International Journal of Diabetes Mellitus
Volume 1, Issue 1 , Pages 22-25, April 2009

Approach to dysglycemia: Do we need to treat impaired glucose tolerance and impaired fasting glucose?

National Center for Diabetes, Endocrinology and Genetics, P.O. Box 13165 Amman 11942, Jordan

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Abstract 

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are not only a surrogate for the state of insulin resistance but are also associated with the microvascular and macrovascular complications traditionally linked to diabetes. They predict an increased risk for death and morbidity due to cardiovascular disease.

There is growing evidence that early detection of this state of “pre-diabetes” enables us to limit these recognized complications and perhaps to halt the progression to diabetes. For all pre-diabetes patients’ life style modifications, emphasizing modest weight loss & moderate physical activity are strongly recommended. Pharmacological intervention may also be necessary. Many studies have shown several drugs, both antidiabetic and nonhypoglycemic agents to be useful. If pharmacological treatment is required, Metformin is considered the first choice because of its safety, tolerability, efficacy and low cost.

 

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1. Introduction 

Diabetes and its complications are a growing concern worldwide. It has become an epidemic menace in most developed and many developing countries. Globally, the number of people with diabetes is expected to almost double in the next two decades, increasing from 194 million in 2003 to 380 million in 2025 [1]. The associated morbidity, mortality and high costs of health care, made type 2 diabetes an important global public health challenge and target for prevention. In Jordan, it was estimated that the total treatment costs (direct and indirect) incurred in regards to diabetes was 1,308 Billion JD per year [2], an enormous public health burden, and made the prevention of diabetes a critical health goal.

Progression to overt diabetes from a pre-diabetic state occurs gradually, over a period of many years; however, current estimates indicate that most individuals (perhaps up to 70%) with pre-diabetic state eventually develop diabetes [3], [4], [5]. Studies have shown that patients during the pre-diabetic state are at increased risk of microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (cardiovascular disease and stroke) complications and thus have higher morbidity and mortality than individuals with normal glucose homeostasis [6].

Between 1997 and 2006, eight major clinical trials examined whether lifestyle or pharmacologic interventions would prevent or delay the development of diabetes in populations with IFG and/or IGT [4], [5], [7], [12]. All of these trials demonstrated a reduction in the development of diabetes of 25–60% over the period of follow-up depending on the type of intervention applied [8], [9], [10], [11].

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2. Definition of pre-diabetes and its natural history 

The ADA defines normal glucose tolerance as a FPG<100mg/dl and 2h PG in response to a 75g OGTT of <140mg/dl [13]. Diabetes is defined as a FPG⩾126mg/dl or a 2h PG⩾200mg/dl during an OGTT. IFG and IGT represent intermediate states of abnormal glucose regulation that exist between normal glucose homeostasis and diabetes. It is a state of heightened risk of developing type 2 diabetes and other associated complications.

Two different categories of pre-diabetes exist: IFG which is defined by an elevated fasting plasma glucose (FPG) concentration (⩾100 and <126mg/dl) [14] and IGT which is defined by an elevated 2-h plasma glucose concentration (⩾140 and <200mg/dl) after a 75-g glucose load on the oral glucose tolerance test (OGTT) in the presence of an FPG concentration <126mg/dl [14].

Studies have shown that an oral glucose tolerance test (OGTT) is a more sensitive measure of early abnormalities in glucose regulation than fasting plasma glucose or HbA1c [6]. This is possibly due to the fact that IGT is a consequence of two processes that are intimately associated with obesity and drive pre-diabetic hyperglycemia: insulin resistance and dyslipidemia [15]. In obesity, as skeletal muscles lose sensitivity to insulin, more glucose is taken up by adipocytes, stimulating the production and release of more free fatty acids (FFAs) and triglycerides (TG). Elevated circulating FFAs in turn promote hyperglycemia by stimulating hepatic gluconeogenesis while inhibiting insulin-mediated glucose uptake and storage as glycogen.

