Abstract
Type 2 diabetes and other non-communicable diseases (NCD) are a growing public health challenge globally. An estimated 285 million people, corresponding to 6.4 % of the world’s adult population has diabetes. This is expected to reach 552 million by 2030, 7.8 % of the adult population, with the African region expected to experience the greatest increase. A much larger segment of the world’s population, approximating 79 million individuals in the US alone, has prediabetes. Multiple factors including genetic predisposition, insulin resistance, increased insulin secretory demand, glucotoxicity, lipotoxicity, impaired incretin release/action, amylin accumulation, and decreased β-cell mass play a causative role in the progressive β-cell dysfunction characteristic of prediabetes. Interventions preventing progression to type 2 diabetes should therefore delay or prevent β-cell failure. This article will first review the principal pathophysiological mechanisms underlying prediabetes and subsequently address treatment considerations based on these in the prevention of type 2 diabetes. In view of long-standing safety data with demonstrated efficacy and cost-effectiveness in the prevention of type 2 diabetes in high-risk individuals, metformin should be considered as initial therapy for those unable to comply with or lifestyle modification or where the latter has been ineffective in decreasing progression to type 2 diabetes.
Similar content being viewed by others
References
IDF, Diabetes Atlas Fourth Edition. International Diabetes Federation (Brussels, Belgium, 2009)
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20(7), 1183–1197 (1997)
The Expert Committee on the diagnosis and classification of diabetes mellitus, Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26(11), 3160–3167 (2003)
American Diabetes Association, Standards of medical care in diabetes-2012. Diabetes Care 35(1), S11–S63 (2012)
The International Expert Committee, International expert committee report on the role of the A1c assay in the diagnosis of diabetes. Diabetes Care 32(7), 1327–1334 (2009)
WHO, Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. diabetes res. Clin. Pract. 93(3), 299–309 (2011)
Report of a WHO/IDF consultation: definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. WHO, Geneva, (2006). http://whqlibdoc.who.int/publications/2006/9241594934_eng.pdf
R.A. DeFronzo, M.A. Abdul-Ghani, Preservation of β-cell function: the key to diabetes prevention. J. Clin. Endocrinol. Metab. 96(8), 2354–2366 (2011)
J. Shaw, R.A. Sicree, P.Z. Zimmet, Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 87(1), 4–14 (2010)
A.G. Tábak, C. Herder, W. Rathmann, E.J. Brunner, M. Kivimäki Prediabetes: a high-risk state for diabetes development. Lancet Published online June 9, (2012) doi:10.1016/S0140-6736(12)60283-9
I. Hopper, B. Billah, M. Skiba, H. Krum, Prevention of diabetes and reduction in major cardiovascular events in studies of subjects with prediabetes: meta-analysis of randomized controlled clinical trials. Eur. J. Cardiovasc. Prev. Rehabil. 18(6), 813–823 (2011)
L. Perreault, Q. Pan, K.J. Mather, K.E. Watson, R.F. Hammam, S.E. Kahn, For the diabetes prevention program research group. Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the diabetes prevention program outcomes study, Lancet published online June 9, (2012). (doi:10.1016/S0140-6736(12)60525-X
A. Tirosh, I. Shai, D. Tekes-Manova, E. Israeli, D. Pereg, T. Shochat, I. Kochba, A. Rudich, For the Israeli diabetes research group, normal fasting plasma glucose levels and type 2 diabetes in young men. N. Engl. J. Med. 353(10), 1454–1462 (2005)
M. Bergman, Inadequacies of absolute threshold levels for diagnosing prediabetes. Diabetes Metab. Res. Rev. 26(1), 5–6 (2010)
E. Ferrannini, M. Massari, M. Nannipieri, A. Natali, R.L. Ridaura, C. Gonzales-Villalpando, Plasma glucose levels as predictors of diabetes: the Mexico city diabetes study. Diabetologia 52(5), 818–824 (2009)
Y. Heianza, Y. Arase, K. Fujihara, H. Tsuji, K. Saito, S.D. Hsieh, S. Kodama, H. Shimano, N. Yamada, S. Hara, H. Sone, Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA1c and impaired fasting glucose the Toranomon hospital health management center study 4 (TOPCS 4). Diabetes Med. 29, e279–e285 (2012)
M.J. Picon, M. Murri, A. Muñoz, J.C. Fernandez-Garcia, R. Gomez-Huelgas, F.J. Tinahones, Hemoglobin A1c versus oral glucose tolerance test in postpartum diabetes screening. Diabetes Care 35(8), 1648–1653 (2012)
