The Vasculature in Prediabetes

In the paper

“Endothelial dysfunction occurs early in the pathogenesis of atherosclerosis, and predicts future cardiovascular events.”

What the sources say

• Supported

  The opening passage describes endothelial dysfunction as an initial part of atherosclerosis. The Discussion reports that forearm endothelial dysfunction marked future cardiovascular events in initially untreated patients with essential hypertension; the paper also states that coronary endothelial dysfunction predicts cardiovascular event rates. (LLM, conf=0.91)

  cites [30] Perticone F Ceravolo R Pujia A Ventura G Iacopino S Scozzafava A Ferraro A Chello M Mastroroberto P Verdecchia P Schillaci G Prognostic significance of endothelial dysfunction in hypertensive patients Circulation 2001 104 191 6 11447085 source
• Not checked yetcites [31] Heitzer T Schlinzig T Krohn K Meinertz T Munzel T Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease Circulation 2001 104 2673 8 11723017 source
• Partly supported

  The Discussion reports that coronary endothelial dysfunction independently predicts later acute cardiovascular events. The Study Limitations section notes dysfunction in patients with angiographically smooth arteries, some of whom likely had early atherosclerosis, but it does not establish that dysfunction occurs early in the pathogenesis of atherosclerosis. (LLM, conf=0.84)

  cites [32] Halcox JP Schenke WH Zalos G Mincemoyer R Prasad A Waclawiw MA Nour KR Quyyumi AA Prognostic value of coronary vascular endothelial dysfunction Circulation 2002 106 653 8 12163423 sourceExperimental — accuracy not yet measured

In the paper

“Without intervention, prediabetes often progresses to diabetes”

In the paper

“The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide.”

• Also stated in: § Introduction · plain

  “As the prevalence of obesity grows worldwide, the prevalence of prediabetes is also increasing.”

What the sources say

• Not checked yetcites [1] Menke A Casagrande S Geiss L Cowie CC Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012 JAMA 2015 314 1021 9 26348752 source
• Not checked yetcites [2] Guariguata L Whiting DR Hambleton I Beagley J Linnenkamp U Shaw JE Global estimates of diabetes prevalence for 2013 and projections for 2035 Diabetes Res Clin Pract 2014 103 137 49 24630390 source

In the paper

“Based on the classification criteria, prediabetes is a heterogeneous disorder.”

In the paper

“Increased inflammation associated with obesity promotes endothelial dysfunction, extracellular matrix (ECM) formation and changes in capillary density and glucose uptake, further promoting insulin resistance.”

In the paper

“endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes.”

In the paper

“vascular dysfunction results not only from effects of hyperglycemia, but also from vascular insulin resistance and from pro-inflammatory and metabolic consequences of attendant obesity.”

In the paper

“prediabetes is associated with increased risk of cardiovascular disease, cancer, renal disease, and dementia.”

• Also stated in: § Risk of Cardiovascular and Renal Disease in Prediabetes · plain

  “Even before the development of diabetes, prediabetes is associated with increased risks of macrovascular disease, nephropathy, neuropathy, cancer and dementia.”

In the paper

“the incidence of diabetes was 4-6% in individuals with IGT alone, 6-9% in individuals with isolated IFG, and 15-19% in individuals with both IGT and IFG.”

What the sources say

• Not checked yetcites [17] Gerstein HC Santaguida P Raina P Morrison KM Balion C Hunt D Yazdi H Booker L Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies Diabetes Res Clin Pract 2007 78 305 12 17601626 source

In the paper

“The relative risk of all-cause mortality was 1.13, 1.13, and 1.32 in the same three groups.”

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

In the paper

“IGT is characterized by impaired muscle insulin sensitivity as well as early and late phase insulin responses.”

What the sources say

• Not checked yetcites [11] Jani R Molina M Matsuda M Balas B Chavez A DeFronzo RA Abdul-Ghani M Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range Diabetes Care 2008 31 311 5 18000182 source
• Not checked yetcites [12] Kanat M Norton L Winnier D Jenkinson C DeFronzo RA Abdul-Ghani MA Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose Acta Diabetol 2011 48 209 17 21553243
• Not checked yetcites [13] Kanat M Mari A Norton L Winnier D DeFronzo RA Jenkinson C Abdul-Ghani MA Distinct beta-cell defects in impaired fasting glucose and impaired glucose tolerance Diabetes 2012 61 447 53 22275086 PMC3266412 source
• Not checked yetcites [14] Meyer C Pimenta W Woerle HJ Van Haeften T Szoke E Mitrakou A Gerich J Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans Diabetes Care 2006 29 1909 14 16873801 source

In the paper

“In the Toranomon Hospital Health Management Center Study 7% of individuals who met HbA1c criteria and 9% of individuals with IFG progressed to diabetes.”