The prevalence of IFG and IGT varies considerably among different ethnic groups. Data also indicate that the prevalence of IFG and IGT is 26% and 15% respectively [16]. Also in Jordan Ajlouni et al reported the prevalence of pre-diabetes (IFG and IGT) to be 10% in 1997 [17]and the prevalence of IFG to be 7.8% in 2004 [18]. The prevalence of IFG and IGT also differs by age and sex, being more common in women than in men and increasing with advancing age [19].

The course of pre-diabetes (both IGT and IFG) is variable and difficult to predict. The different rates of progression reflect different genetic and environmental factors. Furthermore, patients with both IGT and IFG develop diabetes twice the rate as do individuals who manifest a single abnormality [20]. Patients with a higher FPG (i.e. 6.1–6.9mmol/L [110–125mg/dL]) are also at much higher risk of progression to diabetes than those with lower (but abnormal) FPG levels (5.6–6.0mmol/L [100–109mg/dL]) [4].

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3. Pathogenesis of IFG and IGT 

The basic patho-physiological mechanisms underlying pre-diabetes are insulin resistance and defective insulin secretion. However, IFG and IGT differ in the nature of both of these defects [21].

In isolated IFG, there is a predominant hepatic insulin resistance with relatively preserved skeletal muscle sensitivity to insulin. On the other hand, in isolated IGT the hepatic insulin sensitivity is normal to slightly reduced and the resistance of skeletal muscles to insulin is moderate to severe.

IFG and IGT also differ in their pattern of impairment of insulin secretion. In isolated IFG there is a decrease in the first-phase (0–10min) insulin secretory response to intravenous glucose and a reduced early-phase (first 30min) insulin response to oral glucose but the late-phase (60–120min) plasma insulin response during the OGTT is normal. In isolated IGT there is a defect in both early and late-phase insulin secretion.

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4. Microvascular complications of prediabetes 

Classically diabetes is associated with microvascular and macrovascular complications but growing evidence shows that these complications are also present in the pre-diabetic state and that their risk increases with the distribution of blood glucose concentration well below the overt diabetes. The Aus Diab studies, for example, which is a population-based survey of 11,247 adults aged over 25 years found that 21.7% of individuals with pre-diabetes (IGT and/or IFG) had at least one microvascular complication [22].

In a cross-sectional study, neuropathy was found in 26% of 279 patients with diabetes, 11.2% of 89 patients with IGT, and only 3.9% of 577 age-matched normal control subjects [23]. IGT associated neuropathy is a symmetric, distal sensory polyneuropathy with prominent neuropathic pain which is phenotypically similar to diabetic neuropathy [24], [25]. This reflects similar fiber loss and altered nerve morphology in both IGT and diabetes. Autonomic dysfunction manifested mainly as vagal dysautonomia (abnormal heart rate recovery following exercise, blunted R–R interval variability to deep breathing, and reduced expiration to inspiration ratio) is also prevalent in pre-diabetes [26].

Microalbuminuria also has an increased prevalence in IGT. A very large population based study in China [27]demonstrated that the rate of albumin excretion was significantly higher among IGT subjects compared with the non-diabetic control group (7.2±5.7 vs. 4.5±2.8).

Independent studies have noted an approximate fourfold increase in the prevalence of retinopathy among Pima Indians with IGT compared with age-matched control subjects [28]. Data suggest that the first stage of retinal injury occurs during IGT [28].

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5. Macrovascular complications of prediabetes 

A diagnosis of pre-diabetes not only identifies subjects who are at increased risk of diabetes but also at risk of cardiovascular and other macrovascular complications of diabetes. Data have shown that IGT patients are at greater risk of death from all causes and have a two to fivefold increased incidence of new-onset cardiovascular ischemia, fatal and total myocardial infarction, and stroke in comparison with their age-matched normoglycemic control subjects [29], [30]. The Paris prospective study [31] has shown during the ten year follow up period that subjects with impaired glucose tolerance have about 50% increased risk of cardiovascular mortality. Other studies have shown an increased incidence of heart failure and coronary artery disease in patients with IGT irrespective of progression to diabetes [32], [33].

