The Diabetes Epidemic
You are probably aware we are in the midst of a diabetes epidemic! The percentage of the U.S. population with type 2 diabetes mellitus (T2D) has been increasing dramatically since 1995. As shown in the figure below, the prevalence of T2D in 1958 was about 1% of the U.S. population. Over the next 40 years, the prevalence increased at a rate of 0.5% per decade until 1995 to 3% of the population. Then the rate of rise increased to 2% per decade from 1995 to 2013. As of 2013, 7% of the U.S. population had T2D.
And that is just the tip of the iceberg. According to this study that appeared in JAMA in 2015, 9.1% of the U.S. population had diagnosed T2D, 5.2% had undiagnosed T2D, and another 38.0% had prediabetes. That’s a whopping 52.3% of the U.S. population with prediabetes or T2D! Those with prediabetes have a 70% chance of developing T2D in their lifetime (if nothing is done to prevent it).
Diagnosis of Prediabetes and Type 2 Diabetes
There are three lab tests used to diagnose prediabetes and T2D including fasting blood glucose, blood glucose at 2 hours after drinking a 75-gram glucose solution i.e. glucose tolerance test, and HbA1c. The diagnostic criteria for prediabetes and T2D as recommended by the American Diabetes Association (ADA) are shown in the figure below.
Selection of persons who should be tested for prediabetes or T2D according to the ADA are shown in the table below. BMI = body mass index, GDM = gestational diabetes mellitus, IGT = impaired glucose tolerance, IFG = impaired fasting glucose, CVD = cardiovascular disease.
Therefore, it is inexpensive and easy to diagnose prediabetes and T2D. If the above mentioned tests are normal, they still do not rule out insulin resistance and hyperinsulinemia.
The Natural History of Type 2 Diabetes Mellitus
Type 2 diabetes is a complex disorder resulting from an interaction between genes and environment. The evidence for a genetic component of the disease comes from multiple studies. According to this source, “the concordance of T2D in monozygotic twins is ~70% compared with 20-30% in dizygotic twins. The lifetime risk of developing the disease is ~40% in offspring of one parent with T2D, greater if the mother is affected, and approaching 70% if both parents have T2D. A first-degree family history is associated with twofold increased risk of future T2D.”
As will be explained later, the earliest stage of T2D is insulin resistance and hyperinsulinemia which are heritable traits. But the insulin resistance and hyperinsulinemia are expressed by certain features of one’s environment. The current medical establishment’s view is that overnutrition, obesity, and physical inactivity are the pertinent environmental factors. Since 85% of those with T2D are either overweight or obese it is not surprising that the mechanisms of these two disorders are quite similar. See here. But how about the 15% of persons with T2D are not overweight and those who are physically active. Why is their insulin resistance expressed?
In addition to overnutrition, obesity, and physical inactivity my opinion is that diet plays a prominent role in the expression of insulin resistance and hyperinsulinemia. A diet where the majority of calories come from carbohydrates, especially refined carbohydrates and sugar is a major factor in stimulating insulin secretion. Hyperinsulinemia especially when persons eat frequent meals and snacks with sugar and refined carbohydrates can become a chronic feature which leads to insulin resistance. Insulin resistance begets hyperinsulinemia, and we have a vicious cycle. Physical inactivity might also be a consequence of a high carbohydrate diet because the energy needed for physical exertion is not available since it is shunted into fat cells due to hyperinsulinemia. Note that the presence of refined carbohydrates and sugar in our diet is a relatively new feature which may explain the recent uptick in obesity and T2D over the past 40 years. It is widely accepted by the medical establishment that T2D is a state of carbohydrate intolerance and that dietary carbohydrate is both the largest determinant of postprandial blood glucose relative to dietary protein and fat and is the strongest stimulus for insulin secretion. The fact that the medical establishment has not translated these accepted facts into a dietary prescription for a low carbohydrate diet is simply a result of cognitive dissonance resulting from the lipid heart hypothesis i.e. that dietary saturated fat leads to atherosclerotic heart disease. This cognitive dissonance persists even though numerous clinical trials have failed to confirm the hypothesis.
