The traditional approach to diabetes treatment only begins to intervene and manage the condition once the patient is diagnosed with diabetes, which is not to cure it; the focus of this treatment is simply to get the blood sugar as close to normal as possible, usually through a combination of exercise and weight control with the use of medications and management of complications that arise.
Research on how to get to the root of diabetes
While this treatment allows people with diabetes to have a relatively normal life, it does not eradicate the root cause of diabetes.
Thomas Buchanan, MD, PhD, of the University of Southern California, believes that this is exactly why a change in the approach to diabetes treatment is needed.
“Typically, the focus of diabetes treatment is on controlling blood sugar.” said Thomas, who is also the director of the Clinical Research Center at the Keck School of Medicine, “but people aren’t looking at what the underlying condition is that’s causing the problem.”
To address this problem, Thomas was responsible for the Troglitazone in Prevention of Diabetes (TRIPOD) study, which treated women at risk for type 2 diabetes with a class of drugs called thiazolidinediones, commonly known as TZDs. The results were dramatic: these drugs had significant efficacy in preventing flare-ups of the disease.
Given the rising prevalence of type 2 diabetes, largely due to rising levels of obesity in the United States and around the world, diabetes prevention has become an urgent public health priority. tZD could be part of the solution.
Research on new drugs
Unlike some drugs used to treat diabetes, the main advantage of TZD for diabetes is not in directly boosting insulin production or lowering blood glucose levels. Instead, TZD works differently by affecting the pancreatic islet beta cells in the pancreas.
The body uses blood glucose as energy, and insulin is secreted by pancreatic β-cells. As insulin circulates throughout the body, it attaches to individual cells, and once insulin has attached to a cell, the cell is able to receive glucose and take it up to provide itself with energy. In many people with type 2 diabetes, the body is less sensitive to insulin, a condition called insulin tolerance, making it more difficult to absorb glucose from the blood.
Pancreatic cells make more insulin to compensate for this tolerance. Although pancreatic β-cells can produce enough insulin to maintain blood glucose at normal levels for a period of time, the increase in insulin will eventually take its toll. β-cells may become damaged and less able to produce insulin, resulting in insulin deficiency. The body’s ability to process blood sugar decreases, blood sugar levels rise, and type 2 diabetes ensues. It is estimated that about 70 to 80 million Americans have insulin resistance syndrome and 17 million have type 2 diabetes.
Experimental effects of new drugs
Thomas believes that TZD may prevent beta cell overload and attrition. By avoiding this, insulin tolerance does not increase, which in turn may stop the progression of type 2 diabetes.
In the TRIPOD study, 235 Hispanic women who had gestational diabetes (diabetes that women have during pregnancy) and had a higher chance of developing type 2 diabetes were treated with troglitazone and pioglitazone, another TZD. Thomas and his colleagues found that the TZD stabilized beta-cell function and reduced the incidence of diabetes by 55% compared to the control group. Surprisingly, the effects of these drugs seemed to persist even when they were discontinued.
“This is one of the most striking results,” Thomas described, “We found that in people without diabetes, the preventive effect of this drug persisted 8 months after stopping it.”
Technical details: How TZD works
The exact mechanism of how TZD improves β-cell function is not fully understood. The most widely accepted theory is that TZD activates common receptors in adipocytes called peroxisome proliferator-activated receptors – γ or PPAR-γ. These receptors affect glucose and fat metabolism, and once activated, there is increased uptake or uptake by adipocytes, which also stimulates glucose metabolism and Reduces the production of new glucose by the liver.
It is particularly interesting to note that TZD may increase total body fat, but appears to lead to a redistribution of fat, which can help improve insulin sensitivity. Visceral fat, the fat around the abdominal organs, appears to be associated with the development of insulin tolerance, whereas subcutaneous fat, the fat under the skin in other parts of the body, is not associated with the development of insulin tolerance. tZD reduces visceral fat content and increases subcutaneous fat content.
Other benefits
Unrelated to the effects of beta cells, TZD may reduce the risk of cardiovascular disease in people with diabetes. Considering that heart disease and stroke are the most deadly complications of diabetes, it suggests that the drug plays an important role.
While TZD also has the ability to lower blood glucose, it does not do so as well as other drugs.
