The Vasculature in Prediabetes

In the paper

“Lowering glucose without addressing the vascular effects of insulin resistance may be insufficient to reduce risk of cardiovascular events.”

What the sources say

• Partly supported

  The Discussion (page not provided) reports that basal insulin glargine maintained near-normal glycemic control but had a neutral effect on cardiovascular outcomes, supporting the possibility that this intervention was insufficient to reduce cardiovascular risk. It does not establish that unaddressed vascular effects of insulin resistance explain the result; the Discussion also cautions that the trial was not designed to test more versus less intensive glucose lowering. (LLM, conf=0.84)

  cites [27] Investigators OT Gerstein HC Bosch J Dagenais GR Diaz R Jung H Maggioni AP Pogue J Probstfield J Ramachandran A Riddle MC Ryden LE Yusuf S Basal insulin and cardiovascular and other outcomes in dysglycemia N Engl J Med 2012 367 319 28 22686416 sourceExperimental — accuracy not yet measured

In the paper

“dipeptidyl peptidase-4 (DPP4) inhibition prevents the amino-terminus degradation of HMGB1.”

What the sources say

• Supported

  The Discussion states that one month of gliptin treatment prevented DPP-IV-mediated cleavage of HMGB1. The HMGB1 cleavage by DPP-IV section identifies the cleaved portion as the N-terminal region. The evidence is specifically from patients with type 2 diabetes and laboratory analysis. (LLM, conf=0.94)

  cites [80] Marchetti C Di Carlo A Facchiano F Senatore C De Cristofaro R Luzi A Federici M Romani M Napolitano M Capogrossi MC Germani A High mobility group box 1 is a novel substrate of dipeptidyl peptidase-IV Diabetologia 2012 55 236 44 21656024 source

In the paper

“Weight loss explained 64% of the beneficial effect.”

What the sources say

• ?Could not verify

  The Results section (‘Weight loss and Adherence to Metformin’ and ‘Incidence of Diabetes’; page not provided) reports sustained weight loss with metformin and a reduction in diabetes incidence. It does not say that weight loss explained 64% of metformin’s benefit; searches for ‘64%’ and weight-loss mediation found no such analysis in our copy. (LLM, conf=0.72)

  cites [196] Diabetes Prevention Program Research G Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study Lancet Diabetes Endocrinol 2015 3 866 75 26377054 PMC4623946 sourceExperimental — accuracy not yet measured

In the paper

“Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)s improve endothelium-dependent vasodilation and reduce morbidity and mortality in heart failure and nephropathy, including diabetic nephropathy.218-221”

What the sources say

• Not checked yetcites [218] Lewis EJ Hunsicker LG Bain RP Rohde RD The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group N Engl J Med 1993 329 1456 62 8413456 source
• ?Could not verify

  The Discussion (pp. 5–7) and reported results address renal outcomes and heart-failure hospitalization, not endothelium-dependent vasodilation. Searches for that term and for endothelial function found no passage in our copy assessing whether ACE inhibitors or ARBs improve it. (LLM, conf=0.75)

  cites [219] Brenner BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving HH Remuzzi G Snapinn SM Zhang Z Shahinfar S Investigators RS Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy N Engl J Med 2001 345 861 9 11565518 sourceExperimental — accuracy not yet measured
• Not checked yetcites [220] Parving HH Lehnert H Brochner-Mortensen J Gomis R Andersen S Arner P Irbesartan in Patients with Type D and Microalbuminuria Study G The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes N Engl J Med 2001 345 870 8 11565519 source
• Not checked yetcites [221] Demers C McMurray JJ Swedberg K Pfeffer MA Granger CB Olofsson B McKelvie RS Ostergren J Michelson EL Johansson PA Wang D Yusuf S Investigators C Impact of candesartan on nonfatal myocardial infarction and cardiovascular death in patients with heart failure JAMA 2005 294 1794 8 16219883 source

In the paper

“Ford et al estimated a relative risk of cardiovascular disease of 1.20 (95% CI 1.12-1.28) when 6.1 mmol/L (110 mg/dL) was used to define IFG (IFG-WHO)”

What the sources say

• Not checked yetcites [24] Ford ES Zhao G Li C Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence J Am Coll Cardiol 2010 55 1310 7 20338491 source

In the paper

“In general, HbA1c measurement has less predictive value.”

In the paper

“a relative risk of 1.18 (95% CI 1.09-1.28) when 5.5 mmol/L (IFG-ADA) was used.”

What the sources say

• Not checked yetcites [24] Ford ES Zhao G Li C Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence J Am Coll Cardiol 2010 55 1310 7 20338491 source

In the paper

“subjects with prediabetes require more glucose than a subject with overt type 2 diabetes mellitus (T2DM).”

What the sources say

• Not checked yetcites [6] Laakso M Edelman SV Brechtel G Baron AD Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance J Clin Invest 1990 85 1844 52 2189893 PMC296649 source
• Not checked yetcites [7] Laakso M Edelman SV Brechtel G Baron AD Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM Diabetes 1992 41 1076 83 1499861 source

In the paper

“In a population-based Rotterdam Study of adults aged 45 years, 75% of patients with IFG progressed to T2DM over their lifetime.”

What the sources say

• Not checked yetcites [21] Ligthart S van Herpt TT Leening MJ Kavousi M Hofman A Stricker BH van Hoek M Sijbrands EJ Franco OH Dehghan A Lifetime risk of developing impaired glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a prospective cohort study Lancet Diabetes Endocrinol 2016 4 44 51 26575606 source

In the paper

“phenotypes of insulin resistance such as the presence of non-alcoholic fatty liver disease or visceral obesity predict atherosclerosis.”