While some studies have shown that both IGT and IFG confer an increased risk of cardiovascular disease [34], others, like the Funagata diabetes study, suggest that IGT is more strongly associated with cardiovascular disease risk than with fasting hyperglycemia [29].

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6. Rationale for the prevention of diabetes and recommendations for clinical management 

The considerable increase in the incidence of diabetes and its serious long term complications strongly support efforts to prevent or delay its occurrence. This is the rationale behind the consensus statement for the management of patients with pre-diabetes released by the ADA in October, 2006. The panel concluded that intervention was warranted, based on the expectation that delay of diabetes would postpone the requirement for complicated treatment regimens and that microvascular complications (and potentially CVD) would be delayed or prevented [13].

Fortuitously, a wide variety of interventions have been shown to alter the natural course of IFG and IGT and their progression to diabetes. Results of the Diabetes Prevention Program (DPP) and other similar large well-designed prospective studies make it clear that aggressive modification of diet and exercise can prevent or slow the progression from IGT to diabetes [4]. In the Diabetes Prevention Program (DPP), diet and exercise modification was significantly more effective in diabetes risk reduction than pharmacological glucose reduction with Metformin [4] (Table 1). Diet and exercise were also more effective than Metformin in returning IGT subjects to a normal glucose tolerance.

Table 1. Diabetes prevention program.
Cumulative incidence of diabetes (%)P-value
Metformin↓ 31%<0.001
Lifestyle↓ 58%<0.001

Since intensive lifestyle intervention provides the greatest reduction in the occurrence of diabetes, along with a modest reduction in CVD risk factors, patients with IGT should be referred to a nutritionist for counseling on exercise and diet with the goal of losing 5–7% of body weight and increasing moderate aerobic exercise to 150min weekly (the DPP goals) [4] which is the treatment of choice for patients with prediabetes.

Because lifestyle modification is usually difficult to maintain, pharmacological interventions have been studied to prevent the progression to type 2 diabetes. Several oral antidiabetic agents have been shown to be effective at delaying onset of type 2 diabetes. Thiazolidinediones (TZDs) reduced incidence of diabetes by ∼60% (PIPOD and DREAM trials) [35], [36], whilst Metformin (in DPP) [4], Acarbose (in STOP-NIDDM study) [36] and Orlistat (in XENDOS study) [12] are only about half as effective as the TZDs. But the benefits of treatment still need to be balanced against the safety and tolerability of the intervention. If pharmacological treatment is warranted, metformin should be considered first because of its favourable overall safety, tolerability, efficacy, and cost profile.

Finally, drugs that do not primarily target hyperglycemia may also reduce the risk for type 2 diabetes. A large number of trials of ACE-inhibitors or ARBs for various CV indications suggest that these drugs could reduce risk for type 2 diabetes by as much as 25% [37].