Prediabetes: A Call To Action
The currently accepted methods of diagnosing prediabetes and T2D are based on elevations in blood glucose. It is widely accepted that insulin resistance and hyperinsulinemia precede any elevation in blood glucose by decades. During this time when persons are asymptomatic and unaware they have the condition, insulin resistance and hyperinsulinemia can result in multiple serious medical problems including metabolic syndrome, non-alcoholic fatty liver disease, stroke, atherosclerotic cardiovascular disease, hypertension, and cancer.
This review raises concern about the term “prediabetes” since diabetic complications do in fact arise in persons with prediabetes. In other words, persons with prediabetes as well as their physicians may not understand the seriousness of the condition.
In The Diabetes Prevention Program, individuals who entered with a diagnosis of impaired glucose tolerance (IGT) had a 7.9% incidence of background diabetic retinopathy at the time of study end (3 years later). Peripheral neuropathy is also a common finding in IGT, occurring in as many as 5–10% of individuals. In addition, beta-cell failure occurs earlier than previously thought. At the stage of IGT (i.e. prediabetes), individuals have lost over 80% of their beta-cell function. See here. Thus, any elevation of blood glucose be it fasting or during a glucose tolerance test, represents a failure of the beta-cells to release enough insulin to overcome the insulin resistance.
Prediabetes is only different than T2D in its degree of beta-cell failure: the distinction is just an arbitrary cutoff in the continuum of beta-cell failure and hyperglycemia. This is why we should not “watch” prediabetes or worse yet ignore it. Prediabetes means there is a definite problem of insulin resistance, hyperinsulinemia, and beta-cell failure that has been going on for many years. Prediabetes needs to be addressed in the same way as T2D to prevent diabetic complications and its associated diseases.
The Earliest Stage of Prediabetes and Type 2 Diabetes Mellitus: Insulin Resistance and Hyperinsulinemia
Should we be concerned about insulin resistance and hyperinsulinemia with normal glycemia (normal blood sugars)? In short, Yes! Now we understand that by the time prediabetes develops insulin resistance, hyperinsulinemia, and beta-cell failure have been present for decades. In many, the medical consequences of insulin resistance including hypertension, atherosclerotic cardiovascular disease, obesity, dyslipidemia, and cancer can precede the diagnosis of prediabetes or T2D. See here, here, here, here, and here. Therefore, proactive individuals might want to detect insulin resistance in its earliest stage so the appropriate lifestyle changes can be started.
This can be done by measuring a fasting insulin level, triglycerides (TG), and HDL cholesterol (HDL-C). All relatively inexpensive and commonly ordered tests. C-reactive protein is another inexpensive and useful test (see below).
The authors of this study sought a simple method to approximate insulin sensitivity which is normally measured with the euglycemic insulin clamp in research studies. The authors note that “In our study, a fasting insulin of > 12.2 mU/l in normoglycemic individuals is a remarkably specific test for insulin resistance.” Another helpful index is the fasting triglyceride/HDL cholesterol ratio (TG/HDL-C ratio).
This study determined that “the optimal cutoff point of the TG/HDL-C ratio for prediction of hyperinsulinemia was 3.0 (in mg/dL unit) for non-Hispanic whites and Mexican Americans and 2.0 (in mg/dL unit) for non-Hispanic blacks, with reasonable sensitivity and specificity.”
Bottomline, a fasting insulin < 12 mU/l, fasting triglyceride < 150 mg/dl, fasting TG/HDL-C ratio < 2-3 are reasonable indicators of insulin sensitivity. See here.
The Consequences of Hyperinsulinemia and Insulin Resistance
In 1988, Dr. Gerald Reaven coined the term “Syndrome X” and later referred to as metabolic syndrome which consists of at least three of the following five conditions: abdominal obesity (waist circumference >40 inches in men, >35 inches in women), hypertriglyceridemia (>150 mg/dl), low HDL cholesterol (<40 mg/dl in men, <50 mg/dl in women), hypertension (blood pressure >130/85 mm Hg), and elevated fasting glucose (>110 mg/dl).
In this paper, Dr. Reaven stated that “resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases — non-insulin dependent diabetes mellitus, hypertension, and coronary artery disease.” In his research he found, for example, that insulin resistance was present in 50% of persons with hypertension and increases the risk of cardiovascular disease whether or not the hypertension was treated with antihypertensive medications. He felt that T2D represented a subset of persons with insulin resistance i.e. the beta-cells in persons with T2D were unable to produce enough insulin to keep pace with worsening insulin resistance, thus developing hyperglycemia.
