[ed. note: Michael Jorrin, a longtime medical writer who we like to call “Doc Gumshoe” (he’s not a doctor), shares his thoughts and explanations of health and medical topics with Gumshoe readers every few weeks. Readers have asked him about diabetes, both for personal reasons and because of the huge investment opportunity, so he submitted the following article for your consideration. As with all our authors, his thoughts and words are his own.]
Entire libraries – or perhaps I should say, huge chunks of the digital cloud – are devoted to this subject, so perhaps I am rash to attempt to say something worth paying attention to in this brief blog. But the subject is important, not only to each of us as individuals who might be affected by this very common condition, but to each of us as members of a community that increasingly bears the brunt of its consequences.
We will be discussing only Type 2 diabetes in this piece. Type 1 and Type 2 diabetes are entirely different diseases, linked only in that they involve the metabolism of glucose and the role of insulin. Type 1 diabetes is a result of the failure of the pancreatic beta cells that produce insulin, without which sugar (glucose) in the blood cannot be metabolized and employed by the body. This type of diabetes was formerly referred to as “juvenile-onset diabetes,” but now that many children are developing Type 2 diabetes, that distinction between Type 1 and Type 2 diabetes has been recognized as invalid. Type 1 diabetes was also sometimes called “insulin-dependent diabetes,” based on the assumption that Type 2 diabetes could always be managed with oral agents rather than with injected insulin. That assumption also has been abandoned.
In contrast with Type 1 diabetes, where the insulin-producing beta cells fail, in Type 2 diabetes, at least in the earlier stages, the beta cells are working overtime in response to nutritional input. In a sense, the resulting elevated insulin levels are wearing out the insulin receptors throughout the body.
This first installment will do no more than skim the surface of a few of the treatment options, many of which have been attracting a lot of discussion, pro and con, of the familiar kind: are the benefits worth the risks? We won’t go into them in detail in this piece. First, let’s look at some basic points.
One: diabetes is growing, not only in the US, but globally, and the profile of the typical person with diabetes is changing: patients are younger and poorer. This changes the treatment paradigm, and greatly increases the impact on society.
Two: more than most medical conditions, diabetes management depends to a great extent on the patient, and a very large proportion of persons with diabetes do not come up to the mark.
Three: although the consequences of poorly controlled diabetes are numerous and genuinely dire, a person whose diabetes is under good control can lead a life that is very close to completely “normal.”
Four: many persons with diabetes are not diagnosed and treated until they have had the disease for a long time, sometimes several years, and after the long-term complications have taken root.
Five: the treatment regimen for diabetes frequently needs to intensify as the physiology of the patient changes. This is particularly the case with persons who develop diabetes earlier in life and need to continue treatment for many decades.
We may think we know, but what is diabetes, anyway?
The really simple answer is too much sugar – glucose – in the blood, due to a failure of homeostasis, specifically the process of metabolizing glucose through the agency of insulin. You will notice, I hope, that I did not say that glucose metabolism fails because of an insufficiency of insulin. That is true in Type 1 diabetes, but not always true in Type 2 diabetes. When persons start on the long pathway to Type 2 diabetes mellitus (usually abbreviated as T2DM), they secrete plenty of insulin, but the insulin receptors have begun to fail. This is called insulin resistance.
However, a crucial part of the answer to that question is, what defines frank diabetes. Answers, from the American Diabetes Association (ADA) and from the World Health Organization (WHO) depend on measured glucose levels in the blood, or measured levels of a blood fraction called glycated hemoglobin, usually abbreviated as HbA1C.. Both agree that a fasting blood glucose level greater than 126 milligrams per deciliter (mg/dL), or HbA1C greater than 7%, define frank diabetes.
(The value of the HbA1C fraction is important because blood cells bound to glucose survive for over a month, so that the percentage of HbA1C in the blood gives a fairly accurate picture of the individual’s glucose levels over a longer period than a single fasting blood glucose test.)