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References 

  1. International Diabetes Federation, 2006. <www.atlas.idf.org>.
  2. The Ministry of Health, Jordan, Center for Disease Control (CDC) Report, 2004.
  3. Tuomilehto J, Lindstrom J, Eriksson JG, et al. The Finnish diabetes prevention study group: prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–1350
  4. Knowler WC, Barrett-Conner E, Fowler SE, et al. The diabetes prevention program research group: reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403
  5. Vendrame F, Gottlieb PA. Prediabetes: prediction and prevention trials. Endocrinol Metab Clin North Am. 2004;33:75–92
  6. Singleton Robinson, Smith A Gordon, Russell James W, et al. Microvascular complications of impaired glucose tolerance. Diabetes. 2003;52(12):2867–2873
  7. Chiasson JL, Josse RG, Gomis R, et al. The STOPNIDDM trial research group: acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet. 2002;359:2072–2077
  8. Ramachandran A, Snehalatha C, Mary S, et al. Indian Diabetes Prevention Programme (IDPP): 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;49:289–297
  9. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in highrisk Hispanic women. Diabetes. 2002;51:2796–2803
  10. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care. 1997;20:537–544
  11. Gerstein HC, Yusuf S, Boxch J, et al. DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) trial investigators: effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet. 2006;368:1096–1105
  12. Torgerson JS, Hauptman J, Boldrin MN, et al. 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;27:151–161
  13. Nathan David M, Davidson Mayer B, DeFronzo Ralph A, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. A consensus statement from the American Diabetes Association. Diabetes Care. 2007;30:753–759
  14. Genuth S, Alberti KG, Bennett P, et al. Expert committee on the diagnosis and classification of diabetes mellitus: follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160–3167
  15. Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocrine Rev. 2002;23:201–229
  16. Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the US population: National health and nutrition examination survey 1999–2002. Diabetes Care. 2006;29:1263–1268
  17. Ajlouni K, Jaddou H, Batieha A. Diabetes and impaired glucose tolerance in Jordan: prevalence and associated risk factors. J. Intern. Med. 1998;244:317–323
  18. Ajlouni K, Khader YS, Batieha A, et al. An increase in prevalence of diabetes mellitus in Jordan during ten years. J Diabetes Complications. 2008;22:317–324
  19. Nathan David M, Davidson Mayer B, DeFronzo Ralph A, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30(3):753–759
  20. Larson H, Lindgarde F, Berglund G, et al. Prediction of diabetes using ADA or WHO criteria in post-menopausal women: a 10-year follow-up study. Diabetologia. 2004;43:1224–1228
  21. Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of ß-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130–1139
  22. Dunstan David W, Zimmet Paul Z, Welborn Timothy A, et al. The rising prevalence of diabetes and impaired glucose tolerance: the Australian diabetes, obesity and lifestyle study. Diabetes Care. 2002;25:829–834
  23. Franklin GM, Kahn LB, Bender J, et al. Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis valley diabetes study. Am J Epidemiol. 1990;131:633–643
  24. Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care. 2001;24:1448–1453
  25. Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60:108–111
  26. Panzer C, Lauer MS, Brieke A, et al. Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes. 2002;51:803–807
  27. Pan XR, Hu YH, Li GW, et al. Impaired glucose tolerance and its relationship to ECG-indicated coronary heart disease and risk factors among Chinese. Da Qing IGT and diabetes study. Diabetes Care. 1993;16:150–156
  28. Gabir MM, Hanson RL, Dabelea D, et al. Plasma glucose and prediction of microvascular disease and mortality: evaluation of 1997 American Diabetes Association and 1999 World Health Organization criteria for diagnosis of diabetes. Diabetes Care. 2000;23:1113–1118
  29. Tominaga M, Eguchi H, Igarashi K, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata diabetes study. Diabetes Care. 1999;22:920–924
  30. Kuller LH, Velentgas P, Barzilay J, et al. Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Arterioscler Thromb Vasc Biol. 2000;20:823–829
  31. Jouven Xavier, Desnos Michel, Guerot Claude, et al. Predicting sudden death in the population. Circulation. 1999;1978–1983
  32. Nielson Christopher, Lange Theodore. Blood glucose and heart failure in nondiabetic patients. Diabetes Care. 2005;28:607–611
  33. Nielson Christopher, Lange Theodore, Hadjokas Nicholas. Blood glucose and coronary artery disease in nondiabetic patients. Diabetes Care. 2006;29:998–1001
  34. Levitan Emily B, Song Yiqing, Ford Earl S, et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med. 2004;164:2147–2155
  35. Xiang Anny H, Peters Ruth K, Kjos Siri L, et al. Effect of pioglitazone on pancreatic beta cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabete. 2006;55:517–522
  36. Chiasson Jean-Louis, Josse Robert G, Gomis Ramon, et al. STOP – NIDDM trial research group: acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet. 2002;359:2072–2077
  37. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomized clinical trials. Diabetes Metab. 2004;30:487–496

PII: S1877-5934(09)00005-8

doi:10.1016/j.ijdm.2009.03.011

International Journal of Diabetes Mellitus
Volume 1, Issue 1 , Pages 22-25, April 2009

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