What the sources say

• Not checked yetcites [20] Kosaka K Noda M Kuzuya T Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males Diabetes Res Clin Pract 2005 67 152 62 15649575 source

In the paper

“IFG is characterized primarily by impaired hepatic insulin sensitivity and a decrease in the first-phase insulin response”

What the sources say

• Not checked yetcites [11] Jani R Molina M Matsuda M Balas B Chavez A DeFronzo RA Abdul-Ghani M Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range Diabetes Care 2008 31 311 5 18000182 source
• Not checked yetcites [12] Kanat M Norton L Winnier D Jenkinson C DeFronzo RA Abdul-Ghani MA Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose Acta Diabetol 2011 48 209 17 21553243
• Not checked yetcites [13] Kanat M Mari A Norton L Winnier D DeFronzo RA Jenkinson C Abdul-Ghani MA Distinct beta-cell defects in impaired fasting glucose and impaired glucose tolerance Diabetes 2012 61 447 53 22275086 PMC3266412 source
• Not checked yetcites [14] Meyer C Pimenta W Woerle HJ Van Haeften T Szoke E Mitrakou A Gerich J Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans Diabetes Care 2006 29 1909 14 16873801 source

In the paper

“Insulin resistance precedes the development of hyperglycemia and T2DM and results in compensatory hyperinsulinemia.”

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

“Increases in HbA1C that met the ADA definition of prediabetes were associated with increased risk of cardiovascular disease and coronary heart disease, but not with stroke or all-cause mortality.”

In the paper

“In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease.”

In the paper

“Hyperglycemia and insulin resistance are the common threads of this condition, however.”

In the paper

“Hyperglycemia ensues when insulin production cannot overcome insulin resistance.”

In the paper

“The relative risk associated with IGT was similar.”

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

“AGEs activate the ERK, c-Jun N-terminal kinase (JNK), p38, and PI3K pathways and promote activation of NF-κB.”

What the sources say

• Not checked yetcites [57] Huang J-S Guh J-Y Chen H-C Hung W-C Lai Y-H Chuang L-Y Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells Journal of Cellular Biochemistry 2001 81 102 113 11180401
• Not checked yetcites [58] Yeh C-H Sturgis L Haidacher J Zhang X-N Sherwood SJ Bjercke RJ Juhasz O Crow MT Tilton RG Denner L Requirement for p38 and p44/p42 Mitogen-Activated Protein Kinases in RAGE-Mediated Nuclear Factor-κB Transcriptional Activation and Cytokine Secretion Diabetes 2001 50 1495 1504 11375353 source
• Not checked yetcites [59] Lander HM Tauras JM Ogiste JS Hori O Moss RA Schmidt AM Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress J Biol Chem 1997 272 17810 4 9211935 source

In the paper

“activation of the polyol pathway leads to NADPH depletion and reduced concentration of the anti-oxidant glutathione.”

What the sources say

• Not checked yetcites [64] Asahina T Kashiwagi A Nishio Y Ikebuchi M Harada N Tanaka Y Takagi Y Saeki Y Kikkawa R Shigeta Y Impaired Activation of Glucose Oxidation and NADPH Supply in Human Endothelial Cells Exposed to H2O2 in High-Glucose Medium Diabetes 1995 44 520 526 7729609

In the paper

“Activated PKC contributes to endothelial dysfunction,68, 69 increased endothelial permeability,70 and ECM expansion.71”

What the sources say

• Not checked yetcites [68] Guzik TJ Mussa S Gastaldi D Sadowski J Ratnatunga C Pillai R Channon KM Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase Circulation 2002 105 1656 62 11940543
• Not checked yetcites [69] Cosentino F Eto M De Paolis P van der Loo B Bachschmid M Ullrich V Kouroedov A Delli Gatti C Joch H Volpe M Luscher TF High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species Circulation 2003 107 1017 23 12600916
• Not checked yetcites [70] Lynch JJ Ferro TJ Blumenstock FA Brockenauer AM Malik AB Increased endothelial albumin permeability mediated by protein kinase C activation J Clin Invest 1990 85 1991 8 2347922 PMC296668
• Not checked yetcites [71] Koya D Jirousek MR Lin YW Ishii H Kuboki K King GL Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats J Clin Invest 1997 100 115 26 9202063 PMC508171

In the paper

“In hyperglycemia, endothelial vasodilator dysfunction precedes the development of T2DM and is seen in both IFG and IGT.”

What the sources say

• Not checked yetcites [33] Caballero AE Arora S Saouaf R Lim SC Smakowski P Park JY King GL LoGerfo FW Horton ES Veves A Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes Diabetes 1999 48 1856 62 10480619
• Not checked yetcites [34] Vehkavaara S Seppala-Lindroos A Westerbacka J Groop PH Yki-Jarvinen H In vivo endothelial dysfunction characterizes patients with impaired fasting glucose Diabetes Care 1999 22 2055 60 10587842
• Not checked yetcites [35] Rodriguez CJ Miyake Y Grahame-Clarke C Di Tullio MR Sciacca RR Boden-Albala B Sacco RL Homma S Relation of plasma glucose and endothelial function in a population-based multiethnic sample of subjects without diabetes mellitus Am J Cardiol 2005 96 1273 7 16253596
• Not checked yetcites [36] Su Y Liu XM Sun YM Wang YY Luan Y Wu Y Endothelial dysfunction in impaired fasting glycemia, impaired glucose tolerance, and type 2 diabetes mellitus Am J Cardiol 2008 102 497 8 18678313

In the paper

“Insulin vasodilates skeletal muscle6, 37 and coronary38, 39 vasculature.”

