,M J Williams,D W Pearson,Petrie Xmp.,Lean Mej.,D Walmsley,F Lyall,E Christie,J Church,E Thomson,A Farrow,J M Stowers,M Stowers,K McHardy,N Patterson,Alex D. Wright,N A Levi,Shearer Aci.,Thompson Rjw.,G Taylor,S Rayton,M Bradbury,A Glover,A Smyth-Osbourne,C Parkes,J Graham,P England,S Gyde,C Eagle,B Chakrabarti,Josh Smith,J Sherwell,N. W. Oakley,M. Whitehead,G P Hollier,T. Pilkington,J Simpson,Michael W. Anderson,S Martin,J Kean,B Rice,A Rolland,J Nisbet,E M Kohner,A Dornhorst,M C Doddridge,M Dumskyij,S Walji,P Sharp,M Sleightholm,G Vanterpool,G Frost,M Roseblade,S Elliott,S Forrester,Meredith C. Foster,K Myers,R Chapman,J R Hayes,R W Henry,M S Featherston,Archbold Gpr.,M Copeland,R Harper,I Richardson,H A Davison,L Alexander,Scarpello Jhb.,D E Shiers,R J Tucker,Worthington Jrh.,S Angris,A Bates,J Walton,M Teasdale,J Browne,S Stanley,B A Davis,R C Strange,Hadden,L Kennedy,A B Atkinson,P M Bell,D R McCance,J Rutherford,A M Culbert,C Hegan,H Tennet,N Webb,I Robinson,J Holmes,S Nesbitt,A S Spathis,S Hyer,M E Nanson,L M James,J M Tyrell,C Davis,P Strugnell,M Booth,H Petrie,D Clark,S Hulland,J L Barron,B C Gould,J Singer,A Badenoch,M McGregor,L Isenberg,M Eckert,K Alibhai,E Marriot,Christopher E. Cox,R Price,M Fernandez,A Ryle,S Clarke,G Wallace,E Mehmed,J A Lankester,E Howard,A Waite,S MacFarlane,R H Greenwood,J Wilson,M J Denholm,R C Temple,K Whitfield,F Johnson,C Munroe,S Gorick,E Duckworth,M Fatman,S Rainbow,L J Borthwick,D J Wheatcroft,R J Seaman,R A Christie,W Wheatcroft,P Musk,Jennifer White,S McDougal,M Bond,P Raniga,J L Day,M J Doshi,James G. Wilson,J. Howard-Williams,H Humphreys,A Graham,K Hicks,S Hexman,P Bayliss,D Pledger,R W Newton,R T Jung,C Roxburgh,B Kilgallon,L Dick,N Waugh,S Kilby,A Ellingford,J Burns,C Fox,M C Holloway,H M Coghill,N Hein,A J Fox,W Cowan,M Richard,K Quested,S J Evans,Richard B Paisey,Brown Npr.,A J Tucker,R Paisey,F Garrett,J Hogg,P Park,K Williams,P Harvey,R Wilcocks,S Mason,J. C. Frost,C Warren,P Rocket,L Bower,J M Roland,D J Brown,J Youens,K Stanton-King,H Mungall,V Ball,W Maddison,D Donnelly,S King,P Griffin,Sidney C. Smith,S Church,Graham Dunn,Andrew D. Wilson,K Palmer,P M Brown,D Humphriss,Davidson Ajm.,Richard Rose,L Armistead,S Townsend,P Poon,Peacock Ida.,Culverwell Njc.,M H Charlton,Connolly Bps.,J Peacock,J Barrett,J Wain,W Beeston,George L. King,P G Hill,Boulton Ajm.,A M Robertson,V Katoulis,A Olukoga,H McDonald,S Kumar,F Abouaesha,B Abuaisha,E A Knowles,S Higgins,J Booker,J Sunter,K Breislin,R Parker,P Raval,J Curwell,H Davenport,G Shawcross,A Prest,J Grey,H Cole,C Sereviratne,R J Young,J R Clyne,M Gibson,I O'Connell,L M Wong,S J Wilson,K L Wright,Chris Wallace,D McDowell,A C Burden,E M Sellen,R Gregory,M Roshan,N Vaghela,M Burden,C Sherriff,S Mansingh,J Clarke,J Grenfell,Je Tooke,K. M. MacLeod,C Seamark,M Rammell,C Pym,J Stockman,C Yeo,J Piper,L Leighton,Ellen Green,M Hoyle,K Jones,A Hudson,A J James,Angela C. Shore,A Higham,B Martin,Neil Haw.,Butterfield Wjh.,Doll Wrs.,R Eastman,F R Ferris,N Kurinij,K McPherson,R F Mahler,Tom W. Meade,G Shafer,P J Watkins,H Keen,D Siegel,D J Betteridge,R D Cohen,D Currie,Julie L Darbyshire,J V Forrester,T Guppy,D G Johnston,Alistair McGuire,Mike Murphy,A M el-Nahas,B Pentecost,D Spiegelhalter,Alberti Kgmm.,R Denton,Philip Home,S Howell,Jarrett,V Marks,Michael Marmot,J D Ward,Grp Ukpds. +398 more