What the sources say

• Not checked yetcites [28] Stefan N Fritsche A Schick F Haring HU Phenotypes of prediabetes and stratification of cardiometabolic risk Lancet Diabetes Endocrinol 2016 4 789 798 27185609 source

In the paper

“In the Multi-Ethnic Study of Atherosclerosis the incidence of diabetes was 4% in individuals with IFG.”

What the sources say

• Not checked yetcites [19] Yeboah J Bertoni AG Herrington DM Post WS Burke GL Impaired fasting glucose and the risk of incident diabetes mellitus and cardiovascular events in an adult population: MESA (Multi-Ethnic Study of Atherosclerosis) J Am Coll Cardiol 2011 58 140 6 21718910 PMC3146297 source

In the paper

“In the China Da Qing Diabetes Prevention Study 90% of participants with IGT developed T2DM over 20 years.”

What the sources say

• Not checked yetcites [22] Li G Zhang P Wang J Gregg EW Yang W Gong Q Li H Li H Jiang Y An Y Shuai Y Zhang B Zhang J Thompson TJ Gerzoff RB Roglic G Hu Y Bennett PH The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study Lancet 2008 371 1783 9 18502303 source

In the paper

“many patients with prediabetes also have metabolic syndrome”

What the sources say

• Not checked yetcites [15] Cornier MA Dabelea D Hernandez TL Lindstrom RC Steig AJ Stob NR Van Pelt RE Wang H Eckel RH The metabolic syndrome Endocr Rev 2008 29 777 822 18971485 PMC5393149 source

In the paper

“IGT and T2DM ensue when beta cell function fails to compensate.”

What the sources say

• Not checked yetcites [16] Weyer C Bogardus C Mott DM Pratley RE The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus J Clin Invest 1999 104 787 94 10491414 PMC408438 source

In the paper

“In the Diabetes Prevention Program (DPP), the annual incidence of diabetes in patients with IGT was 11% in the control group.”

What the sources say

• Not checked yetcites [18] Diabetes Prevention Program Research G Knowler WC Fowler SE Hamman RF Christophi CA Hoffman HJ Brenneman AT Brown-Friday JO Goldberg R Venditti E Nathan DM 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study Lancet 2009 374 1677 86 19878986 PMC3135022 source

In the paper

“the microvasculature impacts on insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle”

In the paper

“Among patients with prediabetes, factors associated with insulin resistance including increased oxidative stress, inflammation, and dyslipidemia contribute to microvascular and macrovascular disease.”

In the paper

“Subjects who are insulin-resistant require less glucose at a fixed insulin dose than subjects with normal insulin sensitivity”

What the sources say

• Not checked yetcites [6] Laakso M Edelman SV Brechtel G Baron AD Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance J Clin Invest 1990 85 1844 52 2189893 PMC296649 source

In the paper

“insulin resistance can also result from vascular endothelial dysfunction which leads to decreased delivery of insulin and glucose to insulin-sensitive tissues”

In the paper

“Huang et al reported a relative risk of cardiovascular disease of 1.13, 1.26, and 1.30 in IFG-ADA, IFG-WHO, and IGT, respectively.”

What the sources say

• Not checked yetcites [25] Huang Y Cai X Mai W Li M Hu Y Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis BMJ 2016 355 i5953 27881363 PMC5121106 source

In the paper

“In the Atherosclerosis Risk in Communities (ARIC) study, patients with prediabetes (HbA1c 5.7% to 6.5%) were thirty percent more likely to be hospitalized than non-diabetics.”

What the sources say

• Not checked yetcites [26] Schneider AL Kalyani RR Golden S Stearns SC Wruck L Yeh HC Coresh J Selvin E Diabetes and Prediabetes and Risk of Hospitalization: The Atherosclerosis Risk in Communities (ARIC) Study Diabetes Care 2016 39 772 9 26953170 PMC4839170 source

In the paper

“In the Emerging Risk Factors Collaboration study, there was a linear relationship between glucose and the hazard ratio for coronary heart disease in non-diabetics with a fasting glucose above 5.5 mmol/L (100 mg/dL).”

What the sources say

• Not checked yetcites [23] Emerging Risk Factors C Sarwar N Gao P Seshasai SR Gobin R Kaptoge S Di Angelantonio E Ingelsson E Lawlor DA Selvin E Stampfer M Stehouwer CD Lewington S Pennells L Thompson A Sattar N White IR Ray KK Danesh J Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies Lancet 2010 375 2215 22 20609967 PMC2904878 source

In the paper

“Excess glucose is metabolized through the polyol pathway to fructose and its metabolites, which are potent glycating agents.”

What the sources say

• Not checked yetcites [54] Hamada Y Araki N Koh N Nakamura J Horiuchi S Hotta N Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway Biochem Biophys Res Commun 1996 228 539 43 8920948 source

In the paper

“This suggests that the negative effects of glycation pertain to prediabetes as well as diabetes.”

In the paper

“Glycated low density lipoprotein (LDL) cholesterol, once oxidized or AGE-modified, is recognized by scavenger receptors on macrophages and lead to the formation of foam cells.”

What the sources say

• Not checked yetcites [62] Jinnouchi Y Sano H Nagai R Hakamata H Kodama T Suzuki H Yoshida M Ueda S Horiuchi S Glycolaldehyde-modified low density lipoprotein leads macrophages to foam cells via the macrophage scavenger receptor J Biochem 1998 123 1208 17 9604012 source

In the paper

“Insulin induces nitric oxide (NO)-dependent vasodilation in skeletal muscle via stimulation of the insulin receptor, activation of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3 kinase (PI3-kinase), phosphorylation of Akt and subsequent phosphorylation of endothelial NOS (eNOS).”

