In the past decade or so, our attempts to define the "earliest” events in Type 2 diabetes (T2DM) have moved increasingly earlier. We’re considering even the years before what we now consider to be the “pre-diabetes” stage—that is, years considerably before there are any clinical signs or symptoms of disease.
One of the most discussed research accomplishments involves genetic studies, particularly the genome-wide association studies, so-called GWAS. They have identified more than 50 genetic loci and polymorphisms that seem to raise the risk of developing T2DM. There’s debate about the true identity or function of a few of these, but most appear to be related to impacting either the function or mass pancreatic islet beta cells. That leads to the question: what exactly is going on with the beta cells in the years before overt symptoms of the disease?
T2DM as a disease of insulin resistance
Until recently, most clinicians thought of T2DM as a disease of insulin resistance. This conceptualization is still essentially correct. Rates of T2DM continue to expand around the world mainly because people are westernizing, moving from manual to sedentary labor, eating fatty processed foods, gaining weight, and, as a result, showing worsening insulin sensitivity. T2DM clearly seemed to be a disease of populations prone to these weight issues such as aging folks and certain ethnic populations where there was more obesity.
Ten years ago the average practitioner treating patients with T2DM focused almost exclusively on insulin resistance, and appropriately so. The most talked about drug therapy was insulin resistance-centric (metformin and TZDs), and every clinician knew of the importance of diet and exercise. Also, enormous amounts of research were focused on defects in insulin signaling and insulin resistance. Insulin resistance was and still is important in the disease.
A disease of both insulin resistance and beta cell failure
Something began to shift about ten years ago. It became increasingly appreciated that many patients had insulin resistance but never went on to develop diabetes. For example, a commonly cited paradox was that the majority of patients having gastric bypass procedures were enormously insulin resistant and yet had no sign of diabetes. And more and more basic science, epidemiologic, intervention, and genetic studies focused on beta cells playing a key role in T2DM.
Collectively these studies have shown a common theme: that people who develop this condition have some underlying inability within their beta cells that prevents adequate compensation for common metabolic stresses. And this beta cell defect begins long before overt symptoms of diabetes, even pre-diabetes, appear, as reflected in studies of people who later go onto T2DM, or of high risk ethnic groups, who, while still normally glucose tolerate, already show defects in beta cell function, years before they have any clinical signs or symptoms of diabetes.
These findings have led to an active research field of searching for these early causes of inadequate beta cell compensation—often referred to as “susceptible beta cells.” Genetics is an obvious culprit, and at the forefront of investigation, but inadequate prenatal care and/or childhood malnutrition imprinting beta cells for a heightened risk of failure later in life, GI microflora-related immunologic and metabolic effects, food additives, and environmental toxins are all active research topics.
Researchers today consider T2DM to be a kind of “two-hit” disease. Even if you are insulin resistant from too much of the good life, if you have healthy beta cells you should be fine at least in terms of protection against diabetes. Alternatively, if you do have compromised beta cells, you also should be fine if you don’t subject yourself to too many metabolic stresses. A combination of metabolic stresses and compromised beta cells is how trouble starts.
Beta cell failure in the pre-diabetes stage
What do we know about this early stage of susceptible beta cells? Not enough! People predisposed to Type 2 diabetes apparently either don’t grow enough healthy beta cells early in their life, or they die off from some process of early senescence, or the beta cells they do have are dysfunctional. We’re still not sure of exact mechanisms, whether these defects are due to genetic or environmental factors or some combination of the two in most people, and what we can do, and when, to intervene.
It’s obvious that we can’t change genetics, at least with today’s science. And population-based environmental shifts are not easy. Look how successful we have been with controlling obesity. What everyone wants is one of the existing drug therapies for T2DM to magically restore beta cell health—and the drug needs to be safe so it can be used when people are still healthy, i.e., before the start of diabetes or any associated disease. There was great hope for the incretin therapies—GLP-1 receptor agonists or DPP-4 inhibitors. While these are not finished topics, the early information regarding preservation of beta cell function with these agents is disappointing. Ironically, so far the best we have are probably TZDs (see the ACT NOW
study in the March 24th
2011 issue of the New England Journal of Medicine
), but the many health concerns with TZDs prevent any serious discussion about early widespread in persons with prediabetes.
So the good news is we know much more about why people get type 2 diabetes than we did a decade ago. The less good news is we’re still trying to use that information to reverse the tide of the coming worldwide crisis related to diabetes and related metabolic diseases.