Being purposefully repetitive, hyperinsulinemia and insulin resistance with or without normoglycemia are present in a variety of conditions and diseases including hypertension, cardiovascular disease, dyslipidemia, non-alcoholic fatty liver disease, cancer, obesity, metabolic syndrome, and of course T2D.
For example, The Quebec Cardiovascular Study found that fasting insulin levels were an independent predictor of cardiovascular disease in men. In this study, insulin resistance was shown to be an independent predictor of stroke, cardiovascular disease, hypertension, T2D, and cancer. This article discusses both insulin resistance and hyperinsulinemia and explains that one can lead to the other and act as a vicious cycle. It also points out that chronic inflammation as measured by inflammatory markers including cytokines (IL-6) and C-reactive protein is one of the characteristics of the hyperinsulinemic state.
Thus, prediabetes, T2D, metabolic syndrome, obesity, hypertension, dyslipidemia, cardiovascular disease, non-alcoholic liver disease, cancer, and many other diseases can all be thought of as potential consequences of insulin resistance and hyperinsulinemia that occur in persons who have a genetic predisposition which is expressed primarily by their diet and physical activity lifestyle habits.
Lifestyle Changes to Prevent or Treat Prediabetes & Type 2 Diabetes
The good news after hearing the adverse consequences of untreated insulin resistance, hyperinsulinemia, prediabetes, and T2D is that lifestyle changes are the most effective way to prevent, treat, and in many persons to put these conditions into remission. Traditional medical advice is to lose weight (5 to 7% of body weight) for those who are overweight and to exercise 150 minutes per week. The usual advice for losing weight is to reduce caloric intake and until very recently to do so with a low fat diet. The ADA STANDARDS OF MEDICAL CARE IN DIABETES—2016 has become more flexible in its dietary recommendations. Regarding methods to lose weight they state, “These diets may differ in the types of foods they restrict (such as high-fat or high-carbohydrate foods) but are effective if they create the necessary energy deficit,” i.e. a low carbohydrate high fat (LCHF) is fine as long as it is effective. They also state “As there is no single ideal dietary distribution of calories among carbohydrates, fats, and proteins for people with diabetes, macronutrient distribution should be individualized while keeping total calorie and metabolic goals in mind,” i.e. if your blood glucose and body weight are improved or normalized with a LCHF diet, that is fine.
As you can surmise, I believe a LCHF diet consisting of nutrient dense whole foods is the most effective dietary pattern for persons with insulin resistance, hyperinsulinemia, prediabetes, and both type 1 and type 2 diabetes. For persons with diabetes or those having difficulty resolving hyperinsulinemia, the LCHF diet should be ketogenic as well i.e. contain < 50 grams/day of carbohydrate. See my blog post for more details on the ketogenic LCHF diet. Other lifestyle habits that I think are necessary and effective are regular daily moderate exercise, avoidance of tobacco and alcohol, adequate sleep, daily sun exposure, and stress management. Shedding excess body fat is important as well because excess body fat, especially visceral fat, is a cause of inflammation and insulin resistance. See here. A LCHF diet has been shown to be more effective in weight loss than low fat diets up to 1 year after which there was no significant difference. See here.
These lifestyle habits can prevent, treat, or reverse T2D in most persons. Of course, to be maximally effective they need to be followed daily for a lifetime which for many is difficult to do. Unfortunately, I don’t have any magic solutions for that. I can say as a person with type 1 diabetes (T1D) and a physician who has seen all of the diabetic complications and the above mentioned associated diseases, it is much better to follow these lifestyle habits than to suffer the consequences of continuing the same lifestyle behaviors. And I do mean suffer. I’ve personally experienced the pain of diabetic peripheral neuropathy in the first year of treating my T1D with insulin (insulin neuritis) and autonomic neuropathy for about 2.5 years before they resolved with insulin therapy. I’ve seen patients in pain with infected gangrenous limbs before amputation or those who are disabled from blindness, kidney failure, heart failure, etc. and died much younger than they should have. If that is not motivational, not sure what is. Trust me, implement the lifestyle habits above.
What If Lifestyle Habits Are Not Enough?