C. Weyer, C. Bogardus, D.M. Mott, R.E. Pratley, The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis if type 2 diabetes mellitus. J. Clin. Invest. 104(6), 787–794 (1999)
G.C. Weir, S. Bonner-Weir, Five stages of evolving β-cell dysfunction during progression to diabetes, Diabetes 53(12, suppl 3), S16–S21 (2004)
A. Vasudevan, A.J. Garber, Postprandial Hyperglycemia, in Contemporary Endocrinology: Type 2 Diabetes Mellitus : An Evidence-Based Approach to practical Management, ed. by M.N. Feinglos, M.A. Bethel (Humana Press, Totowa, 2008), pp. 97–113
C.H. Courtney, J.M. Olefsky, Insulin Resistance, in Mechanisms of Insulin Action, ed. by A.R. Saltiel, J.E. Pessin (Landes Bioscience and Springer Science + Business Media, New York, 2007), pp. 185–209
D.M. Muoio, T.R. Koves, J. An, C. Newgard, Metabolic Mechanisms of Muscle Insulin Resistance, in Contemporary Endocrinology: Type 2 Diabetes Mellitus : An Evidence-Based Approach to Practical Management, ed. by M.N. Feinglos, M.A. Bethel (Humana Press, Totowa, 2008), pp. 97–113
R.N. Bergman, Banting Lecture 2006. Orchestration of glucose homeostasis, from a small acorn to the California Oak. Diabetes 56(6), 1489–1501 (2007)
M.A. Abdul-Ghani, M.P. Stern, V. Lyssenko, T. Tuomi, L. Groop, R.A. DeFronzo, Minimal contribution of fasting hyperglycemia to the incidence of type 2 diabetes in subjects with normal 2-h plasma glucose. Diabetes Care 33(3), 557–561 (2010)
D.A. Lang, D.R. Matthews, M. Burnett, R.C. Turner, Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes 30(5), 435–439 (1981)
S. O’Rahilly, R.C. Turner, D.R. Matthews, Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N. Engl. J. Med. 318(19), 1225–1230 (1988)
M.M. Byrne, J. Sturis, R.J. Sobel, K.S. Polonsky, Elevated plasma 2 h post challenge predicts defects in beta-cell function. Am. J. Physiol. 270(4 pt1), E572–E579 (1996)
S. Seino, T. Shibasaki, K. Minami, Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J. Clin. Invest. 121(6), 2118–2125 (2011)
J.L. Leahy, Pathogenesis of Type 2 diabetes mellitus, in Contemporary Endocrinology: Type 2 Diabetes Mellitus : An Evidence-Based Approach to Practical Management, ed. by M.N. Feinglos, M.A. Bethel (Humana Press, Totowa, 2008), pp. 17–33
A. Clark, Pancreatic Islet Pathology in Type 2 diabetes, in Pancreatic Beta Cell in Health and Disease, ed. by S. Seino, G.J. Bell (Springer, New York, 2008), pp. 381–398
A. Basu, M.G. Pedersen, C. Cobelli, Commentary. Prediabetes: evaluation of β-cell function. Diabetes 61(2), 270–271 (2012)
M.A. Abdul-Ghani, D. Tripathy, R.A. Defronzo, Contributions of β-Cell dysfunction and insulin resistance to the pathogenesis of Impaired glucose tolerance and impaired fasting glucose. Diabetes Care 29(5), 1130–1139 (2006)
M.A. Abdul-Ghani, K. Williams, R. DeFronzo, M. Stern, What is the best predictor of future type 2 diabetes? Diabetes Care 30(6), 1544–1548 (2007)
M.A. Abdul-Ghani, T. Abdul-Ghani, N. Ali, R.A. DeFronzo, One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes. Diabetes Care 31(8), 1650–1655 (2008)
M.A. Abdul-Ghani, V. Lyssenko, T. Tuomi, R.A. DeFronzo, L. Groop, Fasting versus postload plasma glucose concentration and the risk for future type 2 diabetes :results from the Botnia Study. Diabetes Care 32(2), 281–286 (2009)
J.M. Haus, T.P.J. Solomon, C.M. Marchetti, J.M. Edmison, F. Gonzalez, J.P. Kirwan, Free fatty acid-induced hepatic insulin resistance is attenuated following lifestyle intervention in obese individuals with impaired glucose tolerance. J. Clin. Endocrinol. Metab. 95(1), 323–327 (2010)
E. Ferrannini, A. Gastaldelli, P. Iozzo, Pathophysiology of Prediabetes, in Prediabetes and Diabetes Prevention, ed. by M. Bergman (W.B. Saunders Company, Philadelphia, 2011), pp. 327–340
R.G. Mirmira, Saturated free fatty acids: islet β cell “stress ER”. Endocrine 42(6), 1–2 (2012)
R. Weiss, S. Dufour, S.E. Taksali, W.V. Tamborlane, K.F. Petersen, R.C. Bonadonna, L. Boselli, G. Barbetta, K. Allen, F. Rife, M. savoye, J. Dziura, R. Sherwin, G.I. Shulman, S. Caprio, Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 362, 951–957 (2003)
R.A. DeFronzo, From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58(4), 773–795 (2009)
A. Vella, Mechanism of action of DPP-4 inhibitors-new insights. J. Clin. Endocrinol. Metab. 97(8), 2626–2628 (2012)
