Pathophysiology and Natural History

Pathophysiology

Type 2 diabetes (T2D) is known to have a strong genetic component with contributing environmental determinants. The genetic influence is readily apparent from data of twin and family studies. Identification of T2D susceptibility genes has been elusive, and investigation of a number of candidate genes has been largely negative, yielding a very small population of patients (<5%) with genetic variation in any of the candidate genes studied to date.

It is likely that no single genetic defect will emerge to explain T2D; thus, the disease is heterogeneous, probably multigenic, and likely has a complex etiology. Even though the disease is genetically heterogeneous, there appears to be a fairly consistent phenotype once the disease is fully manifest. Most patients with T2D and fasting hyperglycemia are characterized by:

• Peripheral insulin resistance, mainly in the skeletal muscle but also in the liver and adipose tissue
• Impaired insulin secretion by the pancreas
• Excessive glucose production by the liver.

Although these three metabolic abnormalities have been well studied and characterized, the etiologic sequence has now come into focus. In addition to these three classic defects, there has been a plethora of additional metabolic and hormonal abnormalities identified as newer pharmacologic agents have been developed for the treatment of T2D. As shown in Figure 2-1, five additional defects have been identified, including:

• Excessive glucagon secretion
• Increased glucose reabsorption by the kidney
• Neurotransmitter dysfunction
• Accelerated lipolysis in fat cells
• Decreased incretin effect.

It is probable that the increased hepatic glucose production of T2D is secondary and can be fully reversed with a variety of forms of antidiabetic therapy. In addition, increased hepatic glucose production rates are not major contributors to prediabetes. This leaves insulin resistance, impaired insulin secretion, or both, as initiating abnormalities.

Accumulated evidence strongly supports the idea that both insulin resistance and impaired insulin secretion precede the onset of hyperglycemia and the T2D phenotype. However, insulin resistance is quantitatively more severe in the prediabetic phenotype. In fact, studies have also shown that insulin secretion, including first-phase insulin responses to intravenous (IV) glucose, are either normal or quantitatively increased in the prediabetic state. Thus, substantial evidence from the literature indicates that those individuals who evolve from prediabetes to T2D begin with significant insulin resistance.

Although genetic factors underlie the etiology of T2D in most patients, acquired factors are also likely to be contributory, including such factors as:

• Obesity, particularly central or visceral obesity
• Sedentary lifestyle
• High-fat diet

The aging process also contributes to the expression of T2D in genetically susceptible individuals. When the β-cell function is able to compensate for insulin resistance, hyperinsulinemia develops, which maintains relatively normal glucose tolerance. Therefore, in the compensated insulin-resistant, hyperinsulinemic state, one has either normal glucose tolerance or prediabetes, but not diabetes. A subpopulation of individuals with compensated insulin resistance eventually go on to develop T2D. The magnitude of this subpopulation depends on the methods used to detect glucose intolerance, the particular ethnic groups studied, and several other acquired and metabolic abnormalities that may be present. In addition, during the transition from the compensated state to frank T2D, at least three main pathophysiologic changes can be observed:

• First, basal hepatic glucose production rates progressively increase, which is a characteristic feature of essentially all patients with T2D with fasting hyperglycemia.
• Second, the insulin resistance usually becomes more severe, which may be due to the degree of genetic load and/or acquired conditions, such as obesity, sedentary lifestyle, and aging. Antidiabetic treatment can completely normalize the elevated hepatic glucose production rates and partially ameliorate the insulin resistance so that the degree of insulin resistance returns approximately to the level present in the IGT state.
• The third and most marked change is a decrease in β-cell function and decline in insulin secretory ability. Whether this decline in insulin secretion is because of preprogrammed genetic abnormalities in β-cell function or primarily due to acquired defects, such as glucose or metabolic toxicity, β-cell exhaustion, or both, remains to be elucidated. Nevertheless, a marked decrease in β-cell function accompanies this transition and is thought to be a major contributor to the transition from prediabetes to T2D.

In summary, the proposed etiologic sequence is that insulin resistance and abnormalities of pancreatic insulin secretion (either or both may be genetic in origin) are manifest initially. The pancreas tries to compensate for insulin resistance, which leads to increased insulin secretion to maintain the prediabetic state. In time, the compensation fails and β-cell function declines, leading to hyperglycemia. Note, however, that most patients with T2D, particularly the majority who are obese at the time of initial diagnosis, are still hyperinsulinemic. In addition, the conversion of prediabetes to T2D can also be influenced by:

• Ethnicity and genetics
• Degree of obesity
• Distribution of body fat
• Sedentary lifestyle
• Aging
• Other concomitant medical conditions.