The ADA describes the range of 100 to 125 mg/dL fasting blood glucose as impaired glucose tolerance, meaning, basically, that adverse changes are already taking place in the individual, which may lead to frank diabetes. WHO sets the cut-point for impaired glucose tolerance a bit higher, at 110 mg/dL.
But what’s the meaning of that very precise cut-point, 126 mg/dL fasting plasma glucose (FPG), to define diabetes?
The diagnosis problem: when should treatment for T2DM start?
That cut-point, whether it’s 126 mg/dL FPG or greater than 7% HbA1C, tells clinicians that it’s time to start treating the patient’s diabetes. More than almost any other medical condition, diagnosis of T2DM can’t be based primarily on symptoms, because for the majority of persons who are just crossing that admittedly arbitrary line between impaired glucose tolerance (or, as it’s often termed, prediabetes) the symptoms are so mild as often to go entirely unrecognized. But the harms, many of them irreversible, are already beginning. And these adverse consequences of diabetes are far from trivial. We’ll go into them later on, but let’s say a bit more about the diagnosis of T2DM.
The most obvious early symptoms of T2DM are frequent urination and thirst. The reason for this is that when there is excessive glucose circulating in the blood, the kidneys excrete some of it in the urine, leading to a reduced proportion of water in the blood and reduced blood volume. The body compensates for this by drawing water from other body compartments, to restore blood volume. And the response of the individual is thirst.
However, unless people are highly aware of these early symptoms, they are unlikely to seek medical attention. And even though a blood glucose test is quick and cheap, routine tests for diabetes – unlike a blood pressure check – are by no means as commonly performed as would be desirable. Therefore, there are many, many individuals with undiagnosed T2DM, as we’ll see.
As diabetes progresses, the symptoms do become more intense. Insulin receptors throughout the body are more resistant to the increasing levels of insulin secreted in response to higher blood glucose levels, and less glucose is transported into cells and converted to energy. That’s when persons with diabetes begin to feel more and more fatigued, and may seek medical attention. But by then, their T2DM is pretty far along.
So, why the 126 mg/dL cut-point to initiate treatment?
Yes, it’s arbitrary, but it’s based on lots of data. People can tolerate the pre-diabetic fasting blood glucose range for quite a long time without anything really terrible happening, but once their FBG goes beyond 125 mg/dL, the incidence of adverse consequences starts to rise steeply. The treatment of T2DM is focused on the prevention of these complications.
Most of the complications of diabetes follow from the unfortunate fact that excessive amounts of glucose in the bloodstream are toxic, causing damage to many organ systems as well as to the circulatory system itself. You’re probably aware of many of these already, but here’s a quick run-down:
Complications of diabetes
One of the earliest adverse effects of elevated blood glucose is eye disease, including retinopathy, macular edema, cataracts, and glaucoma. Almost 30% of persons with diabetes develop retinopathy, and poorly treated T2DM is the leading cause of new cases of blindness.
Diabetes leads to nerve damage (neuropathy), both in the sensory and motor nervous systems and in the autonomic nervous system – the part of the nervous system that keeps our hearts beating and regulates our breathing, among other functions. Persons with diabetes may feel numbness in their feet, for example, which coupled with vascular damage can have severe consequences.
Damage to the circulatory system is a serious and common consequence of diabetes. Diabetes contributes to coronary artery disease, and, in fact, about two-thirds of persons with diabetes die of heart disease. It also increases the rate of strokes. And diabetes is the single largest factor is leg amputations, other than those resulting from major trauma. About 65,000 lower limb amputations due to diabetes are done in the US every year.
Finally, diabetes is the principal cause of kidney failure. Almost 50,000 people with diabetes start treatment for end-stage kidney disease every year.
Those are the complications that people with untreated or poorly treated diabetes are subject to. Fortunately, a person with well-controlled diabetes can avoid most of those consequences and enjoy a long and normal life.