What the sources say

• Not checked yetcites [40] Dimmeler S Fleming I Fisslthaler B Hermann C Busse R Zeiher AM Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation Nature 1999 399 601 5 10376603 source
• Not checked yetcites [41] Zeng G Quon MJ Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells J Clin Invest 1996 98 894 8 8770859 PMC507502 source
• Not checked yetcites [42] Zeng G Nystrom FH Ravichandran LV Cong LN Kirby M Mostowski H Quon MJ Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells Circulation 2000 101 1539 45 10747347 source
• Not checked yetcites [43] Montagnani M Ravichandran LV Chen H Esposito DL Quon MJ Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells Mol Endocrinol 2002 16 1931 42 12145346 source
• Not checked yetcites [44] Cardillo C Nambi SS Kilcoyne CM Choucair WK Katz A Quon MJ Panza JA Insulin stimulates both endothelin and nitric oxide activity in the human forearm Circulation 1999 100 820 5 10458717 source

In the paper

“O-GlcNAcylation of eNOS at Ser 1177 decreases its activity.”

What the sources say

• Not checked yetcites [72] Du XL Edelstein D Dimmeler S Ju Q Sui C Brownlee M Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site J Clin Invest 2001 108 1341 8 11696579 PMC209429 source

In the paper

“Hyperglycemia per se influences endothelial function in prediabetes.”

In the paper

“Activated PKC in turn promotes oxidative stress by activating NADPH oxidase.”

What the sources say

• Not checked yetcites [66] Inoguchi T Li P Umeda F Yu HY Kakimoto M Imamura M Aoki T Etoh T Hashimoto T Naruse M Sano H Utsumi H Nawata H High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells Diabetes 2000 49 1939 45 11078463 source
• Not checked yetcites [67] Inoguchi T Sonta T Tsubouchi H Etoh T Kakimoto M Sonoda N Sato N Sekiguchi N Kobayashi K Sumimoto H Utsumi H Nawata H Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase J Am Soc Nephrol 2003 14 S227 32 12874436 source

In the paper

“During hyperglycemia, excess shunting of glucose through the hexosamine pathway results in the O-GlcNAcylation of serine and threonine residues on proteins”

What the sources say

• Not checked yetcites [72] Du XL Edelstein D Dimmeler S Ju Q Sui C Brownlee M Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site J Clin Invest 2001 108 1341 8 11696579 PMC209429 source

In the paper

“Glycation of complex III proteins enhances mitochondrial superoxide production.”

What the sources say

• Not checked yetcites [63] Rosca MG Mustata TG Kinter MT Ozdemir AM Kern TS Szweda LI Brownlee M Monnier VM Weiss MF Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation Am J Physiol Renal Physiol 2005 289 F420 30 15814529 source

In the paper

“insulin stimulates endothelin-1 (ET-1) production via raf-1, p38 mitogen activated protein kinase (MAPK)/ERK kinase (MEK), and extracellular signal-regulated kinase 1/2 (ERK1/2).”

What the sources say

• Not checked yetcites [44] Cardillo C Nambi SS Kilcoyne CM Choucair WK Katz A Quon MJ Panza JA Insulin stimulates both endothelin and nitric oxide activity in the human forearm Circulation 1999 100 820 5 10458717 source
• Not checked yetcites [45] Eringa EC Stehouwer CD Merlijn T Westerhof N Sipkema P Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles Cardiovasc Res 2002 56 464 71 12445887 source
• Not checked yetcites [46] Eringa EC Stehouwer CD van Nieuw Amerongen GP Ouwehand L Westerhof N Sipkema P Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium Am J Physiol Heart Circ Physiol 2004 287 H2043 8 15059773 source
• Not checked yetcites [47] Potenza MA Marasciulo FL Chieppa DM Brigiani GS Formoso G Quon MJ Montagnani M Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production Am J Physiol Heart Circ Physiol 2005 289 H813 22 15792994 source

In the paper

“intra-cellular glucose concentrations reflect plasma glucose concentrations.”

In the paper

“Binding of AGEs to the receptor for AGE (RAGE) enhances the expression of adhesion molecules on endothelial cells to promote the migration and differentiation of monocytes into macrophages.”

What the sources say

• Not checked yetcites [60] Schmidt AM Hori O Chen JX Li JF Crandall J Zhang J Cao R Yan SD Brett J Stern D Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes J Clin Invest 1995 96 1395 403 7544803 PMC185762 source

In the paper

“Insulin resistance contributes to endothelial dysfunction in prediabetes (Figure 1).”

In the paper

“endothelial cells take up glucose through the insulin-independent carrier GLUT-1”

What the sources say

• Not checked yetcites [53] Artwohl M Brunmair B Furnsinn C Holzenbein T Rainer G Freudenthaler A Porod EM Huttary N Baumgartner-Parzer SM Insulin does not regulate glucose transport and metabolism in human endothelium Eur J Clin Invest 2007 37 643 50 17635575 source

In the paper

“AGEs also stimulate monocytes to secrete inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6.”

What the sources say

• Not checked yetcites [61] Vlassara H Brownlee M Manogue KR Dinarello CA Pasagian A Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling Science 1988 240 1546 8 3259727 source

In the paper

“A high hemoglobin glycation index, defined as the measured HbA1c minus a predicted HbA1c calculated from blood glucose, has been associated with cardiovascular disease, in treatment-naïve patients with prediabetes and diabetes.”