The heterogeneous nature of T2D and its natural history result in a varied response to the different antidiabetic agents over time.

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The Natural History of Diabetes

Type 2 diabetes is at one end of the continuum represented by the fully compensated insulin-resistant state to prediabetes and then to frank T2D. A triad of metabolic defects characterize T2D: insulin resistance, nonautoimmune β-cell dysfunction and inappropriately increased hepatic glucose production (Figure 2-2). The natural history of T2D directly reflects the interrelationships between these three defects. The primary and earliest pathogenic lesion is insulin resistance and the β-cell is able to compensate for a variable length of time by secreting supraphysiologic amounts of insulin. Insulin resistance, compensatory hyperinsulinemia and mild postprandial hyperglycemia characterize prediabetes. Over time, however, the β-cell begins to fail and as relative insulin deficiency occurs, fasting hyperglycemia and full-blown T2D develops. In addition, as insulin levels fall, the inhibitory effect of insulin on hepatic glucose production decreases and significant fasting hyperglycemia develops. Further progression of the disease is marked by an absolute insulin deficiency. Obesity, aging, weight gain in adulthood and physical inactivity are some of the environmental factors that impact the rate of development of diabetes.

Screening patients for prediabetes is probably the best way for early identification of high-risk individuals. Screening can be performed by measurement of glycosylated hemoglobin (A1C), fasting or 2-hour plasma glucose testing after a 75-g oral glucose load. In general clinical practice, measurement of A1C is often the preferred method of diagnosis because of convenience (fasting is not required, so it can be measured at any time of day) and greater reproducibility. However, A1C testing is more expensive and may not be available in regions of the developing world.

For asymptomatic individuals, testing for prediabetes should begin at age at age 45 or earlier in any overweight or obese adults (BMI ≥25 kg/m²) with one or more additional risk factors for T2D. In individuals with normal blood glucose and/or A1C results, testing should be repeated at least every 3 years. In children and adolescents, testing for prediabetes should be considered in overweight or obese individuals with two or more additional risk factors for T2D.

Individuals meeting the criteria for prediabetes should be informed of their risks, and be made aware of risk-reduction strategies. The presence of impaired fasting glucose (IFG), impaired fasting glucose (IGT) and elevated A1C indicate an increased risk for other syndromes associated with insulin resistance, such as hypertension and dyslipidemia, that also require an aggressive diagnostic and therapeutic plan.

Understanding the natural history of T2D aids the clinician in identifying those patients most at risk for developing diabetes and aids in devising an effective treatment plan for those who already have the disease. Each of the available classes of oral antidiabetic agents has a different mechanism of action and is, therefore, potentially most effective at different stages in the continuum from prediabetes to frank diabetes. Given that insulin resistance is one of the major pathogenic factors in the prediabetic state and continues to persist in frank diabetes, efforts to enhance insulin sensitivity in the liver using metformin (MET) as a first-line agent are useful. Thiazolidinediones (TZD) also enhance insulin sensitivity (primarily in peripheral tissues) and are also useful in the prevention and early treatment of diabetes; however, they have fallen out of favor due to their side effect profile. Other pharmacological agents shown to reduce the incidence of diabetes includeangiotensin-converting enzyme (ACE) inhibitors (DREAM trial), α-glucosidase inhibitors (STOP-NIDDM trial), and orlistat (XENDOS trial). Metformin is the agent with the strongest evidence base and best long-term safety profile for the prevention of diabetes, although lifestyle changes (such as increased exercise and weight loss) are even more effective. Perhaps the sodium glucose cotransporter type 2 inhibitor (SGLT2) and glucogonlike peptide 1 receptor agonist (GLP-1 RA) classes will prove to be useful in prevention of T2D.

The potential benefits of intervention before the onset of diabetes and aggressive treatment once the disease becomes manifest are tremendous. Identifying and treating the individual prediabetes and related cardiovascular (CV) comorbidities reduce the incidence of macrovascular disease and T2D. Early intervention in T2D certainly reduces the incidence of microvascular disease and will most likely slow the progression of the disease itself. The primary care provider is uniquely positioned to promote and provide early prevention and to have a substantial impact on lessening the burden placed on individuals and society by T2D.

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