However, there is one unfortunate fact that leads us back to that pesky 126 mg/dL figure, which is that many persons with diabetes do not receive the diagnosis, and do not begin treatment of any kind, until their blood glucose exceeds that cut-point, sometimes by a wide and dangerous margin. Conscientious folks like us, who have annual physical examinations complete with blood tests, and then pay attention to their physicians, who compare this year’s results with last year’s and the year before, are doing what they need to do to avoid the dire consequences of diabetes, as well as of other threats to their health.
But there are lots and lots of people who don’t do this – strong, healthy, happy men and women (and children!) – who have no symptoms, and therefore no need to go to the doctor. Until, for some reason, they do. And then comes the unpleasant discovery that they have diabetes, and not just a borderline case. In far too many cases, the person has gone far beyond that 126 mg/dL threshold. Some newly diagnosed T2DM patients have FPG levels of 200 mg/dL and higher, with truly serious implications for the progression of diabetic complications. For example, a 1999 study of persons with newly diagnosed diabetes found that, on average, they already had established retinopathy of about 6.5 years duration.
At the time of diagnosis, many persons with diabetes also have a condition labelled metabolic syndrome, which is defined as low HDL cholesterol, high triglycerides, high blood pressure, and a waist measurement greater than 40 inches in men and 35 inches in women. There is considerable dispute as to whether “metabolic syndrome” is really a syndrome or just a grouping of heart disease risk factors, but there is strong statistical evidence that this particular constellation of factors does indeed accelerate the process of atherosclerosis.
More relevant to the diabetes question is the observation that atherosclerotic plaques in persons with diabetes have a greater number of fissures, making them more unstable and likely to rupture. They also have a greater lipid core burden and a richer inflammatory component. These factors suggest that patients with diabetes are more likely to have vulnerable atherosclerotic plaque, perhaps explaining why they are prone to sustain cardiovascular events.
A bit more about the role of insulin in our metabolism
The quick take is that insulin permits our cells to metabolize glucose and form adenosine triphosphate (ATP), which is our primary source of energy. But that’s by no means the whole story. Insulin is also highly active in the metabolism of fats and proteins; in fact, prolonged insulin deficiencies (such as in advanced diabetes) leads to a reduced ability to synthesize proteins, and therefore muscle wasting and many cellular disorders. And insulin has several functions in the storage of glucose in the liver as glycogen, and the release of glucose from the liver in periods when glucose is not being taken in as food – i.e., “between meals.”
Insulin is secreted by specialized cells in the pancreatic islets of Langerhans, designated beta cells, in response to food intake, especially carbohydrates. Carbohydrates are quickly and easily converted into simple sugars, primarily glucose, in the alimentary tract. The other sugars – fructose and galactose – are converted into glucose in the liver, so that glucose is what eventually transports almost all carbohydrates to their ultimate destination in the body.
Insulin then interacts with receptors in most cells, permitting the entry of glucose and its conversion to ATP for energy.
The release of insulin from the beta cells starts within about two minutes of food intake. This is referred to as first-phase insulin secretion, to distinguish it from basal insulin secretion, which goes on independent of a meal, and helps to maintain a relatively even source of energy throughout the day.
Insulin has a quite short half-life, about 6 minutes, so that the insulin released at any specific time is mostly gone in 10 to 15 minutes. Of course, as more glucose is released into the bloodstream by the digestive process, more insulin will be released in response; however, dietary sugars and simple carbohydrates are converted into glucose very quickly, so that the first-phase insulin response tends to be relatively short.
The first-phase and basal insulin secretions each account for about half of the total insulin releases. However, the first-phase insulin secretion is thought to have more of an impact on the development of T2DM. This is because, while basal insulin secretion is relatively steady and results in fairly constant, but low levels of insulin throughout the day, the first-phase secretion is short and produces high concentrations of insulin for brief periods.
It is these brief periods of high insulin concentration that are thought to result in insulin resistance in insulin receptors throughout the body. Insulin resistance essentially means that glucose is not transported into cells, and high concentrations of unmetabolized glucose persist in the circulation.