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 [37] Anderson EA Hoffman RP Balon TW Sinkey CA Mark AL Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans J Clin Invest 1991 87 2246 52 2040704 PMC296986 source
• Not checked yetcites [38] Iozzo P Chareonthaitawee P Rimoldi O Betteridge DJ Camici PG Ferrannini E Mismatch between insulin-mediated glucose uptake and blood flow in the heart of patients with Type II diabetes Diabetologia 2002 45 1404 9 12378381
• Not checked yetcites [39] Lautamaki R Airaksinen KE Seppanen M Toikka J Harkonen R Luotolahti M Borra R Sundell J Knuuti J Nuutila P Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease Diabetes 2006 55 511 6 16443788

In the paper

“Vascular insulin resistance leads to downregulation of IRS-1 and 2 and decreased phosphorylation of Akt and eNOS, whereas the ET-1 pathway remains unaffected.”

What the sources say

• Not checked yetcites [48] Jiang ZY Lin YW Clemont A Feener EP Hein KD Igarashi M Yamauchi T White MF King GL Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats J Clin Invest 1999 104 447 57 10449437 PMC408521 source
• Not checked yetcites [49] Gudbjornsdottir S Elam M Sellgren J Anderson EA Insulin increases forearm vascular resistance in obese, insulin-resistant hypertensives J Hypertens 1996 14 91 7 12013500

In the paper

“Increased intracellular NADH leads to an increase in glycerol-3-phosphate and activation of protein kinase C (PKC).”

What the sources say

• Not checked yetcites [65] Tilton RG Baier LD Harlow JE Smith SR Ostrow E Williamson JR Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+ Kidney Int 1992 41 778 88 1513100

In the paper

“Glycation is less in prediabetes than that defining diabetes.”

In the paper

“reduced adiponectin concentrations are associated with increased inflammation and risks of diabetes and cardiovascular disease.”

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
• Not checked yetcites [97] Li S Shin HJ Ding EL van Dam RM Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis JAMA 2009 302 179 88 19584347 source
• Not checked yetcites [98] Schulze MB Shai I Rimm EB Li T Rifai N Hu FB Adiponectin and future coronary heart disease events among men with type 2 diabetes Diabetes 2005 54 534 9 15677512 source

In the paper

“M1-like macrophages secrete inflammatory cytokines such as TNF-α and IL-6, and studies in M1-like macrophage knockout mice suggest they also promote insulin resistance.”

What the sources say

• Not checked yetcites [84] Patsouris D Li PP Thapar D Chapman J Olefsky JM Neels JG Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals Cell Metab 2008 8 301 9 18840360 PMC2630775 source

In the paper

“Under stimulation by B cells, effector T cells and Th1cells release cytokines such as interferon-γ to further stimulate activation of macrophages and induce a shift in macrophages from an M2-like phenotype to an M1-like phenotype.”

What the sources say

• Not checked yetcites [83] Lumeng CN Bodzin JL Saltiel AR Obesity induces a phenotypic switch in adipose tissue macrophage polarization J Clin Invest 2007 117 175 84 17200717 PMC1716210 source

In the paper

“The total number of T cells, B cells, neutrophils and mast cells is also increased, whereas the number of T-helper (Th2) and regulatory T cells (Treg) is unchanged or decreased.”

In the paper

“While leptin suppresses appetite and enhances energy expenditure, it also stimulates pro-inflammatory immune cells, increases ROS production by endothelial cells, and facilitates formation of foam cells.”

What the sources say

• Not checked yetcites [89] Santos-Alvarez J Goberna R Sanchez-Margalet V Human leptin stimulates proliferation and activation of human circulating monocytes Cell Immunol 1999 194 6 11 10357875
• Not checked yetcites [90] Surmi BK Atkinson RD Gruen ML Coenen KR Hasty AH The role of macrophage leptin receptor in aortic root lesion formation Am J Physiol Endocrinol Metab 2008 294 E488 95 18182468
• Not checked yetcites [91] Kiguchi N Maeda T Kobayashi Y Fukazawa Y Kishioka S Leptin enhances CC-chemokine ligand expression in cultured murine macrophage Biochem Biophys Res Commun 2009 384 311 5 19409880

In the paper

“lipid-laden macrophages accumulate in crown-like structures around dead adipocytes.”

• Also stated in: § Endothelial Vasodilator Dysfunction in Prediabetes · plain

  “The presence of these crown-like structures is associated with inflammation and insulin resistance.”