What the sources say

• Not checked yetcites [56] Ahn CH Min SH Lee DH Oh TJ Kim KM Moon JH Choi SH Park KS Jang HC Ha J Sherman AS Lim S Hemoglobin Glycation Index Is Associated With Cardiovascular Diseases in People With Impaired Glucose Metabolism J Clin Endocrinol Metab 2017 102 2905 2913 28541544 PMC6283438 source

In the paper

“Inflammation associated with visceral obesity contributes to insulin resistance and endothelial dysfunction in many patients with prediabetes.”

In the paper

“Visceral adipose tissue has an increased number of adipose resident macrophages.”

What the sources say

• Not checked yetcites [81] Weisberg SP McCann D Desai M Rosenbaum M Leibel RL Ferrante AW Jr Obesity is associated with macrophage accumulation in adipose tissue J Clin Invest 2003 112 1796 808 14679176 PMC296995 source
• Not checked yetcites [82] Xu H Barnes GT Yang Q Tan G Yang D Chou CJ Sole J Nichols A Ross JS Tartaglia LA Chen H Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance J Clin Invest 2003 112 1821 30 14679177 PMC296998 source

In the paper

“FFAs activate NADPH oxidase via PKC to generate ROS.”

What the sources say

• Not checked yetcites [66] Inoguchi T Li P Umeda F Yu HY Kakimoto M Imamura M Aoki T Etoh T Hashimoto T Naruse M Sano H Utsumi H Nawata H High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells Diabetes 2000 49 1939 45 11078463 source

In the paper

“consumption of a meal high in fat acutely decreases brachial artery reactivity in humans.”

What the sources say

• Not checked yetcites [74] Vogel RA Corretti MC Plotnick GD Effect of a single high-fat meal on endothelial function in healthy subjects Am J Cardiol 1997 79 350 4 9036757 source

In the paper

“Increased free fatty acids also contribute to insulin resistance and endothelial dysfunction in obese patients with prediabetes.”

In the paper

“FFAs also induce production of high mobility group box 1 (HMGB1) resulting in activation of the nucleotide-binding domain and leucine-rich repeat-containing (NLR) family and the pyrin and HIN domain (PYHIN) (NLRP3) inflammasome.”

What the sources say

• Not checked yetcites [79] Wang L Chen Y Li X Zhang Y Gulbins E Zhang Y Enhancement of endothelial permeability by free fatty acid through lysosomal cathepsin B-mediated Nlrp3 inflammasome activation Oncotarget 2016 7 73229 73241 27689324 PMC5341975 source

In the paper

“The generation of ROS in turn promotes inflammation by activating NF-κB.”

In the paper

“Adipose tissue also influences systemic endothelial function through secretion of inflammatory cytokines such as TNF-α, IL-6, leptin, and resistin.”

What the sources say

• Not checked yetcites [88] Fontana L Eagon JC Trujillo ME Scherer PE Klein S Visceral fat adipokine secretion is associated with systemic inflammation in obese humans Diabetes 2007 56 1010 3 17287468 source

In the paper

“FFAs also reduce ATP-induced mobilization and influx of calcium in endothelial cells.”

What the sources say

• Not checked yetcites [78] Esenabhalu VE Schaeffer G Graier WF Free fatty acid overload attenuates Ca2+ signaling and NO production in endothelial cells Antioxid Redox Signal 2003 5 147 53 12716474 source

In the paper

“Adiponectin concentrations decrease with increased visceral obesity”

What the sources say

• Not checked yetcites [95] Ryan AS Berman DM Nicklas BJ Sinha M Gingerich RL Meneilly GS Egan JM Elahi D Plasma adiponectin and leptin levels, body composition, and glucose utilization in adult women with wide ranges of age and obesity Diabetes Care 2003 26 2383 8 12882866 source
• Not checked yetcites [96] Cote M Mauriege P Bergeron J Almeras N Tremblay A Lemieux I Despres JP Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men J Clin Endocrinol Metab 2005 90 1434 9 15598678 source

In the paper

“High fat intake induces endothelial dysfunction in mice”

What the sources say

• Not checked yetcites [73] Keogh JB Grieger JA Noakes M Clifton PM Flow-mediated dilatation is impaired by a high-saturated fat diet but not by a high-carbohydrate diet Arterioscler Thromb Vasc Biol 2005 25 1274 9 15774905 source

In the paper

“Aldosterone enhances Ang II-stimulated ERK1/2 phosphorylation in vascular smooth muscle cells.”

What the sources say

• Not checked yetcites [104] Mazak I Fiebeler A Muller DN Park JK Shagdarsuren E Lindschau C Dechend R Viedt C Pilz B Haller H Luft FC Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells Circulation 2004 109 2792 800 15159288 source

In the paper

“diminished forearm endothelial t-PA release is associated with an increased risk of cardiovascular events.”

What the sources say

• Not checked yetcites [128] Minai K Matsumoto T Horie H Ohira N Takashima H Yokohama H Kinoshita M Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors J Am Coll Cardiol 2001 37 1565 70 11345366 source
• Not checked yetcites [129] Robinson SD Ludlam CA Boon NA Newby DE Endothelial fibrinolytic capacity predicts future adverse cardiovascular events in patients with coronary heart disease Arterioscler Thromb Vasc Biol 2007 27 1651 6 17463331 source

In the paper

“Increased circulating PAI-1 activity or antigen is associated with increased risk of thrombotic events including myocardial infarction and stroke.”