In turn, the continuing presence of glucose in the bloodstream triggers the secretion of additional insulin from the pancreatic beta cells, resulting in abnormally high levels of insulin in the bloodstream. This feedback mechanism then can lead to further resistance by the insulin receptors and further demand on the beta cells to secrete insulin in response to the increasing concentrations of glucose in the bloodstream.
The result, all too often, is frank Type 2 diabetes.
The pathology of diabetes has a great deal to do with the individual’s dietary habits. The more the diet consists of simple, refined carbohydrates – e.g., white bread, white rice, and above all, sugar – the more quickly glucose gets into the bloodstream. Sugary soft drinks are considered to be a particular menace, because the glucose can enter the bloodstream extremely rapidly – it doesn’t have to go through any digestive process. Essentially, it gets to the bloodstream before the insulin does, which is not good. Also, there’s pretty good evidence that sugar unaccompanied by solid food does not trigger a robust first-phase insulin response. It takes solid food in the gut to do this, which is another reason that sugary soft drinks may be harmful.
How big a problem is Type 2 diabetes?
You already know the answer: huge. But just to drive the point home, here are some statistics, courtesy of the American Diabetes Association:
In the US alone, about 25 million people have T2DM. That’s about 8% of the population. In about 7 million of these, diabetes is undiagnosed.
Nearly 80 million people in the US have “prediabetes.”
Prevalence is higher in Hispanics (10.2%), African-Americans (18.7%), and American Indian and Alaskan Natives (16.1%).
If present trends continue, about a third of all American adults will have diabetes by the year 2050.
However, we’re far from being the most affected country. Take China, for example, where almost 12% of the population actually has diabetes (this is based on a sample of 91,000 adults). The incidence of diabetes has increased from less than 1% in 1980 to the present level, probably because of increased prosperity and a huge change in the nutritional practices as more Chinese people have moved to urban areas. It’s also estimated that half of the entire Chinese population are prediabetic, and that by mid-century fully 40% of the population will be diabetic.
The countries with the highest incidence of diabetes tend to be low to middle income – not, as one might assume, the well-to-do countries with the most abundant diets. As a population’s diet changes from a typical agrarian diet to a more urban, “convenience-food” oriented diet with a higher proportion of refined starches, sugar, and fats, diabetes soars. An example is the present plight of the Pima Indians in Arizona and Mexico, half of whom are diabetic. This group had subsisted for centuries on a very sparse diet – whatever was available in those desert regions. But their diet has changed radically in the past few decades. Fast food and soda pop dominate. However, the genetic makeup of the Pimas has not changed – they are still genetically adapted to their sparse diet, so they store fat very efficiently – the so-called “thrifty gene.” Almost all the diabetic Pima Indians are obese.
What does this imply for the management of diabetes?
It’s clear that Type 2 diabetes is primarily a life-style disease. (Note, as with many or most diseases, there is also a clear genetic component; however, this has little relevance either to prevention or management of the disease.) Rates in China were extremely low until prosperity descended upon the nation, and hundreds of millions of Chinese left their farms to work in towns and cities, totally changing their lives. And it’s doubtful whether more than a tiny few Pimas had diabetes until fast food invaded their territories.
Since it is at root a life-style disease, it stands to reason that, at least in some cases, it could be managed by adjustments in life style. More than almost any chronic disease, diabetes is largely patient-managed. A certain proportion of patients, admittedly not very large, are indeed able to manage their disease entirely through diet and exercise – which is to say, they are able to keep their blood glucose levels in an acceptable range and avoid the life-altering complications of diabetes.
These patients are likely to be persons in whom T2DM was diagnosed relatively early, that is, when their FBG was close to the 126 mg/dL marker. And they probably do not need to make huge changes in their lifestyle to bring their disease under control.