What the sources say

• Not checked yetcites [85] Cinti S Mitchell G Barbatelli G Murano I Ceresi E Faloia E Wang S Fortier M Greenberg AS Obin MS Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans J Lipid Res 2005 46 2347 55 16150820 source
• Not checked yetcites [86] Murano I Barbatelli G Parisani V Latini C Muzzonigro G Castellucci M Cinti S Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice J Lipid Res 2008 49 1562 8 18390487
• Not checked yetcites [87] Apovian CM Bigornia S Mott M Meyers MR Ulloor J Gagua M McDonnell M Hess D Joseph L Gokce N Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects Arterioscler Thromb Vasc Biol 2008 28 1654 9 18566296 PMC2728436

In the paper

“FFAs reduce tyrosine phosphorylation of IRS-1/2 and inhibit the PI3K/Akt pathway, leading to decreased glucose transport and decreased phosphorylation of eNOS.”

What the sources say

• Not checked yetcites [75] Dresner A Laurent D Marcucci M Griffin ME Dufour S Cline GW Slezak LA Andersen DK Hundal RS Rothman DL Petersen KF Shulman GI Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity J Clin Invest 1999 103 253 9 9916137 PMC407880 source
• Not checked yetcites [76] Wang XL Zhang L Youker K Zhang MX Wang J LeMaire SA Coselli JS Shen YH Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase Diabetes 2006 55 2301 10 16873694
• Not checked yetcites [77] Griffin ME Marcucci MJ Cline GW Bell K Barucci N Lee D Goodyear LJ Kraegen EW White MF Shulman GI Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade Diabetes 1999 48 1270 4 10342815 source

In the paper

“In humans, resistin concentrations are increased in prediabetes and elevated resistin concentrations are associated with cardiovascular events.”

What the sources say

• Not checked yetcites [92] Reilly MP Lehrke M Wolfe ML Rohatgi A Lazar MA Rader DJ Resistin is an inflammatory marker of atherosclerosis in humans Circulation 2005 111 932 9 15710760
• Not checked yetcites [93] Muse ED Feldman DI Blaha MJ Dardari ZA Blumenthal RS Budoff MJ Nasir K Criqui MH Cushman M McClelland RL Allison MA The association of resistin with cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis Atherosclerosis 2015 239 101 8 25585029 PMC4331252
• Not checked yetcites [94] Ohmori R Momiyama Y Kato R Taniguchi H Ogura M Ayaori M Nakamura H Ohsuzu F Associations between serum resistin levels and insulin resistance, inflammation, and coronary artery disease J Am Coll Cardiol 2005 46 379 80 16022972

In the paper

“Insulin-induced capillary recruitment and microvascular dilation, measured by laser Doppler flowmetry during iontophoresis of acetylcholine, correlate with insulin sensitivity and are reduced in obese compared to lean women.”

What the sources say

• Not checked yetcites [108] de Jongh RT Serne EH IJ RG de Vries G Stehouwer CD Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance Circulation 2004 109 2529 35 15136505 source

In the paper

“Endothelial t-PA release is diminished in obesity and in conditions associated with prediabetes, such as hypertension, but the effect of hyperglycemia is not well-defined.”

What the sources say

• Not checked yetcites [130] Ridderstrale W Saluveer O Carlstrom M Jern S Hrafnkelsdottir TJ The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering J Thromb Thrombolysis 2011 32 399 404 21614456 source
• Not checked yetcites [131] Van Guilder GP Hoetzer GL Greiner JJ Stauffer BL DeSouza CA Metabolic syndrome and endothelial fibrinolytic capacity in obese adults Am J Physiol Regul Integr Comp Physiol 2008 294 R39 44 17959703 source

In the paper

“T-PA antigen levels are also associated with increased risk of thrombotic events, but this is largely because 80% of t-PA antigen circulates complexed to PAI-1.”

What the sources say

• Not checked yetcites [124] Chandler WL Alessi MC Aillaud MF Henderson P Vague P Juhan-Vague I Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels Circulation 1997 96 761 8 9264480 source

In the paper

“Impaired endothelium-dependent vasodilation results not only in impaired macrovascular function, but also in microvascular dysfunction, as measured by retinal artery vasodilation and heat-induced skin hyperemia.”

What the sources say

• Not checked yetcites [105] Dorner GT Garhofer G Kiss B Polska E Polak K Riva CE Schmetterer L Nitric oxide regulates retinal vascular tone in humans Am J Physiol Heart Circ Physiol 2003 285 H631 6 12750062 source
• Not checked yetcites [106] Choi PJ Brunt VE Fujii N Minson CT New approach to measure cutaneous microvascular function: an improved test of NO-mediated vasodilation by thermal hyperemia J Appl Physiol (1985) 2014 117 277 83 24903917 PMC4122693 source
• Not checked yetcites [107] Kellogg DL Jr Liu Y Kosiba IF O’Donnell D Role of nitric oxide in the vascular effects of local warming of the skin in humans J Appl Physiol (1985) 1999 86 1185 90 10194201 source

In the paper

“the prevalence of microalbuminuria, a marker of microvascular dysfunction, is increased in prediabetes and predicts cardiovascular morbidity.”