What the sources say

• Not checked yetcites [113] Thogersen AM Jansson JH Boman K Nilsson TK Weinehall L Huhtasaari F Hallmans G High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor Circulation 1998 98 2241 7 9826309 source

In the paper

“Stimulated t-PA release in the human forearm vasculature correlates with t-PA release in the coronary vasculature”

What the sources say

• Not checked yetcites [128] Minai K Matsumoto T Horie H Ohira N Takashima H Yokohama H Kinoshita M Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors J Am Coll Cardiol 2001 37 1565 70 11345366 source
• Not checked yetcites [129] Robinson SD Ludlam CA Boon NA Newby DE Endothelial fibrinolytic capacity predicts future adverse cardiovascular events in patients with coronary heart disease Arterioscler Thromb Vasc Biol 2007 27 1651 6 17463331 source

In the paper

“Aldosterone also increases insulin-like growth factor (IGF)-1 receptor expression and hybridization with IRS-1 leading to insulin resistance.”

What the sources say

• Not checked yetcites [103] Sherajee SJ Fujita Y Rafiq K Nakano D Mori H Masaki T Hara T Kohno M Nishiyama A Hitomi H Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor Arterioscler Thromb Vasc Biol 2012 32 257 63 22173225 source

In the paper

“PAI-1 levels also predict the development of diabetes in at-risk patients.”

What the sources say

• Not checked yetcites [114] Festa A D’Agostino R Jr Tracy RP Haffner SM Insulin Resistance Atherosclerosis S Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study Diabetes 2002 51 1131 7 11916936 source

In the paper

“Activation of the renin-angiotensin-aldosterone system in obesity further accentuates vascular insulin resistance.”

In the paper

“Very-low-density lipoprotein (VLDL) increases PAI-1 expression via a response element localized from 672 to 657 of the promoter region.”

What the sources say

• Not checked yetcites [119] Eriksson P Nilsson L Karpe F Hamsten A Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia Arterioscler Thromb Vasc Biol 1998 18 20 6 9445251 source

In the paper

“Aldosterone induces degradation of IRS-1 in vascular smooth muscle cells via a mineralocorticoid receptor-, ROS- and Src-dependent mechanism.”

What the sources say

• Not checked yetcites [102] Hitomi H Kiyomoto H Nishiyama A Hara T Moriwaki K Kaifu K Ihara G Fujita Y Ugawa T Kohno M Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells Hypertension 2007 50 750 5 17646573 source

In the paper

“Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of t-PA in vivo.”

What the sources say

• Not checked yetcites [112] Alessi MC Poggi M Juhan-Vague I Plasminogen activator inhibitor-1, adipose tissue and insulin resistance Curr Opin Lipidol 2007 18 240 5 17495595 source

In the paper

“Glucose increases PAI-1expression via Sp1 sites.”

What the sources say

• Not checked yetcites [115] Chen YQ Su M Walia RR Hao Q Covington JW Vaughan DE Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells J Biol Chem 1998 273 8225 31 9525928 source

In the paper

“In the Nurses’Health Study, increased e-selectin and ICAM-1concentrations independently predicted incident diabetes.”

What the sources say

• Not checked yetcites [100] Meigs JB Hu FB Rifai N Manson JE Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus JAMA 2004 291 1978 86 15113816 source

In the paper

“Impaired vascular fibrinolytic function contributes to the risk of cardiovascular disease in individuals with insulin resistance and prediabetes.”

In the paper

“Thus, PAI-1 concentrations correlate with body mass and markers of insulin resistance.”

In the paper

“Angiotensin II (Ang II) causes serine (Ser307) phosphorylation and degradation of IRS-1 via the proto-oncogene tyrosine-protein kinase Src.”

What the sources say

• Not checked yetcites [101] Taniyama Y Hitomi H Shah A Alexander RW Griendling KK Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II Arterioscler Thromb Vasc Biol 2005 25 1142 7 15802620 source

In the paper

“Increases in adiponectin were also associated with increases in HDL-cholesterol particle size.”

What the sources say

• Not checked yetcites [99] Goldberg RB Temprosa M Mele L Orchard T Mather K Bray G Horton E Kitabchi A Krakoff J Marcovina S Perreault L White N Diabetes Prevention Program Research G Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the Diabetes Prevention Program Metabolism 2016 65 764 75 27085783 PMC5122461 source

In the paper

“Hyperglycemia increases the expression of several microRNAs found in the endothelium, including miR-320, miR-221, miR-503, and miR-125b.”

What the sources say

• Not checked yetcites [135] Shantikumar S Caporali A Emanueli C Role of microRNAs in diabetes and its cardiovascular complications Cardiovasc Res 2012 93 583 93 22065734 PMC3291087 source
• Not checked yetcites [144] Wang XH Qian RZ Zhang W Chen SF Jin HM Hu RM MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats Clin Exp Pharmacol Physiol 2009 36 181 8 18986336 source
• Not checked yetcites [145] Li Y Song YH Li F Yang T Lu YW Geng YJ MicroRNA-221 regulates high glucose-induced endothelial dysfunction Biochem Biophys Res Commun 2009 381 81 3 19351599 PMC2670889 source
• Not checked yetcites [146] Caporali A Meloni M Vollenkle C Bonci D Sala-Newby GB Addis R Spinetti G Losa S Masson R Baker AH Agami R le Sage C Condorelli G Madeddu P Martelli F Emanueli C Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia Circulation 2011 123 282 91 21220732 source
• Not checked yetcites [147] Villeneuve LM Kato M Reddy MA Wang M Lanting L Natarajan R Enhanced levels of microRNA-125b in vascular smooth muscle cells of diabetic db/db mice lead to increased inflammatory gene expression by targeting the histone methyltransferase Suv39h1 Diabetes 2010 59 2904 15 20699419 PMC2963550 source

In the paper

“Several lines of evidence suggest that microvascular function (determined by capillary blood flow, the number of perfused capillaries, and capillary insulin permeability) is key to skeletal muscle insulin action in health and prediabetes.”