But here’s a more typical newly-diagnosed T2DM patient…
Our patient, a 55-year old male, had a routine health screening at his place of work. He was found to have slightly elevated blood pressure and total cholesterol, and a FPG of 160 mg/dL. The health-care worker discussed the results with this person and recommended that he consult a physician. At this time, our patient considered himself to be entirely healthy. He was physically strong and active; true, he carried a few more inches around his middle than he had when he was a young man, but who, at his age, had not thickened in the waist. He postponed going to the doctor and soon forgot about the whole thing.
About a year later, his wife notices that he has been getting up several times in the night to go to the bathroom, and she has heard on a TV program that frequent urination is a sign of diabetes. She remembers what he had told her about his health screening, and strongly urges him to see a doctor. So, reluctantly, he goes.
At the initial physical examination, his blood pressure and total cholesterol continue to be somewhat elevated, but not alarmingly so. However, his HbA1C is 8.2%, and his FPG is 200 mg/dL. He has frank T2DM, and has probably had it for a few years. Furthermore, he is definitely overweight – over the cut-point defining obesity, and his blood pressure and lipid profile are also well over the recommended goals for patients with T2DM, putting him at significantly elevated risk for heart disease.
His doctor prescribes three different medications – an angiotensin-receptor blocker (ARB) for his high blood pressure, a statin for his elevated cholesterol, and metformin to lower his blood glucose. In addition, the doctor strongly urges a regimen of exercise and diet. And another strong recommendation is that he monitor his own blood sugar several times daily, using a simple needle-stick device.
Our patient is quite surprised by these recommendations, and more than a bit put off. He continues to consider himself to be in good health. He works hard, eats whatever he wants, and enjoys life. His initial reaction is to blow the whole thing off. His wife, however, is concerned. Moreover, she has relatives with diabetes who have experienced the severe complications that occur as the disease progresses. She employs a combination of logic and charm, and caps it with the winning tactic: “Do it for me!”
Will our patient stick with his treatment?
That’s a tough question. At present, he doesn’t have any symptoms that really bother him. Okay, so he has to get up in the middle of the night a few times. So what’s the big deal? And he has heard all the stuff about how doctors and drug companies are only out for the money. On the other hand, he too knows people with diabetes, some of whom have been hit hard by the disease. He’s likely to give it a try. But he’s also likely to do things like forget to refill his prescription and go off his diet from time to time … or even pretty often.
He may also experience some side effects from one or more of the three new drugs he’s supposed to be taking. He may actually feel worse with the treatment than he did before. That’s not much of an inducement to stay with the treatment plan.
Non-adherence to treatment is a huge factor in diabetes management. In some medical practice, patients with diabetes are urged to stay in contact with a health-worker known as a Certified Diabetes Educator (CDE), who can spend a lot more time with the patient that the doctor can, and reinforces behaviors like keeping to a healthy diet, exercise, and regular self-monitoring of blood glucose. Practices that use these CDEs do considerably better with their diabetic patients than practices that leave patient adherence to chance.
What’s the prognosis for our patient?
It depends, of course, on whether he’s adherent/compliant to treatment. If he is, he’s likely to do pretty well on the metformin regimen (plus whatever is necessary to keep his blood pressure and lipids under control) for a number of years.
Metformin (Glucophage) is the standard first-line agent for the treatment of T2DM. It was initially found to reduce blood glucose in the 1920s, but not investigated until much later. It has been available in some European countries for more than 50 years, but was only approved in the US in 1995. It works essentially in two ways:
One, it inhibits the release of glucose from the liver. Among the liver’s multiple functions is the storage of glucose in the form of glycogen. This stored glucose is then released back into the bloodstream so as to furnish the body with a steady source of energy; persons with diabetes do not need this additional glucose to be added to their bloodstream, and metformin helps to prevent this.
Two, it increases the sensitivity of the insulin receptors, and increases uptake of glucose throughout the body.
For the great majority of diabetics, however, metformin is not a permanent answer. Most will need a second agent, with a somewhat different mechanism of action. Also, in many persons with diabetes, the pancreatic beta cells essentially wear out, so that after some years with the disease, the patient requires insulin from an external source – exogenous insulin, such as patients with Type 1 diabetes require from the start.