In the paper

“Tissue-type plasminogen activator (t-PA) is stored in the endothelium and protects against local thrombosis.”

What the sources say

• Not checked yetcites [110] Emeis JJ van den Eijnden-Schrauwen Y van den Hoogen CM de Priester W Westmuckett A Lupu F An endothelial storage granule for tissue-type plasminogen activator J Cell Biol 1997 139 245 56 9314543 PMC2139817
• Not checked yetcites [111] Manneville JB Etienne-Manneville S Skehel P Carter T Ogden D Ferenczi M Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells J Cell Sci 2003 116 3927 38 12928328

In the paper

“In the Maastricht Study, microvascular function was impaired in prediabetes and there was a linear relationship between microvascular dysfunction and HbA1c and fasting glucose.”

What the sources say

• Not checked yetcites [109] Sorensen BM Houben AJ Berendschot TT Schouten JS Kroon AA van der Kallen CJ Henry RM Koster A Sep SJ Dagnelie PC Schaper NC Schram MT Stehouwer CD Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular Dysfunction: The Maastricht Study Circulation 2016 134 1339 1352 27678264

In the paper

“In patients with IGT in the DPP, intensive lifestyle modification increased adiponectin and decreased CRP, IL-6, fibrinogen, and adhesion molecules e-selectin and intercellular adhesion molecule-1 (ICAM-1), as well as insulin resistance.”

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

In the paper

“Insulin and insulin-like growth factor also increase PAI-1 expression; several forkhead proteins are involved in the regulation of PAI-1 expression by insulin.”

What the sources say

• Not checked yetcites [116] Schneider DJ Sobel BE Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states Proc Natl Acad Sci U S A 1991 88 9959 63 1719559 PMC52846
• Not checked yetcites [117] Vulin AI Stanley FM A Forkhead/winged helix-related transcription factor mediates insulin-increased plasminogen activator inhibitor-1 gene transcription J Biol Chem 2002 277 20169 76 11919188
• Not checked yetcites [118] Jag UR Zavadil J Stanley FM Insulin acts through FOXO3a to activate transcription of plasminogen activator inhibitor type 1 Mol Endocrinol 2009 23 1587 602 19608644 PMC2754891

In the paper

“T-PA is released both constitutively and in response to receptor stimulation by bradykinin, acetylcholine or methacholine, substance P, and norepinephrine.”

What the sources say

• Not checked yetcites [125] Jern S Selin L Bergbrant A Jern C Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm Thromb Haemost 1994 72 588 94 7878638
• Not checked yetcites [126] Brown NJ Gainer JV Murphey LJ Vaughan DE Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway Circulation 2000 102 2190 6 11056091
• Not checked yetcites [127] Newby DE McLeod AL Uren NG Flint L Ludlam CA Webb DJ Fox KA Boon NA Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis Circulation 2001 103 1936 41 11306520

In the paper

“Increased shear force also stimulates t-PA release.”

In the paper

“Ang II, aldosterone, and inflammatory cytokines such as IL-6 and TNF-α, all of which are increased in visceral obesity, also stimulate PAI-1 expression.”

What the sources say

• Not checked yetcites [120] Vaughan DE Lazos SA Tong K Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis J Clin Invest 1995 95 995 1001 7884001 PMC441432
• Not checked yetcites [121] Brown NJ Kim KS Chen YQ Blevins LS Nadeau JH Meranze SG Vaughan DE Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production J Clin Endocrinol Metab 2000 85 336 44 10634408

In the paper

“Conversely, cGMP decreases PAI-1 expression and impaired endothelial NO production may contribute to impaired fibrinolytic balance in prediabetes.”

What the sources say

• Not checked yetcites [122] Bouchie JL Hansen H Feener EP Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system Arterioscler Thromb Vasc Biol 1998 18 1771 9 9812917
• Not checked yetcites [123] Ayers K Byrne LM DeMatteo A Brown NJ Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome Hypertension 2012 59 893 8 22353614 PMC3402551

In the paper

“Glucose can easily traverse narrow paracellular gaps.”

In the paper

“Liraglutide treatment increases NO, decreases ET-1, normalizes endothelial function, and increases microvasculature blood flow and glucose disposal in obese rats.”

What the sources say

• 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

In the paper

“Fluid-phase transport can occur through paracellular junctions or by transcytosis through vesicles formed in endothelial cells.”

In the paper

“the gradient in insulin concentration from plasma to interstitial fluid is increased in humans with prediabetes and in mouse models of prediabetes during an insulin clamp,152-154 suggesting impaired microvascular insulin delivery.”

