The effect of metformin on measurements of insulin sensitivity and β cell response in 18 horses and ponies with insulin resistance

Equine Veterinary Journal

Volumn 40, Issue 5, 2008, Pages 493-500

  Durham, A E ^a   Rendle, D I ^a   Newton, J R ^b  

^a LIPHOOK EQUINE HOSPITAL   (United Kingdom)

^b ANIMAL HEALTH TRUST   (United Kingdom)

Author keywords

Horse; Insulin resistance; Laminitis; Metformin; Obesity

Indexed keywords

ANTIDIABETIC AGENT; INSULIN; METFORMIN;

ANIMAL; ANIMAL DISEASE; ANIMAL LAMENESS; AREA UNDER THE CURVE; ARTICLE; BLOOD; DOSE RESPONSE; DRUG ADMINISTRATION; DRUG EFFECT; FEMALE; FOOT DISEASE; GLUCOSE BLOOD LEVEL; HORSE; HORSE DISEASE; HYPERINSULINISM; INSULIN RESISTANCE; MALE; METABOLISM; PANCREAS ISLET BETA CELL; SECRETION; TREATMENT OUTCOME;

ANIMALS; AREA UNDER CURVE; BLOOD GLUCOSE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; FEMALE; FOOT DISEASES; HORSE DISEASES; HORSES; HYPERINSULINISM; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN RESISTANCE; INSULIN-SECRETING CELLS; LAMENESS, ANIMAL; MALE; METFORMIN; TREATMENT OUTCOME;

ANIMALIA; EQUIDAE;

EID: 47049123814     PISSN: 04251644     EISSN: None     Source Type: Journal    
DOI: 10.2746/042516408X273648     Document Type: Article

References (100)