The transition from an entirely oral treatment plan to a regimen that includes injected insulin (whether self-administered or given through a pump) is complex, and makes large demands of the health-care provider team as well as the patient. One among many problems is that patients tend to regard this as very bad news – evidence that their treatment is not working, and that they are in the final stages of a dread disease that will kill them, or, at the very least, put them in jeopardy of loosing a lower limb to amputation.
These patients should be reassured by the knowledge that many persons with Type 1 diabetes have led long and satisfactory lives, successfully managing their disease from childhood to a ripe old age.
A quick look at some other classes of oral agents for T2DM
Sulfonylureas, approved in the US in 1955, were the first oral drug for T2DM to be FDA approved. They stimulate the beta cells to produce more insulin. Their chief drawback is that they can cause episodes of dangerously low blood glucose (hypoglycemia), potentially resulting in fainting spells. Amaryl (glimepride), Diabeta (micronase), and Glucotrol (glipizide) are common sulfonylureas.
Meglitinides and d-phenylalanine derivatives act to boost the first-phase insulin response. They are very short acting and have no effect on the basal insulin response. Prandin (repaglinide) and Starlix (nateglinide) are members of this class.
Thiazolidinediones, also known as glitazones, act on muscle and adipose tissue to increase glucose utilization, and on the liver to decrease glucose release. Avandia (rosiglitazone) and Actos (pioglitazone) are members of this class. Another agent, Rezulin (troglitazone) has been withdrawn for safety reasons.
DPP-4 (dipeptyl peptidase 4) inhibitors, also known as gliptins. These agents enable the action of incretin, a digestive peptide that boosts the first-phase insulin response. The gliptins block the action of the enzyme DPP-4 that breaks incretins down. Januvia (sitagliptin), Onglyza (saxagliptin), and Tradjenta (linagliptin) are DPP-4 inhibitors.
Incretin mimetics, as the name implies, mimic the activity of incretins. Byetta (exenatide) and Victoza (liraglutide) are incretin mimetics.
SGLT-2 (sodium glucose transporter 2) inhibitors, the most recent T2DM agents, have an entirely different mechanism of action. The normal action of SGLT-2 in the kidney is to excrete excess sodium, but return glucose to the bloodstream. SGLT-2 inhibitors block this action, preventing the reabsorption of glucose, thus lowering blood glucose levels. Invokana (canagliflozin) and Farxiga (dapagliflozin) are recently approved SGLT-2 inhibitors; others are in the works.
As with all drugs, drugs for the treatment of T2DM have side effects, most of which are not serious and which tend to be transient. However, a consequence of these side effects is that many patients initially feel worse after they start taking their medications than they did before. This does not help with compliance.
The entire process of glucose metabolism and the role of insulin are highly complex, and there are multiple points at which external agents can modify it. Also, the Type 2 diabetes disease process changes over time, from the initial phase where the body is permeated with excess insulin, to the late stages where the insulin-producing cells are nearing exhaustion. These complexities call for a range of therapeutic options. The brief summary of the current oral agents for T2DM barely scratches the surface of what’s going on in diabetes research.
As an indication of the scope of diabetes research, 6,247 clinical trials in diabetes are currently registered with the NIH. This is hardly surprising, considering how immense the problem of diabetes is, not only for the nearly 400 million people in the world who have this disease, but for the nations and societies that must somehow provide treatment. And there’s no getting away from the reality that the scope of the problem of diabetes provides an equally major opportunity for any entity that develops new and effective treatment strategies. Doc Gumshoe promises to bring you a bit more up to date in a future blog. I look forward to your comments.
P.S. As luck would have it, about an hour after I sent Travis this diabetes piece, the Centers for Disease Control posted new diabetes prevalence numbers – 29 million, or 9% of the population, mostly Type 2, up 3 million from 3 years ago. And as before, fully one quarter are undiagnosed. Wonder what’s happening in China.