What the sources say

• Not checked yetcites [152] Sjostrand M Gudbjornsdottir S Holmang A Lonn L Strindberg L Lonnroth P Delayed transcapillary transport of insulin to muscle interstitial fluid in obese subjects Diabetes 2002 51 2742 8 12196467 source
• Not checked yetcites [153] Kubota T Kubota N Kumagai H Yamaguchi S Kozono H Takahashi T Inoue M Itoh S Takamoto I Sasako T Kumagai K Kawai T Hashimoto S Kobayashi T Sato M Tokuyama K Nishimura S Tsunoda M Ide T Murakami K Yamazaki T Ezaki O Kawamura K Masuda H Moroi M Sugi K Oike Y Shimokawa H Yanagihara N Tsutsui M Terauchi Y Tobe K Nagai R Kamata K Inoue K Kodama T Ueki K Kadowaki T Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle Cell Metab 2011 13 294 307 21356519 source
• Not checked yetcites [154] Sandqvist M Strindberg L Schmelz M Lonnroth P Jansson PA Impaired delivery of insulin to adipose tissue and skeletal muscle in obese women with postprandial hyperglycemia J Clin Endocrinol Metab 2011 96 E1320 4 21677042 source

In the paper

“They are co-transcribed and act in conjunction with their host genes, Srebp1 and Srebp2, to regulate cholesterol synthesis.”

What the sources say

• Not checked yetcites [143] Najafi-Shoushtari SH Kristo F Li Y Shioda T Cohen DE Gerszten RE Naar AM MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis Science 2010 328 1566 9 20466882 PMC3840500 source

In the paper

“a variety of microRNAs have been shown to influence pancreatic beta cell development and function.”

What the sources say

• Not checked yetcites [136] Lynn FC Skewes-Cox P Kosaka Y McManus MT Harfe BD German MS MicroRNA expression is required for pancreatic islet cell genesis in the mouse Diabetes 2007 56 2938 45 17804764 source
• Not checked yetcites [137] Melkman-Zehavi T Oren R Kredo-Russo S Shapira T Mandelbaum AD Rivkin N Nir T Lennox KA Behlke MA Dor Y Hornstein E miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors EMBO J 2011 30 835 45 21285947 PMC3049206 source

In the paper

“The most abundant microRNA in the liver is miR-122.”

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 [140] Esau C Davis S Murray SF Yu XX Pandey SK Pear M Watts L Booten SL Graham M McKay R Subramaniam A Propp S Lollo BA Freier S Bennett CF Bhanot S Monia BP miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting Cell Metab 2006 3 87 98 16459310 source

In the paper

“Administration of the phosphodiesterase (PDE5) inhibitor sildenafil to obese mice prevents inflammation162 and insulin resistance.159”

What the sources say

• Not checked yetcites [162] Kang L Ayala JE Lee-Young RS Zhang Z James FD Neufer PD Pozzi A Zutter MM Wasserman DH Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice Diabetes 2011 60 416 26 21270253 PMC3028340 source
• 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

In the paper

“These microRNAs participate in the regulation of cholesterol synthesis, fatty acid metabolism, and insulin signaling.”

What the sources say

• Not checked yetcites [141] Davalos A Goedeke L Smibert P Ramirez CM Warrier NP Andreo U Cirera-Salinas D Rayner K Suresh U Pastor-Pareja JC Esplugues E Fisher EA Penalva LO Moore KJ Suarez Y Lai EC Fernandez-Hernando C miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling Proc Natl Acad Sci U S A 2011 108 9232 7 21576456 PMC3107310
• Not checked yetcites [142] Rayner KJ Suarez Y Davalos A Parathath S Fitzgerald ML Tamehiro N Fisher EA Moore KJ Fernandez-Hernando C MiR-33 contributes to the regulation of cholesterol homeostasis Science 2010 328 1570 3 20466885 PMC3114628
• Not checked yetcites [143] Najafi-Shoushtari SH Kristo F Li Y Shioda T Cohen DE Gerszten RE Naar AM MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis Science 2010 328 1566 9 20466882 PMC3840500 source

In the paper

“Skeletal muscle represents the bulk of insulin-sensitive tissue and is a major determinant of glucose tolerance.”

In the paper

“Direct visualization of fluorescent insulin across the endothelium of capillaries perfusing mouse muscle using confocal microscopy shows that insulin moves across the capillary endothelium by a mechanism that is unsaturable, insulin receptor-independent, and conforms to the properties of fluid phase transport”

What the sources say

• Not checked yetcites [158] Williams IM Valenzuela FA Kahl SD Ramkrishna D Mezo AR Young JD Wells KS Wasserman DH Insulin exits skeletal muscle capillaries by fluid-phase transport J Clin Invest 2018 in press PMC5785264 29309051

In the paper

“Inhibition of miR-122 reduces plasma cholesterol and hepatic steatosis, though the specific gene regulatory pathways involved are unclear.”

What the sources say

• Not checked yetcites [140] Esau C Davis S Murray SF Yu XX Pandey SK Pear M Watts L Booten SL Graham M McKay R Subramaniam A Propp S Lollo BA Freier S Bennett CF Bhanot S Monia BP miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting Cell Metab 2006 3 87 98 16459310 source

In the paper

“Impaired adipose tissue blood flow does not contribute substantially to glucose disposal in prediabetes but may contribute to impaired lipid storage in adipocytes and increased ectopic lipid stores.”