1. Aguilar-Salinas, C.A., Rojas, R., Gomez-Perez, F.J., Mehta, R., Franco, A., Olaiz, G. and Rull, J.A. (2005) The metabolic syndrome: A concept hard to define. Arch. med. Res. 36, 223-231.
2. Akbar, D.H. (2003) Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine 20, 215-218.
3. Alberti, K. and Zimmet, P. (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classifcation of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539-553.
4. Alberti, K.G., Zimmet, P. and Shaw, J. (2005) IDF Epidemiology Task Force Consensus Group. The metabolic syndrome-a new worldwide definition. Lancet 366, 1059-1062.
5. Anon (2003) American Association of Clinical Endocrinology position statement on insulin resistance syndrome. Endocrine Pract. 9, 237-252.
6. Argenzio, R.A. and Hintz, H.F. (1971) Volatile fatty acid tolerance and effect of glucose and VFA on plasma insulin levels in ponies. J. Nutr. 101, 723-729.
7. Asplin, K.E., Sillence, M.N., Pollitt, C.C. and McGowan, C.M. (2007) Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies. Vet. J. 174, 530-535.
8. Bailey, C.J. (2005) Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diab. Obes. Metab. 7, 675-691.
9. Bailey, S.R., Haberson-Butcher, J.L., Ransom, K.J., Elliott, J. and Menzies-Gow, N.J. (2008) Hypertension and insulin resistance in a mixed population of ponies predisposed to laminitis: further characterizing pre-laminitic metabolic syndrome. Am. J. vet. Res. 69, 122-129.
10. Bailey, S.R., Menzies-Gow, N.J., Harris, P.A., Haberson-Butcher, J.L., Crawford, C., Berhane, Y., Boston, R.C. and Elliott, J. (2007) Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis. J. Am. vet. med. Ass. 231, 1365-1373.
11. Balkau, B. and Charles, M.A. (1999) Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet. Med. 16, 442-443.
12. Bellomo, A., Mancinella, M., Troisi, G., Ettorre, E. and Marigliano, V. (2007) Diabetes and metabolic syndrome. Arch. Gerontol. Geriatr., Suppl. 44, 61-67.
13. Bergman, R.N., Prager, R., Volund, A. and Olefsky, J.M. (1987) Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J. Clin. Investig. 79, 790-800.
14. Bhalla, R.C., Toth, K.F., Tan, E., Bhatty, R.A., Mathias, E. and Sharma, R.V. (1996) Vascular effects of metformin. Possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat. Am. J. Hypertension 9, 570-576.
15. Caballero, A.E., Delgado, A., Aguilar-Salinas, C.A., Herrera, A.N., Castillo, J.L., Cabrera, T., Gomez-Perez, F.J. and Rull, J.A. (2004) The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J. clin. Endocrinol. Metab. 89, 3943-3948.
16. Chan, N.N., Fauvel, N.J. and Feher, M.D. (1998) Non-steroidal anti-inflammatory drugs and metformin: a cause for concern? Lancet 352, 201.
17. Coffman, J.R. and Colles, C.M. (1983) Insulin tolerance in laminitic ponies. Can. J. comp. Med. 47, 347-351.
18. Cornelisse, C.J., Robinson, N.E., Berney, C.A., Eberhart, S., Hauptman, J.E. and Derksen, F.J. (2006) Thermographic study of in vivo modulation of vascular responses to phenylephrine and endothelin 1 by dexamethasone in the horse. Equine vet. J. 38, 119-126.
19. Dandona, P., Chaudhuri, A., Ghanim, H. and Mohanty, P. (2007) Proinflammatory effects of glucose and anti-inflammatory effect of insulin: relevance to cardiovascular disease. Am. J. Cardiol., Suppl. 99, 15B-26B.
20. Dandona, P., Aljada, A., Ghanim, H., Mohanty, P., Tripathy, C., Hofmeyer, D. and Chaudhuri, A. (2004) Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J. clin. Endocrinol. Metab. 89, 5043-5047.
21. DeFronzo, R.A. and Goodman, A.M. (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. New Engl. J. Med. 333, 541-549.
22. DeFronzo, R.A., Tobin, J.D. and Andres, R. (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am. J. Physiol. 237, E214-223.
23. Derosa, G., D'Angelo, A., Tinelli, C., Devangelio, E., Consoli, A., Miccoli, R., Penno, G., Del Prato, S., Paniga, S. and Cicero, A.F. (2007) Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. Diabetes Metab. 33, 129-134.
24. Despres, J.P., Lamarche, B., Mauriege, P., Cantin, B., Lupien, P.J. and Dagenais, G.R. (1996) Risk factors for ischaemic heart disease: is it time to measure insulin? Europ. Heart J. 17, 1453-1454.
25. Detaille, D., Guigas, B., Chauvin, C., Batandier, C., Fontaine, E., Wiernsperger, N. and Leverve, X. (2005) Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 54, 2179-2187.