E. Muscelli, A. Casolaro, A. Gastaldelli, a Mari, G. Seghieri, B. Astiarraga, Y. Chen, M. alba, J. Holst, E. Ferrannini, Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. J. Clin. Endocrinol. 97(8), 2818–2819 (2012)
M. Bergman, Treatment of prediabetes. Louvain Med 131(3), 104–113 (2012)
R.E. Ratner, A. Sathasivam, Treatment recommendations for prediabetes, in Prediabetes and Diabetes Prevention, ed. by M. Bergman (W.B. Saunders Company, Philadelphia PA., 2011), pp. 385–397
J. Armato, R.A. DeFronzo, M. Abdul-Ghani, R. Ruby, Successful treatment of prediabetes in clinical practice: targeting insulin resistance and β-cell dysfunction. Endocr. Pract. 18(3), 342–350 (2012)
V. Aroda, R. Ratner, Approach to the patient with prediabetes. J. Clin. Endcorinol. Metab. 93(9), 3259–3265 (2008)
A. Ramachandran, C. Snehalatha, Diabetes Prevention Programs, in Prediabetes and Diabetes Prevention, ed. by M. Bergman (W.B. Saunders Company, Philadelphia PA, 2011), pp. 353–372
J.P. Crandall, W.C. Knowler, S.E. Kahn, D. Marrero, J.C. Florez, G.A. Bray, S. M. Haffner, M. Hoskin, D.M. Nathan, For the diabetes prevention program research group. Nat. Clin. Pract., www.nature.com/clinicalpractice, published online 20 May (2008). doi:10.1038/ncpendmet0843
W.A. Hsueh, L. Orloski, K. Wyne, Prediabetes: the importance of early identification and intervention. Postgrad. Med. 122(4), 129–142 (2010)
D.M. Nathan, M.B. Davidson, R.A. DeFronzo, R.J. Heine, R.R. Henry, R. Pratley, B. Zinman, Impaired fasting glucose and impaired glucose tolerance: implications for care consensus statement from American diabetes association. Diabetes Care 30, 753–759 (2007)
J.L. Chiasson, R.G. Josse, R. Gomis, M. Hanefeld, A. Karasik, M. Laakso, STOP-NIDDM trial research group, Acarbose for prevention of type 2 diabetes: the STOP-NIDDM randomised trial. Lancet 359, 2072–2077 (2002)
R. Kawamori, N. Tajima, Y. Iwamoto, A. Kashiwagi, K. Shimamoto, K. Kaku, Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance. Lancet 1607–1614 (2009)
R. Moriya, T. Shirakura, J. Ito, S. Mashiko, T. Seo, Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice. Am. J. Physiol. Endocrinol. Metab. 297, E1358–E1364 (2009)
Effect of nateglinide on the incidence of diabetes and cardiovascular events, Navigator study group. N. Engl. J. Med. 362(16), 1463–1476 (2010)
The ORIGIN Trial Investigators, Basal Insulin and Cardiovascular and Other Outcomes in dysglycemia. N. Engl. J. Med. 367(4), 319–328 (2012)
J. Segura, L.M. Ruilope, Treatment of prehypertension in diabetes and metabolic synderome: what are the pros? Diabetes Care 32(11, suppl 2), S284–S289 (2009)
L. Niskanen, T. Hedner, L. Hansson, J. Lanke, A. Niklason, For the CAPP study group. Diabetes Care 24(12), 2091–2096 (2001)
R. DeFronzo, M. Abdul-Ghani, Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am. J. Cardiol. 108(suppl), 3B–24B (2011)
E.N. Taylor, F.B. Hu, G.C. Curhan, Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care 29(5), 1065–1070 (2006)
C. Manrique, M. Johnson, J.R. Sowers, Thiazide diuretics alone or with β-blockers impair glucose metabolism in hypertensive patients with abdominal obesity. Hypertension 55(1), 15–17 (2010)
W.J. Elliott, P.M. Meyer, Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 369(9557), 201–207 (2007)
N. Sattar, D. Preiss, H.M. Murray, P. Welsh, B.M. Buckley, A.J.M. de Craen, S.R.K. Seshasai, J.J. McMurray, D.J. Freeman, J.W. Jukema, P.W. Macfarlane, C.J. Packard, D.J. Stott, R.G. Westendorp, J. Shepherd, B.R. Davis, S.L. Pressel, R. Marchioli, R.M. Marfisi, A.P. Maggioni, L. Tavazzi, G. Tognoni, J. Kjekhus, T.R. Perdersen, T.J. Cook, A.M. Gotto, M.B. Clearfield, J.R. Downs, H. Nakamura, Y. Ohashi, K. Mizuno, I. Ford, Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet 375(9716), 735–742 (2010)
P.M. Ridker, A. Pradhan, J.G. MacFadyen, P. Libby, R.J. Glynn, Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trail. Lancet 380(9841), 565–571 (2012)
A. Goldfine, Statins: is it really time to reassess benefits and risk? N. Engl. J. Med. 366(19), 1752–1755 (2012)
Conflict of Interest
The author has no conflicts to report.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bergman, M. Pathophysiology of prediabetes and treatment implications for the prevention of type 2 diabetes mellitus. Endocrine 43, 504–513 (2013). https://doi.org/10.1007/s12020-012-9830-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-012-9830-9