Interviewer: There are nearly 80 million Americans with pre-diabetes, an often unrecognized and dangerous condition that put patients at risk for developing not only diabetes but also heart disease and stroke.
Dr. Timothy Graham, Director of the Utah Cardiometabolic Risk Reduction Clinic treats and researches the condition. Dr. Graham, at your clinic you assess patients for pre- diabetes. Why is this important?
Dr. Timothy Graham: Up to 30 to 40% of the general population has pre-diabetes. And the problem with actually getting to the point of having pre-diabetes is that you are then at a five to 10% risk per year of progressing to diabetes.
And what I try to emphasize to my patients is that by the time your blood sugars have risen to the point where we diagnose you with pre-diabetes, you have already had a process of disease in place that may have lasted for one or more decades. And there are other risks that are attendant with the high glucose levels.
So, for instance, when someone comes into the clinic newly diagnosed with pre-diabetes or even early Type 2 diabetes, many of them will already have signs of congestive heart failure or have damage to their blood vessels that might put them at higher risk for heart disease or strokes. So the earlier we can diagnose and start preventative treatments and medications, the better we think the outcomes will be in the long run.
Interviewer: So what exactly is the difference between pre-diabetes and diabetes?
Dr. Timothy Graham: Now, I think what's important to recognize is that the fundamental aspects of physiology that lead to the sort of less severe elevation of blood glucose and pre- diabetes are the exact same ones that lead to the more severe elevation in diabetes. So it's really just should be looked at the stage of the disease process rather than a distinct identity.
There is no doubt that everything that goes into creating pre- diabetes is exactly what continues and gets worse to create diabetes. It is true that by the time an individual has diabetes the disease process is perhaps more advanced and harder to reverse.
Interviewer: So remind us of one of the basic mechanisms that are in play here about what's the relationship between blood glucose levels and insulin and what goes wrong.
Dr. Timothy Graham: Generally speaking, when we eat a meal we have blood sugar that comes from our gut, from our intestine. It enters by absorption into our bloodstream. And in our bloodstream it is sensed by cells in the pancreas called beta islet cells. These cells are designed to do nothing else but make insulin for the most part, and when glucose floods into the body they know to secrete insulin. The insulin then circulates through the body and acts primarily at two or three places.
Primarily in the liver, insulin acts to turn off glucose production. When we're not eating, the only way we typically get glucose in circulation is by what the liver makes.
The insulin that floods into the system after a meal also induces uptake of glucose into muscle where it's stored as a substance called glycogen. And a certain amount also goes into fat or adipose tissue where it's used to synthesize actually triglycerides which are a storage form of fat.
So insulin kind of acts in these three different places to essentially lower your blood sugar levels after a meal, first by tucking the glucose into muscle and fat, and secondly by turning off the production of glucose by your liver.
Interviewer: What happens if pre-diabetes is not treated?
Dr. Timothy Graham: So one of the defining features of both pre-diabetes and diabetes, and when I talk about diabetes here, I mean Type 2 diabetes. In this country and in most other countries throughout the world 90% of people who have diabetes have Type 2 diabetes. And Type 2 diabetes is specifically defined by the presence of insulin resistance.
And what that means is your pancreatic beta cells can make insulin just fine, but when that insulin is produced and goes into circulation, it does not act effectively in liver, muscle, and adipose tissue to do what it's supposed to do. And that's because of molecular defect inside the cells that make up those tissues.
What's important to know about insulin resistance is that it varies dramatically from person to person. We have very good quantitative ways of measuring it and that a given individual can be insulin resistant for many years before they develop pre-diabetes or diabetes.
And it's generally been a black box up until fairly recently, that is, we've never really been able to predict among the insulin resistant people who will develop pre-diabetes or diabetes and when they will develop it. But we're changing that now because we're starting to look at the other pieces of the puzzle that go into the actual disease process.
If you think about it, if you're insulin resistant, the response of the body is to make more insulin. So if I have a block to the ability of this hormone to lower my blood glucose levels, the glucose levels stay higher and they keep activating more production of insulin by the pancreas. So the average person with pre-diabetes and most people with early stage Type 2 diabetes will have much higher insulin levels than you or I will.
Interviewer: I believe there's been quite a rise in diabetes in the American population over the last 10 to 20 years. What accounts for that?
Dr. Timothy Graham: So I think it's multi-factorial. There's no doubt as a nation we are more obese. So much so that right now, I believe the most recent 2012 statistics would show that nationwide 60% of the population is either overweight or obese. So it's more common to be overweight or obese than it is to be no which is kind of shocking when you think about it.
Now there's an exceptional line of evidence that supports that excess fat on the body leads to insulin resistance which in turn leads to the development of high blood sugar in diabetes and pre-diabetes. I think what's fascinating is that coupled with this obesity epidemic is an epidemic of inactivity. We probably all see that our kids play outside less than they used to. This time spent not active is, in fact, an independent risk factor even if we control for body weight.
I would say that there's also a less understood transgenerational effect that is fueling the epidemic of diabetes right now. For instance, if your mother was obese or insulin resistant during her pregnancy, even if she didn't have gestational diabetes, you are much higher risk for developing pre-diabetes or diabetes later in life.
And this may be a cumulative effect from generation to generation. Plus finally, there's very good evidence that some of these compounds, like phenol A and others, can have direct effects to sort of program the metabolism of children in utero and in their early childhood so that by the time they're adults they're more prone to diabetes. That's kind of an unspoken about issue, but it really there and it's pretty much acknowledged by people who study environmental health.
Interviewer: There are so many factors that could be influencing the development of diabetes. How do you even begin to approach the problem?
Dr. Timothy Graham: To me there's two ways to react to that. As a clinician, one wants to throw one's arms up in the air and say, "Wow. This is just too big. We can't fix this. All we can do is just sort of hold our head above the water and tread water."
But as a basic scientist I feel like understanding each of these mechanisms as critical because if we can drill down to understand exactly how each of these insults, if you will, leads to the disease. To me if we understand that sort of set of molecular mechanisms, we can actually manipulate them to our benefit.
So, for instance, if we find that a specific environmental toxin activates a certain pathway, it would not at all be inconceivable for us to design a medication that counteracts that, or improve manufacturing processes so that that toxin is eliminated or both.
So the more we understand the molecular level about this process and the various piece of it, which are many, the more opportunities there actually are and the more we understand how we might be able to actually interfere with the process that finally leads to Type 2 diabetes.
Interviewer: What motivates you to look at this problem so carefully?
Dr. Timothy Graham: There really are no approved medications for this. Even the oral medications we have for Type 2 diabetes tend to be somewhat plagued by concerns about their effects on the cardiovascular system. So if you sort of look at the field as a whole, there's an urgent need to develop new approaches to treating the problem.
I think what really excites me is there are so many untapped areas where we can start to come up with new strategies. So, for instance, I mentioned earlier the idea that fat is this major hormonal organ that produces all sorts of substances. Well, if we come back to the basic observation that the strongest association we see in clinical medicine with Type 2 diabetes is with obesity, then it seems like fat is a pretty good place to start.
So I really directed my attention as a basic scientist understanding how fat cells work, what they product, and how they can interfere with that process. I firmly believe that the work we're doing here at the University of Utah in my lab and in other labs like mine here in the Molecular Medicine Program and in the Division of Endocrinology. I believe as a group we're all putting together entirely new ways and approaches to coming up with new treatments for Type 2 diabetes prevention as well as reversal.
updated: November 16, 2021
originally published: January 24, 2014