26. Eiler, H., Frank, N., Andrews, F.M., Oliver, J.W. and Fecteau, K.A. (2005) Physiologic assessment of blood glucose homeostasis via combined intravenous glucose and insulin testing in horses. Am. J. vet. Res. 66, 1598-1604.
27. Forhead, A.J. and Dobson, H. (1997) Plasma glucose and cortisol responses to exogenous insulin in fasted donkeys. Res. vet. Sci. 62, 265-269.
28. Frank, N., Elliott, S.B., Brandt, L.E. and Keisler, D.H. (2006) Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance. J. Am. vet. med. Ass. 228, 1383-1390.
29. Fridlyand, L.E. and Philipson, L.H. (2006) Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes. Metab. 8, 136-145.
30. Fulop, T., Tessier, D. and Carpentier, A. (2006) The metabolic syndrome. Path. Biolog. 54, 375-386.
31. Galassi, A., Reynolds, K. and He, J. (2006) Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am. J. Med. 119, 812-819.
32. Garber, A.J., Duncan, T.G., Goodman, A.M., Mills, D.J. and Rohlf, J.L. (1997) Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am. J. Med. 103, 491-497.
33. Garcia, M.C. and Beech, J. (1986) Equine intravenous glucose tolerance test: glucose and insulin responses of healthy horses fed grain or hay and of horses with pituitary adenoma. Am. J. vet. Res. 47, 570-572.
34. Giannarelli, R., Aragona, M., Coppelli, A. and Del Prato, S. (2003) Reducing insulin resistance with metformin: the evidence today. Diabetes Metab. 29, 6S28-6S35.
35. Ginsberg, H.N. (2000) Insulin resistance and cardiovascular disease. J. clin. Invest. 106, 453-458.
36. Grant, P.J. (2003) Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab. 29, 6S44-6S52.
37. Grundy, S.M., Becker, D., Clark, L.T., Cooper, R.S., Denke, M.A., Howard, W.J., Hunninghake, D.B., Illingworth, D.R., Luepker, R.V., McBride, P., McKenney, J.M., Pasternak, R.C., Stone, N.J. and Van Horn, L. (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 106, 3143-3421.
38. Haffner, S.M., Stern, M.P., Hazuda, H.P., Mitchell, B.D. and Patterson, J.K. (1990) Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? J. Am. med. Ass. 263, 2893-2898.
39. Hanley, A.J., Williams, K., Gonzalez, C., D'Agostino, R.B., Wagenknecht, L.E., Stern, M.P. and Haffner, S.M. (2003) Prediction of type 2 diabetes using simple measures of insulin resistance: combined results from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study. Diabetes 52, 463-469.
40. Hoffman, R.M., Boston, R.C., Stefanovski, D., Kronfeld, D.S. and Harris, P.A. (2003) Obesity and diet affect glucose dynamics and insulin sensitivity in Thoroughbred geldings. J. anim. Sci. 81, 2333-2342.
41. Hood, D.M., Wagner, I.P. and Brumbaugh, G.W. (2001) Evaluation of hoof wall surface temperature as an index of digital vascular perfusion during the prodromal and acute phases of carbohydrate-induced laminitis in horses. Am. J. vet. Res. 62, 1167-1172.
42. Ikeda, T., Iwata, K. and Murakami, H. (2000) Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine. Biochem. Pharmacol. 59, 887-890.
43. Inzucchi, S.E. (2002) Oral antihyperglycemic therapy for type 2 diabetes. J. Am. Med. Ass. 287, 360-372.
44. Jeffcott, L.B., Field, J.R., McLean, J.G. and O-Dea, K. (1986) Glucose tolerance and insulin sensitivity in ponies and Standardbred horses. Equine vet. J. 18, 97-101.
45. Johnson, N.A., Stannard, S.R., Rowlands, D.S., Chapman, P.G., Thompson, C.H., O'Connor, H., Sachinwalla, T. and Thompson, M.W. (2006) Effect of short-term starvation versus high-fat diet on intramyocellular triglyceride accumulation and insulin resistance in physically fit men. Expt. Physiol. 91, 693-703.
46. Johnson, P.J. (2002) The equine metabolic syndrome. Peripheral Cushing's syndrome. Vet. Clin. N. Am.: Equine Pract. 18, 271-293.
47. Johnson, P.J., Scotty, N.C., Wiedmeyer, C., Messer, N.T. and Kreeger, J.M. (2005) Diabetes mellitus in a domesticated Spanish mustang. J. Am. vet. med. Ass. 226, 584-588.
48. Johnson, P.J., Messer, N.T., Slight, S.H., Wiedmeyer, C., Buff, P. and Ganjam, V.K. (2004) Endocrinopathic laminitis in the horse. Clin. Techn. equine Pract. 3, 45-56.
49. Kahn, S.E. (2001) The importance of beta-cell failure in the development and progression of type 2 diabetes. J. clin. Endocrinol. Metabol. 86, 4047-4058.
50. Kalck, K., Frank, N. and Elliott, S.B. (2007) ACVIM abstract #31. Glucose dynamics during the developmental phase of oligofructose-induced laminitis in horses. J. vet. int. Med. 21, 581.