What the sources say

• Not checked yetcites [151] Emanuel AL Meijer RI Muskiet MH van Raalte DH Eringa EC Serne EH Role of Insulin-Stimulated Adipose Tissue Perfusion in the Development of Whole-Body Insulin Resistance Arterioscler Thromb Vasc Biol 2017 37 411 418 28126826

In the paper

“Overexpression of miR-375 is associated with reduced insulin secretion, thought to be mediated by inhibition of myotrophin, a protein involved in insulin exocystosis.”

What the sources say

• Not checked yetcites [138] Poy MN Eliasson L Krutzfeldt J Kuwajima S Ma X Macdonald PE Pfeffer S Tuschl T Rajewsky N Rorsman P Stoffel M A pancreatic islet-specific microRNA regulates insulin secretion Nature 2004 432 226 30 15538371

In the paper

“The transition from normoglycemia to prediabetes and diabetes involves changes in the expression of many genes involved in fat and glucose metabolism.”

What the sources say

• Not checked yetcites [133] Rome S Are extracellular microRNAs involved in type 2 diabetes and related pathologies? Clin Biochem 2013 46 937 45 23499584

In the paper

“Fluid-phase transport is determined by the balance between hydrostatic and oncotic pressures.”

In the paper

“Insulin-induced blood flow increases its own tissue delivery, as well as the delivery of nutrient substrates.”

What the sources say

• Not checked yetcites [155] Barrett EJ Wang H Upchurch CT Liu Z Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature Am J Physiol Endocrinol Metab 2011 301 E252 63 21610226 PMC3154531

In the paper

“miR-375, an islet-specific microRNA that regulates both insulin secretion and beta cell mass.”

What the sources say

• Not checked yetcites [138] Poy MN Eliasson L Krutzfeldt J Kuwajima S Ma X Macdonald PE Pfeffer S Tuschl T Rajewsky N Rorsman P Stoffel M A pancreatic islet-specific microRNA regulates insulin secretion Nature 2004 432 226 30 15538371
• Not checked yetcites [139] Poy MN Hausser J Trajkovski M Braun M Collins S Rorsman P Zavolan M Stoffel M miR-375 maintains normal pancreatic alpha- and beta-cell mass Proc Natl Acad Sci U S A 2009 106 5813 8 19289822 PMC2656556 source

In the paper

“miR-375 also regulates many genes involved in cellular proliferation, which likely underlies its effect on the maintenance of beta cell mass.”

What the sources say

• Not checked yetcites [139] Poy MN Hausser J Trajkovski M Braun M Collins S Rorsman P Zavolan M Stoffel M miR-375 maintains normal pancreatic alpha- and beta-cell mass Proc Natl Acad Sci U S A 2009 106 5813 8 19289822 PMC2656556 source

In the paper

“In addition to reducing hyperglycemia, weight loss leads to significant improvements in other cardiovascular risk factors including blood pressure, lipids and biomarkers of inflammation.”

In the paper

“In the DPP study of 3234 patients with IGT and BMI ≥24 kg/m2 (≥22 kg/m2 for Asian-Americans), intensive lifestyle modification led to a loss of 5.6 kg over an average follow-up of 2.8 years, and this was associated with a 58% reduction in incident diabetes.”

What the sources say

• Not checked yetcites [189] Knowler WC Barrett-Connor E Fowler SE Hamman RF Lachin JM Walker EA Nathan DM Diabetes Prevention Program Research G Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 2002 346 393 403 11832527 PMC1370926 source

In the paper

“Genetic deletion of the α2 subunit has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.”

In the paper

“Treatments that improve insulin action in rodent models of prediabetes normalize collagen levels and increase muscle capillaries.”

What the sources say

• 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
• Not checked yetcites [162] Kang L Ayala JE Lee-Young RS Zhang Z James FD Neufer PD Pozzi A Zutter MM Wasserman DH Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice Diabetes 2011 60 416 26 21270253 PMC3028340 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 [179] Kang L Mokshagundam S Reuter B Lark DS Sneddon CC Hennayake C Williams AS Bracy DP James FD Pozzi A Zent R Wasserman DH Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice Diabetes 2016 65 1590 600 27207548 PMC4878430 source

In the paper

“Relaxin did not improve insulin action in isolated muscle, demonstrating the reliance on the microvascular for its insulin-sensitizing effect.”

What the sources say

• 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

“Anti-CD44 antibody treatment reduces inflammation, and improves insulin sensitivity in obese mice.”

What the sources say

• Not checked yetcites [177] Kodama K Toda K Morinaga S Yamada S Butte AJ Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice Diabetes 2015 64 867 75 25294945 PMC4392898 source

In the paper

“There was no impairment in insulin action in muscle isolated from lean VEGF-A knockout mice, demonstrating the requirement for intact microvasculature for this effect.”

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

In the paper

“siRNA knockdown of FAK impairs glucose tolerance and insulin action in lean mice.”