In the paper

“Acute glucose and insulin administration decrease t-PA activity in the rat.”

What the sources say

• Not checked yetcites [132] Pandolfi A Giaccari A Cilli C Alberta MM Morviducci L De Filippis EA Buongiorno A Pellegrini G Capani F Consoli A Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat Acta Diabetol 2001 38 71 6 11757804 source

In the paper

“microRNAs can alter the expression of genes in insulin-producing and insulin-sensitive tissues, including the pancreas, liver, and vasculature.”

What the sources say

• Not checked yetcites [134] Fernandez-Hernando C Ramirez CM Goedeke L Suarez Y MicroRNAs in metabolic disease Arterioscler Thromb Vasc Biol 2013 33 178 85 23325474 PMC3740757 source
• Not checked yetcites [135] Shantikumar S Caporali A Emanueli C Role of microRNAs in diabetes and its cardiovascular complications Cardiovasc Res 2012 93 583 93 22065734 PMC3291087 source

In the paper

“vasodilators can partially prevent159, 160 or reverse161 diet-induced insulin resistance in rodents.”

What the sources say

• Not checked yetcites [159] Ayala JE Bracy DP Julien BM Rottman JN Fueger PT Wasserman DH Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice Diabetes 2007 56 1025 33 17229936 source
• Not checked yetcites [160] Chai W Fu Z Aylor KW Barrett EJ Liu Z Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats Am J Physiol Endocrinol Metab 2016 311 E640 8 27436611 PMC5142002 source
• Not checked yetcites [161] Bonner JS Lantier L Hocking KM Kang L Owolabi M James FD Bracy DP Brophy CM Wasserman DH Relaxin treatment reverses insulin resistance in mice fed a high-fat diet Diabetes 2013 62 3251 60 23801576 PMC3749347 source

In the paper

“An increase in microvascular blood flow could facilitate insulin efflux should it result in increased capillary hydrostatic pressure.”

In the paper

“rats and mice made insulin-resistant by high fat intake have such severe impairment of microvascular blood flow that the delivery of glucose to skeletal muscle limits insulin-stimulated glucose uptake during an insulin clamp.”

What the sources say

• Not checked yetcites [148] Duplain H Burcelin R Sartori C Cook S Egli M Lepori M Vollenweider P Pedrazzini T Nicod P Thorens B Scherrer U Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase Circulation 2001 104 342 345 11457755 source
• Not checked yetcites [149] Wallis MG Wheatley CM Rattigan S Barrett EJ Clark ADH Clark MG Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats Diabetes 2002 51 3492 3498 12453905 source
• Not checked yetcites [150] Halseth AE Bracy DP Wasserman DH Limitations to basal and insulin-stimulated skeletal muscle glucose uptake in the high-fat-fed rat Am J Physiol Endocrinol Metab 2000 279 E1064 71 11052961 source

In the paper

“These microRNAs may promote endothelial dysfunction by inhibiting genes involved in angiogenesis, vascular repair, and inflammatory suppression.”

In the paper

“Access to perfused tissues requires not only increased blood flow, but also capillary egress.”

In the paper

“Relaxin acts on RXFP1 receptors expressed on vascular endothelial and smooth muscle cells.”

In the paper

“microRNAs may also link the metabolic dysregulation seen in prediabetes with vascular dysfunction.”

What the sources say

• Not checked yetcites [135] Shantikumar S Caporali A Emanueli C Role of microRNAs in diabetes and its cardiovascular complications Cardiovasc Res 2012 93 583 93 22065734 PMC3291087 source

In the paper

“Attenuated increases in insulin-stimulated limb blood flow result in decreased limb glucose uptake.”

What the sources say

• Not checked yetcites [6] Laakso M Edelman SV Brechtel G Baron AD Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance J Clin Invest 1990 85 1844 52 2189893 PMC296649 source
• Not checked yetcites [7] Laakso M Edelman SV Brechtel G Baron AD Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM Diabetes 1992 41 1076 83 1499861 source

In the paper

“The endothelium poses a major barrier for insulin as the diameter of insulin approaches the size of the paracellular space.”

In the paper

“The glycosaminoglycan hyaluronan is increased in tissues of prediabetic animals”

What the sources say

• Not checked yetcites [173] Kang L Lantier L Kennedy A Bonner JS Mayes WH Bracy DP Bookbinder LH Hasty AH Thompson CB Wasserman DH Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance Diabetes 2013 62 1888 96 23349492 PMC3661617 source
• Not checked yetcites [174] Chajara A Raoudi M Delpech B Leroy M Basuyau JP Levesque H Increased hyaluronan and hyaluronidase production and hyaluronan degradation in injured aorta of insulin-resistant rats Arterioscler Thromb Vasc Biol 2000 20 1480 7 10845861 source

In the paper

“CD44, the main hyaluronan cell surface receptor is associated with T2DM, as shown by expression-based genome-wide association studies.”

What the sources say

• Not checked yetcites [176] Kodama K Horikoshi M Toda K Yamada S Hara K Irie J Sirota M Morgan AA Chen R Ohtsu H Maeda S Kadowaki T Butte AJ Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes Proc Natl Acad Sci U S A 2012 109 7049 54 22499789 PMC3344989 source

In the paper

“Weight loss is the mainstay of reducing the risk of progression to diabetes in patients with prediabetes.”

In the paper

“A reduction of hyaluronan using PEGylated hyaluronidase in high fat-fed mice improves insulin action.”