51. Katakam, P.V., Ujhelyi, M.R., Hoenig, M. and Miller, A.W. (2000) Metformin improves vascular function in insulin-resistant rats. Hypertension 35, 108-112.
52. Katwa, L.C., Johnson, P.J., Ganjam, V.K., Kreeger, J.M. and Messer, N.T. (1999) Expression of endothelin in equine laminitis. Equine vet. J. 31, 243-247.
53. Katz, A., Nambi, S.S., Mather, K., Baron, A.D., Follmann, D.A., Sullivan, G. and Quon, M.J. (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J. clin. Endocrinol. Metabol. 85, 2402-2410.
54. Kay, J.P., Alemzadeh, R., Langley, G., D'Angelo, L., Smith, P. and Holshouser, S. (2001) Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 50, 1457-1461.
55. Knowler, W.C., Barrett-Connor, E., Fowler, S.E., Hamman, R.F., Lachin, J.M., Walker, E.A. and Nathan, D.M. (2002) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New Engl. J. Med. 346, 393-403.
56. Kraemer de Aguiar, L.G., Laflor, C.M., Bahia, L., Villela, N.R., Wiernsperger, N., Bottino, D.A. and Bouskela, E. (2007) Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome. Diabet. Med. 24, 272-279.
57. Kronfeld, D.S., Treiber, K.H. and Geor, R.J. (2005) Comparison of nonspecific indications and quantitative methods for the assessment of insulin resistance in horses and ponies. J. Am. vet. med. Ass. 226, 712-719.
58. Kyaw-Tanner, M. and Pollitt, C.C. (2004) Equine laminitis: increased transcription of matrix metalloproteinase-2 (MMP-2) occurs during the developmental phase. Equine vet. J. 36, 221-225.
59. Laakso, M. (1993) How good a marker is insulin level for insulin resistance? Am. J. Epidemiol. 137, 959-965.
60. Legro, R.S., Finegood, D. and Dunaif, A. (1998) A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J. clin. Endocrinol. Metabol. 83, 2694-2698.
61. Lund, S.S., Tarnow, L., Stehouwer, C.D., Schalkwijk, C.G., Frandsen, M., Smidt, U.M., Pedersen, O., Parving, H.H. and Vaag, A. (2007) Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. Diabetes Obes. Metab. 9, 394-407.
62. Mansell, P.I. and Macdonald, I.A. (1990). The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans. Metabolism 39, 502-510.
63. Martin, B.C., Warram, J.H., Krolewski, A.S., Bergman, R.N., Soeldner, J.S. and Kahn, C.R. (1992) Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 340, 925-929.
64. Marx, N., Froehlich, J., Siam, L., Ittner, J., Wierse, G., Schmidt, A., Scharnagl, H., Hombach, V. and Koenig, W. (2003) Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscl. Thromb. vasc. Biol. 23, 283-288.
65. Mather, K.J., Verma, S. and Anderson, T.J. (2001) Improved endothelial function with metformin in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 37, 1344-1350.
66. Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F. and Turner, R.C. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412-419.
67. Mehta, N.N. and Reilly, M.P. (2004) Mechanisms of the metabolic syndrome. Drug Disc. Today: Dis. Mechan. 1, 187-194.
68. Mlinar, B., Marc, J., Janez, A. and Pfeifer, M. (2007) Molecular mechanisms of insulin resistance and associated diseases. Clinica chimica Acta; Int. J. Clin. Chem. 375, 20-35.
69. Nadeau, J.A., Frank, N., Valipe, S.R. and Elliot, S.B. (2006) Blood lipid, glucose, and insulin concentrations in Morgan horses and Thoroughbreds. J. equine vet. Sci. 26, 401-405.
70. Nathan, D.M., Buse, J.B., Davidson, M.B., Heine, R.J., Holman, R.R., Sherwin, R. and Zinman, B. (2006) Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29, 1963-1972.
71. Orio, F., Palomba, S., Cascella, T., De Simone, B., Manguso, F., Savastano, S., Russo, T., Tolino, A., Zullo, F., Lombardi, G., Azziz, R. and Colao, A. (2005) Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study. J. Clin. Endocrinol. Metab. 90, 6072-6076.
72. Pass, M.A., Pollitt, S. and Pollitt, C.C. (1998) Decreased glucose metabolism causes separation of hoof lamellae in vitro: a trigger for laminitis? Equine vet. J., Suppl. 26, 133-138.
73. Pavlovic, D., Kocic, R., Kocic, G., Jevtovic, T., Radenkovic, S., Mikic, D., Stojanovic, M. and Djordjevic, P.B. (2000) Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obes. Metabol. 2, 251-256.
74. Petrie, J.R., Ueda, S., Webb, D.J., Elliott, H.L. and Connell, J.M. (1996) Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease. Circulation 93, 1331-1333.
75. Powell, D.M., Reedy, S.E., Sessions, D.R. and Fitzgerald, B.P. (2002) Effect of short-term exercise training on insulin sensitivity in obese and lean mares. Equine vet. J., Suppl. 34, 81-84.