What the sources say

• Not checked yetcites [184] Bisht B Srinivasan K Dey CS In vivo inhibition of focal adhesion kinase causes insulin resistance J Physiol 2008 586 3825 37 18587052 PMC2538921

In the paper

“Hyaluronan is a major component of the glycocalyx of capillary lumens, where it may affect the access of insulin to tissues.”

In the paper

“The pro-inflammatory prediabetic state results in an increase in skeletal muscle collagens and other ECM proteins162, 171 and ECM remodeling.172”

What the sources say

• Not checked yetcites [162] Kang L Ayala JE Lee-Young RS Zhang Z James FD Neufer PD Pozzi A Zutter MM Wasserman DH Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice Diabetes 2011 60 416 26 21270253 PMC3028340 source
• Not checked yetcites [171] Coletta DK Mandarino LJ Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria Am J Physiol Endocrinol Metab 2011 301 E749 55 21862724 PMC3214002
• 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

In the paper

“ECM expansion occurs in adipose tissue of obese subjects and limits adipocyte fat storage,185 leading to ectopic fat stores in liver and skeletal muscle, lipotoxicity, oxidative stress, and inflammation.186”

What the sources say

• Not checked yetcites [185] Crewe C An YA Scherer PE The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis J Clin Invest 2017 127 74 82 28045400 PMC5199684 source
• Not checked yetcites [186] Williams AS Kang L Wasserman DH The extracellular matrix and insulin resistance Trends Endocrinol Metab 2015 26 357 66 26059707 PMC4490038 source

In the paper

“Increased PAI-1 in prediabetes contributes to fibrosis, as does elevated concentrations of the adipokine thrombospondin-1.”

What the sources say

• Not checked yetcites [169] Varma V Yao-Borengasser A Bodles AM Rasouli N Phanavanh B Nolen GT Kern EM Nagarajan R Spencer HJ 3rd Lee MJ Fried SK McGehee RE Jr Peterson CA Kern PA Thrombospondin-1 is an adipokine associated with obesity, adipose inflammation, and insulin resistance Diabetes 2008 57 432 9 18057090 PMC2877915 source

In the paper

“Relaxin administration caused endothelial relaxation and reversed insulin resistance in obese mice.”

What the sources say

• 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

“The ECM is a dynamic structure comprised of proteins and proteoglycans that remodels in responses to injury and inflammation.”

What the sources say

• Not checked yetcites [166] Hynes RO The extracellular matrix: not just pretty fibrils Science 2009 326 1216 9 19965464 PMC3536535 source

In the paper

“The integrin α2 subunit is highly expressed in endothelial cells, fibroblasts and other cell types.”

In the paper

“Skeletal muscle ILK knockout has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.”

What the sources say

• Not checked yetcites [179] Kang L Mokshagundam S Reuter B Lark DS Sneddon CC Hennayake C Williams AS Bracy DP James FD Pozzi A Zent R Wasserman DH Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice Diabetes 2016 65 1590 600 27207548 PMC4878430 source

In the paper

“Capillary skeletal and cardiac muscle rarefaction resulted in glucose intolerance and impairments in skeletal and cardiac muscle insulin-stimulated glucose uptake in vivo.”

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

In the paper

“In the XENDOS study, orlistat therapy resulted in a 5.8 kg weight loss and reduced the progression of IGT to T2DM by 37%.”

What the sources say

• Not checked yetcites [192] Torgerson JS Hauptman J Boldrin MN Sjostrom L XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients Diabetes Care 2004 27 155 61 14693982 source

In the paper

“At ten years, the sustain risk reduction was 34% in the lifestyle arm compared to placebo even though weights were no longer different between groups.”

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 effect was greater in more obese patients and those with a higher fasting glucose.”

What the sources say

• Not checked yetcites [189] Knowler WC Barrett-Connor E Fowler SE Hamman RF Lachin JM Walker EA Nathan DM Diabetes Prevention Program Research G Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 2002 346 393 403 11832527 PMC1370926 source

In the paper

“The reduction of incident diabetes appears to be proportionate to the amount of weight loss, but plateaus at a loss of 10% of body mass.”

In the paper

“The latter requires degradation of GLP-1 to GLP-1 (9-36) by DPP-4 and involves NO.”

What the sources say

• Not checked yetcites [211] Green JB Bethel MA Armstrong PW Buse JB Engel SS Garg J Josse R Kaufman KD Koglin J Korn S Lachin JM McGuire DK Pencina MJ Standl E Stein PP Suryawanshi S Van de Werf F Peterson ED Holman RR Group TS Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes New England Journal of Medicine 2015 373 232 42 26052984

In the paper

“Sildenafil treatment also improved fibrinolytic balance, decreasing PAI-1 concentrations without altering t-PA concentrations.”

What the sources say

• Not checked yetcites [234] Ramirez CE Nian H Yu C Gamboa JL Luther JM Brown NJ Shibao CA Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial J Clin Endocrinol Metab 2015 100 4533 40 26580240 PMC4667163 source