What the sources say

• Not checked yetcites [173] Kang L Lantier L Kennedy A Bonner JS Mayes WH Bracy DP Bookbinder LH Hasty AH Thompson CB Wasserman DH Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance Diabetes 2013 62 1888 96 23349492 PMC3661617 source

In the paper

“Collectively, these data suggest endothelial dysfunction and capillary rarefaction are mechanisms by which ECM remodeling may mediate muscle insulin resistance.”

In the paper

“The α2β1 integrin receptor regulates cell migration, proliferation and survival.”

What the sources say

• Not checked yetcites [182] Madamanchi A Santoro SA Zutter MM alpha2beta1 Integrin Adv Exp Med Biol 2014 819 41 60 25023166 source

In the paper

“Increased recruitment of pro-inflammatory macrophages to muscle167 and adipose81 results in transforming growth factor β (TGFβ)-mediated fibrosis.168”

What the sources say

• Not checked yetcites [167] Varma V Yao-Borengasser A Rasouli N Nolen GT Phanavanh B Starks T Gurley C Simpson P McGehee RE Jr Kern PA Peterson CA Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action Am J Physiol Endocrinol Metab 2009 296 E1300 10 19336660 PMC2692398 source
• Not checked yetcites [81] Weisberg SP McCann D Desai M Rosenbaum M Leibel RL Ferrante AW Jr Obesity is associated with macrophage accumulation in adipose tissue J Clin Invest 2003 112 1796 808 14679176 PMC296995 source
• Not checked yetcites [168] Yadav H Quijano C Kamaraju AK Gavrilova O Malek R Chen W Zerfas P Zhigang D Wright EC Stuelten C Sun P Lonning S Skarulis M Sumner AE Finkel T Rane SG Protection from obesity and diabetes by blockade of TGF-beta/Smad3 signaling Cell Metab 2011 14 67 79 21723505 PMC3169298 source

In the paper

“ECM remodeling is necessary for increased capillary growth and proliferation.”

What the sources say

• Not checked yetcites [165] Bonner JS Lantier L Hasenour CM James FD Bracy DP Wasserman DH Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance Diabetes 2013 62 572 80 23002035 PMC3554359 source

In the paper

“The expanded ECM in prediabetes produces a distinct signal that alters activation of integrin and other cell surface receptors.”

In the paper

“Expansion of the muscle ECM and decreased muscle capillaries are associated with insulin resistance.”

What the sources say

• Not checked yetcites [178] Kang L Mayes WH James FD Bracy DP Wasserman DH Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice Diabetologia 2014 57 603 13 24305966 PMC4155606 source

In the paper

“Changes in ECM may affect insulin and glucose delivery either by causing capillary regression or neo-vascular growth (Figure 4).”

In the paper

“ECM remodeling170, 172, 173, 178 causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.162, 179-181”

What the sources say

• Not checked yetcites [170] Inoue M Jiang Y Barnes RH 2nd Tokunaga M Martinez-Santibanez G Geletka L Lumeng CN Buchner DA Chun TH Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice Endocrinology 2013 154 4548 59 24140711 PMC3836064 source
• Not checked yetcites [172] Berria R Wang L Richardson DK Finlayson J Belfort R Pratipanawatr T De Filippis EA Kashyap S Mandarino LJ Increased collagen content in insulin-resistant skeletal muscle Am J Physiol Endocrinol Metab 2006 290 E560 5 16249255 source
• Not checked yetcites [173] Kang L Lantier L Kennedy A Bonner JS Mayes WH Bracy DP Bookbinder LH Hasty AH Thompson CB Wasserman DH Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance Diabetes 2013 62 1888 96 23349492 PMC3661617 source
• Not checked yetcites [178] Kang L Mayes WH James FD Bracy DP Wasserman DH Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice Diabetologia 2014 57 603 13 24305966 PMC4155606 source

In the paper

“Thrombospondin-1 contributes to the skeletal muscle meta-fibrosis and insulin resistance in high fat-fed mice.”

What the sources say

• Not checked yetcites [170] Inoue M Jiang Y Barnes RH 2nd Tokunaga M Martinez-Santibanez G Geletka L Lumeng CN Buchner DA Chun TH Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice Endocrinology 2013 154 4548 59 24140711 PMC3836064 source

In the paper

“In patients with IGT followed for six years in the Da Qing Study, diet, exercise, and combined diet and exercise reduced incident T2DM by 31%, 46% and 42% respectively compared to control.”

What the sources say

• Not checked yetcites [187] Pan XR Li GW Hu YH Wang JX Yang WY An ZX Hu ZX Lin J Xiao JZ Cao HB Liu PA Jiang XG Jiang YY Wang JP Zheng H Zhang H Bennett PH Howard BV Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study Diabetes Care 1997 20 537 44 9096977 source

In the paper

“Activation of these receptors leads to vasodilation due to actions on both endothelium163 and smooth muscle.164”

What the sources say

• Not checked yetcites [163] Leo CH Jelinic M Ng HH Marshall SA Novak J Tare M Conrad KP Parry LJ Vascular actions of relaxin: nitric oxide and beyond Br J Pharmacol 2017 174 1002 1014 27590257 PMC5406296 source
• Not checked yetcites [164] Sarwar M Samuel CS Bathgate RA Stewart DR Summers RJ Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration-response curves reflect differential coupling to G proteins Br J Pharmacol 2015 172 1005 19 25297987 PMC4314191 source

In the paper

“FAK phosphorylation is decreased in muscle from obese rats”

What the sources say

• Not checked yetcites [183] Bisht B Goel HL Dey CS Focal adhesion kinase regulates insulin resistance in skeletal muscle Diabetologia 2007 50 1058 69 17333113 source

In the paper

“In the Finnish Diabetes Prevention Program, weight loss counseling targeted to 5% total body weight, decreased total and saturated fat consumption, increased fiber consumption and increased activity to 30 min/day resulted in a 58% reduction in incident T2DM in individuals with IGT and BMI greater than 25 kg/m2.”