76. Pratt, S.E., Geor, R.J. and McCutcheon, L.J. (2005) Repeatability of 2 methods for assessment of insulin sensitivity and glucose dynamics in horses. J. vet. intern. Med. 19, 883-888.
77. Ralston, S.L. (2002) Insulin and glucose regulation. Vet. Clin. N. Am.: Equine Pract. 18, 295-304.
78. Ralston, S.L. (2007) Evidence based equine nutrition. Vet. Clin. N. Am.: Equine Pract. 23, 365-384.
79. Reaven, G.M. (1988) Role of insulin resistance in human disease. Diabetes 37, 1595-1607.
80. Rijnen, K.E.P.M. and van der Kolk, J.J. (2003) Determination of reference range values indicative of glucose metabolism and insulin resistance by use of glucose clamp techniques in horses and ponies. Am. J. vet. Res. 64, 1260-1264.
81. Rodgerson, D.H., Belknap, J.K., Moore, J.N. and Fontaine, G.L. (2001) Investigation of mRNA expression of tumor necrosis factor-alpha, interleukin-1beta, and cyclooxygenase-2 in cultured equine digital artery smooth muscle cells after exposure to endotoxin. Am. J. vet. Res. 62, 1957-1963.
82. Rouru, J., Huupponen, R., Pesonen, U. and Koulu, M. (1992) Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese Zucker rats. Life Sci. 50, 1813-1820.
83. Salpeter, S., Greyber, E., Pasternak, G. and Salpeter, E. (2006) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Systematic Reviews 1, CD002967.
84. Scheen, A.J. (1996) Clinical pharmacokinetics of metformin. Clin. Pharmacokin. 30, 359-371.
85. Straczkowski, M., Stepien, A., Kowalska, I. and Kinalska, I. (2004) Comparison of simple indices of insulin sensitivity using the euglycemic hyperinsulinemic clamp technique. Med. Sci. Monitor 10, CR480-484.
86. Suzuki, M., Takamisawa, I., Yoshimasa, Y. and Harano, Y. (2007) Association between insulin resistance and endothelial dysfunction in type 2 diabetes and the effects of pioglitazone. Diabet. Res. Clin. Pract. 76, 12-17.
87. Tiley, H.A., Geor, R.J. and McCutcheon, L.J. (2007) Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. Am. J. vet. Res. 68, 753-759.
88. Treiber, K.H., Kronfeld, D.S., Hess, T.M., Boston, R.C. and Harris, P.A. (2005) Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses. Am. J. vet. Res. 66, 2114-2121.
89. Treiber, K.H., Kronfeld, D.S., Hess, T.M., Byrd, B.M., Splan, R.K., Staniar, W.B. (2006) Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies. J. Am. vet. med. Ass. 228, 1538-1545.
90. Turner, R.C., Cull, C.A., Frighi, V. and Holman, R.R. (1999) Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. J. Am. med. Ass. 281, 2005-2012.
91. Uwaifo, G.I., Fallon, E.M., Chin, J., Elberg, J., Parikh, S.J. and Yanovski, J.A. (2002) Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care 25, 2081-2087.
92. Vick, M.M., Sessions, D.R., Murphy, B.A., Kennedy, E.L., Reedy, S.E. and Fitzgerald, B.P. (2006) Obesity is associated with altered metabolic and reproductive activity in the mare: effects of metformin on insulin sensitivity and reproductive cyclicity. Reprod. Fert. Develop. 18, 609-617.
93. Vitale, C., Mercuro, G., Cornoldi, A., Fini, M., Volterrani, M. and Rosano, G.M. (2005) Metformin improves endothelial function in patients with metabolic syndrome. J. Int. Med. 258, 250-256.
94. Wallace, T.M. and Matthews, D.R. (2002) The assessment of insulin resistance in man. Diabetic Med. 19, 527-534.
95. Webber, J., Taylor, J., Greathead, H., Dawson, J., Buttery, P.J. and Macdonald, I.A. (1994) Effects of fasting on fatty acid kinetics and on the cardiovascular, thermogenic and metabolic responses to the glucose clamp. Clin. Sci. (London) 87, 697-706.
96. Weiss, D.J., Evanson, O.A., McClenahan, D., Fagliari, J.J. and Jenkins, K. (1997) Evaluation of platelet activation and platelet-neutrophil aggregates in ponies with alimentary laminitis. Am. J. vet. Res. 58, 1376-1380.
97. Weyer, C., Tataranni, P.A., Bogardus, C. and Pratley, R.E. (2001) Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 24, 89-94.
98. Wheatcroft, S.B., Williams, I.L., Shah, A.M. and Kearney, M.T. (2003) Pathophysiological implications of insulin resistance on vascular endothelial function. Diabetic Med. 20, 255-268.
99. Wiernsperger, N.F. and Bouskela, E. (2003) Microcirculation in insulin resistance and diabetes: more than just a complication. Diabetes Metabol. 29, 6S77-87.
100. Wright, A.D., Cull, C.A., Macleod, K.M. and Holman, R.R. (2006) Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J. Diabetes Complic. 20, 395-401.