Reactive oxygen species have also been shown to participate in the genesis of type 2 diabetes. Although the beta cells remain intact, with hyperglycemia resulting from an interplay between insulin deficiency and insulin resistance, oxidative stress destroys specific glucose transporter proteins (GLUTs) in the cell membrane and cytosol. GLUT 2, found in beta islet cells, mediates glucose uptake with compensatory release of insulin during hyperglycemic states (Figure 1). Similarly, under the influence of insulin, muscle, and adipose tissue uptake of glucose is mediated by GLUT 4. Destruction of these proteins by reactive oxygen species results in insulin deficiency and insulin resistance. But which comes first between the two?

    Litonjua noted that while previous theories have never convincingly settled the debate, recent studies involving Thais and Europeans (Pimenta et al., J Am Med, 1995; Velho et al., Diabetes, 1996) show that insulinopenia or the inability of the beta cells to release or produce insulin comes first in the development of type 2 diabetes.

    Prevailing Concept. Obesity determined by body mass index may precipitate type 2 DM.

    Wind of Change. Only visceral obesity is related to type 2 diabetes.

    Litonjua noted that BMI is no longer deemed very accurate in determining the amount of adipose tissue in the body because it is affected by such variables as ethnicity and body composition. In contrast, visceral obesity, reflected by waist circumference, is more closely related to adiposity and is a more accurate predictor of diabetic risk.

    "The risk for diabetes is not related to the body mass index alone. There is a greater risk for type 2 diabetes as the waist increases in circumference," said Litonjua.

    He noted that studies have shown that the adipose tissue is actively involved in both metabolism of steroids and production of hormones (Figure 2), which can perpetuate obesity (adiposin, acylation-stimulating protein), increase the risk of coronary artery disease (plastinogen activator inhibitor I), and cause insulin resistance (leptin, tumor necrosis factor-alpha, interleukin-6).

    More noteworthy, according to Litonjua, is the rising incidence of childhood obesity owing to inactivity or what he calls "Nintendonization" of the young. As a result, type 2 diabetes is beginning to occur at younger ages. Litonjua said it is estimated that in a few years type 2 diabetes in the young will be more common than type 1.

Diagnosis and Management

    Prevailing Concept. Glycated hemoglobin (HbA1c) is the "average" blood glucose for the past four months.

    Wind of Change. HbA1c is an asymmetric weighted measure of mean glycemic control.

    Litonjua said glycated hemoglobin levels are now understood to be an assymetric weighted measure in which 50 percent of the value is contributed by the most recent 30 days prior to blood extraction and 25 percent each by the past 30 to 60 and 60 to 120 days. HbA1c helps tell whether the hyperglycemia is due to diabetes or acute stress. HbA1c can also serve as a guide for combination therapy; if it is greater than eight percent (normal is six), no time should be wasted on monotherapy, said Litonjua.

    Prevailing Concept. Use sulfonylureas as first line treatment.

    Wind of Change. Treat type 2 diabetes based on pathophysiology.

    Litonjua said the thinking now is to "know the genesis of the hyperglycemia and use the corresponding agent" (Figure 3) for each. Insulin deficiency is best addressed with sulfonylureas. But for insulin resistance thiazolidinediones (glitazone) and biguanides (metformin) are the choice drugs. Metformin is also effective when the fasting plasma glucose is higher than the postprandial glucose; glitazone when postprandial inhibition of liver glycogeniolysis is the target. Alpha-glucosidases delay glucose absorption from the gut but metformin works better by inhibiting it.

    Prevailing Concept. Use of intermediate-acting or rapid-acting insulin or a combination.

    Wind of Change. Basal-bolus concept.

"The winds of change are coming. Let us sense them. Let us listen to them and heed them. For they are bringing changes in the way we look at diabetes mellitus."   -Dr. Litonjua

    Litonjua said the current mode of insulin use is prone to prone to unnatural fluctuations in insulin levels with peaks that could risk the development of hypoglycemia. The basal-bolus concept attempts to approximate the natural variations in insulin secretion that go hand in hand with postprandial and basal levels of blood glucose. He noted that just like that of blood sugar, the level of serum insulin never reaches zero, but is maintained under normal conditions at a basal level of 10 uUl/mL.

    He said the basal-bolus approach could be made possible with the use of a rapid-acting insulin (Lispro or Aspart), which is also removed from the blood in two hours, and a long-acting basal insulin (Glargine) with a constant, peak-free diffusion in the blood for 22 to 24 hours.

    However, this raises the problem of multiple injections-one during each meal and another at night or in the morning-and make patient compliance difficult. An emerging alternative is inhaled insulin. It is, however, more rapidly dissipated than subcutaneous insulin, requiring greater amounts to be inhaled to maintain its level in the blood.

    Prevailing Concept. Independent control of blood pressure and blood sugar.

    Wind of Change. Simultaneous tight control of blood sugar and blood pressure.

    Litonjua said studies have shown that coexisting hypertension and diabetes multiply the risk of cardiovascular death, and that tight control of both, as shown in the United Kingdom Prospective Diabetes Study (UKPDS), lowers the risks of diabetic complications, including death.

    He said this is the rationale for the ongoing ADVANCE study being conducted in 200 centers around the world, including the Philippines. Supported by Servier, ADVANCE will look into the impact of blood pressure lowering (using Preterax) and tight glucose with Diamicron on the reduction of macrovascular and microvascular events among high-risk type 2 diabetic patients. The results could shape new "winds of change" in the management of diabetes.

 

 

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