What the sources say

• Not checked yetcites [188] Tuomilehto J Lindstrom J Eriksson JG Valle TT Hamalainen H Ilanne-Parikka P Keinanen-Kiukaanniemi S Laakso M Louheranta A Rastas M Salminen V Uusitupa M Finnish Diabetes Prevention Study G Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance N Engl J Med 2001 344 1343 50 11333990 source

In the paper

“serum hyaluronan is increased in T2DM.”

What the sources say

• Not checked yetcites [175] Dasu MR Devaraj S Park S Jialal I Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects Diabetes Care 2010 33 861 8 20067962 PMC2845042 source

In the paper

“The DPP Outcomes Study followed participants for up to 15 years and found a persistent reduction in incident diabetes of 18%.196”

What the sources say

• Not checked yetcites [196] Diabetes Prevention Program Research G Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study Lancet Diabetes Endocrinol 2015 3 866 75 26377054 PMC4623946 source

In the paper

“There was no added benefit of combined metformin and lifestyle modification.”

What the sources say

• Not checked yetcites [191] Ramachandran A Snehalatha C Mary S Mukesh B Bhaskar AD Vijay V Indian Diabetes Prevention P The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1) Diabetologia 2006 49 289 97 16391903 source

In the paper

“In the STOP-NIDDM trial acarbose reduced the incidence of diabetes by 25% in individuals with IGT and a FPG from 5.6 to 7.7 mmol/L.200”

What the sources say

• Not checked yetcites [200] Chiasson JL Josse RG Gomis R Hanefeld M Karasik A Laakso M Group S-NTR Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial Lancet 2002 359 2072 7 12086760 source

In the paper

“Coronary artery calcification was decreased in men but not in women.”

What the sources say

• Not checked yetcites [196] Diabetes Prevention Program Research G Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study Lancet Diabetes Endocrinol 2015 3 866 75 26377054 PMC4623946 source

In the paper

“In Actos Now for Prevention of Diabetes (ACT NOW), treatment with pioglitazone 45 mg per day reduced incident diabetes 72% over 2.4 years in patients with IGT and at least one other risk factor for T2DM and BMI ≥ 25 kg/m2.203”

What the sources say

• Not checked yetcites [203] DeFronzo RA Tripathy D Schwenke DC Banerji M Bray GA Buchanan TA Clement SC Henry RR Hodis HN Kitabchi AE Mack WJ Mudaliar S Ratner RE Williams K Stentz FB Musi N Reaven PD Study AN Pioglitazone for diabetes prevention in impaired glucose tolerance N Engl J Med 2011 364 1104 15 21428766 source

In the paper

“Voglibose (0.2 mg tid) treatment reduced incident diabetes 41% compared to placebo in a trial in Japan.202”

What the sources say

• Not checked yetcites [202] Kawamori R Tajima N Iwamoto Y Kashiwagi A Shimamoto K Kaku K Voglibose Ph-3 Study G Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance Lancet 2009 373 1607 14 19395079 source

In the paper

“In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, rosiglitazone 8 mg/d reduced incident diabetes 60% in patients with IFG or IGT older than 29 years.205”

What the sources say

• Not checked yetcites [205] Investigators DT Gerstein HC Yusuf S Bosch J Pogue J Sheridan P Dinccag N Hanefeld M Hoogwerf B Laakso M Mohan V Shaw J Zinman B Holman RR Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial Lancet 2006 368 1096 105 16997664 source

In the paper

“In the Swedish Obese Subjects (SOS), a prospective, non-randomized study of bariatric surgery (gastric banding, vertical-banded gastroplasty, and Roux-en-Y gastric bypass) patients and obese controls, among patients without diabetes at baseline, incident diabetes was reduced by 76%.”

What the sources say

• Not checked yetcites [194] Carlsson LM Peltonen M Ahlin S Anveden A Bouchard C Carlsson B Jacobson P Lonroth H Maglio C Naslund I Pirazzi C Romeo S Sjoholm K Sjostrom E Wedel H Svensson PA Sjostrom L Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects N Engl J Med 2012 367 695 704 22913680 source

In the paper

“but metformin improves endothelial function in patients with metabolic syndrome and improvement in FMD correlates with improvement in insulin resistance.199”

What the sources say

• Not checked yetcites [199] Vitale C Mercuro G Cornoldi A Fini M Volterrani M Rosano GM Metformin improves endothelial function in patients with metabolic syndrome J Intern Med 2005 258 250 6 16115299 source

In the paper

“Pharmacological weight loss therapy also reduces the risk of progression to diabetes.”

In the paper

“Regression to normal glucose tolerance results in an approximately 6% reduction in ten-year risk of cardiovascular risk by Framingham criteria.”

What the sources say

• Not checked yetcites [190] Perreault L Temprosa M Mather KJ Horton E Kitabchi A Larkin M Montez MG Thayer D Orchard TJ Hamman RF Goldberg RB Diabetes Prevention Program Research G Regression from prediabetes to normal glucose regulation is associated with reduction in cardiovascular risk: results from the Diabetes Prevention Program outcomes study Diabetes Care 2014 37 2622 31 24969574 PMC4140157 source

In the paper