David Nathan, director of the Diabetes Center at Massachusetts General Hospital and professor of medicine at Harvard Medical School, said, “Taking TZDs as monotherapy is not ideal. In fact, they are much less effective than sulfonylureas or metformin (standard diabetes drugs).” David said that combining TZDs with other drugs may have a greater effect, although he cautioned that the effectiveness of this treatment has not been fully studied.
Another potential benefit of TZD is the ability to lower levels of free fatty acids in the blood, a new focus of attention for diabetes experts because of their association with diabetes complications. “I think this is an important feature of TZD,” said Paul Jellinger, MD, PhD, a past president of the American Association for Clinical Endocrinology, “and it’s a significant benefit of TZD that has not been widely recognized.”
A new direction?
Based in part on the results of the TRIPOD study, Thomas believes the focus of diabetes treatment needs to shift.
“Basically, right now, we’re treating people with diabetes whose blood glucose levels are high enough to cause long-term complications, and we need to figure out how to lower their blood glucose levels,” he said, “but by the time a person has diabetes, they may have lost 80% of their beta cell function. Some people have reduced glucose tolerance (a feature of prediabetes), and they’ve lost about 50% of their beta cell function.”
Thomas hopes that people with diabetes and their doctors will better understand the difference between differences in disease presentation (elevated blood glucose levels) and the loss of beta cell function that may cause elevated blood glucose levels.
He said, “The current model of diabetes treatment focuses on the sprint, which is what the blood glucose level is, rather than the marathon, which is the entire progression of the disease.”
However, other experts warn that the results of the TRIPOD study and the effectiveness and safety of TZD have yet to be confirmed.
Fran Kaufman, chief of the Division of Endocrinology at Children’s Hospital Los Angeles and president of the American Diabetes Association (ADA), said, “TZD is a very important addition to our research.” But she warned that more studies are needed to confirm it, and “whether other studies will show the same strong effect of TZD as the TRIPOD study, we don’t know yet.”
Risks and costs
The potential dangers of TZD were most evident in 2000, when the US Food and Drug Administration (FDA) required the makers of troglitazone tablets to recall them from the market after reports of serious, even fatal, liver toxicity. The other two TZDs currently on the market, pioglitazone and rosiglitazone, do not exhibit the same risk, and others are in various stages of development. the FDA continues to recommend regular liver function tests for people using TZDs.
The problems with troglitazone tablets illustrate the risks associated with using any newly developed drug. Thomas said, “Like any drug that is only used for a short period of time, we just don’t know what the long-term risks of TZD are.”
As mentioned earlier, TZD has also been associated with weight gain. Although the excess fat may be subcutaneous and therefore not as dangerous as visceral fat, the long-term effects of weight gain are unclear; some patients gain so much weight that they need to stop treatment. Studies have also shown that taking TZD increases the risk of edema, a buildup of fluid in the tissues.
Other potential problems have been reported, with one investigation of patients taking TZD finding an increased risk of congestive heart failure, contrary to studies demonstrating the cardioprotective properties of the drug.
Finally, the cost of TZDs may affect their usefulness; they are much more expensive than other drugs used to treat diabetes. Although Fran is hopeful that the price will come down as more TZD studies come out, Thomas is concerned that this may not happen until the patent on a particular TZD expires.
Who needs TZD?
Considering the possible benefits of TZDs, people may wonder if they should use them. The truth is that TZDs do not apply in all cases, and many of the possible benefits have not been identified.
For example, despite promising TRIPOD research, TZDs are not recommended for the treatment of prediabetes. “I’m often asked if I should treat all patients with insulin resistance syndrome with TZD,” Thomas said, “and the answer is no.” Insulin resistance is caused by a range of factors, and treatment should be based on individual symptoms, Thomas noted.
It’s also important to know that other studies, such as the Diabetes Prevention Program (DPP), have demonstrated the effectiveness of behavioral interventions, such as regular exercise and weight loss, in slowing or preventing the progression of prediabetes to type 2 diabetes. Depending on the individual, changes in diet and increased exercise may be the best form of treatment.
At this time, doctors generally recommend caution with TZD because of its potential risks. But the beneficial effects of TZD point to a possible future for diabetes treatment.
“TRIPOD shows that by focusing on relieving the stress on the beta cells, we can slow the progression of abnormal glucose tolerance and type 2 diabetes,” Thomas said, “and we can stabilize patients.”