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

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].

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].

View Large Image Download to PowerPoint

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].

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.

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].

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].

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].