This can happen when insulin resistance has been longstanding and beta-cell failure is advanced even with proper implementation of the above lifestyle habits. Fortunately, this occurs in only a minority of persons. What to do next? First, excess body fat needs to be shed (if present). This is easier with a ketogenic LCHF diet (KLCHF) than any other approach in my opinion. See here. A KLCHF does not require calorie restriction in the traditional sense. Yes, caloric intake must go down to shed excess body fat, but with the KLCHF approach it can be accomplished without hunger or a need for willpower to resist eating. The KLCHF reduces hyperinsulinemia and improves insulin resistance which in turn allows the fat cells to release their fat reserves which can then be used for energy in place of food. There are a few medications that can help.
Metformin for Prediabetes & Type 2 Diabetes
Metformin has been used for T2D for the past 40 – 50 years in Canada and Europe and more recently in the U.S. since 1995. Metformin decreases the amount of glucose made by the liver, improves glucose uptake into cells, increases glycogen storage in muscle, and decreases fatty acid levels which indirectly improves insulin resistance and beta-cell function. The net result is both glucose and insulin levels in people with T2D decrease with metformin therapy. Metformin monotherapy lowered HbA1c by 1.12% versus placebo in this meta-analysis. In this clinical trial metformin prevented the development of diabetes by 31% over an average of 2.8 years of follow-up. Note: the lifestyle intervention prevented the development of diabetes by 58% in the same study.
Metformin has a good safety profile. “Its most common side effects are gastrointestinal including an increase in the frequency of bowel movements, diarrhea, nausea, and abdominal pain. These symptoms are generally transient, resolve spontaneously, and can often be avoided by gradual escalation of dosage. Metformin treatment has not been associated with hypoglycemia unless used in conjunction with other glucose-lowering medicines (sulfonylureas or insulin). In U.S. clinical trials, about 4% of participants were unable to continue metformin due to adverse effects. Metformin is associated with weight loss when used to treat diabetes and thus differs from a number of other antidiabetic medications that are associated with weight stability or gain. To date, metformin is indicated only for diabetes management and not for weight loss in individuals with or without diabetes.” See here. Of course, physicians can prescribe it off label at their discretion.
Insulin and Other Medications for Type 2 Diabetes
Sulfonylureas and meglitinides are oral medications used for T2D that work by forcing the beta-cells to secrete more insulin independent of the current blood glucose. Thus they can worsen insulin resistance and beta-cell failure and cause hypoglycemia. A small percentage of persons with T2D may eventually need exogenous insulin therapy due to beta-cell failure. Use of exogenous insulin in T2D can also have adverse effects as pointed out in this review article. It discusses the connection between insulin resistance, hyperinsulinemia, diabetic complications and associated diseases. It also points out the double edged sword of using exogenous insulin in the treatment of T2D. “Overall, exogenous insulin produces favorable (reduction of hyperglycemia) and adverse (promotion of atherogenesis) effects. This is a warning for a less extensive use of insulin in type 2 diabetes. In patients with blood glucose levels > 300 mg/dL, an initial insulin administration can decrease glucotoxicity: after that, a reduction of insulin resistance by weight reduction, an increase in physical exercise, and the use of insulin sensitizers, such as metformin or the glitazones, would probably be a more rational choice to prevent cardiovascular complications in patients with type 2 diabetes.”
In my opinion, a low carbohydrate diet should be “standard of care” as the first line of therapy for insulin resistance, hyperinsulinemia, prediabetes, and both type 1 and type 2 diabetes mellitus as pointed out in this review article along with the other lifestyle habits outlined above.
Insulin resistance and hyperinsulinemia represent the earliest stage of prediabetes and T2D and lead to many serious and life-shortening chronic diseases in many cases prior to the diagnosis of diabetes. Prediabetes is more serious than previously thought. Prediabetes signifies insulin resistance, hyperinsulinemia, and beta-cell failure. Prediabetes and T2D are occurring in epidemic proportions and have the potential to bankrupt the healthcare systems of many great nations.
Yet, there is a relatively simple approach to reverse this trend: lifestyle change that includes a very low carbohydrate nutrient dense whole food diet, regular moderate physical activity, avoidance of tobacco and alcohol, adequate sleep, daily sun exposure, and stress management. In my opinion, these lifestyle habits have the greatest probability of reducing both insulin resistance and hyperinsulinemia toward and to normal compared with any antidiabetic medication. Restoration of insulin homeostasis and control of appetite are the two major mechanisms that allow for sustained and reduced caloric intake and body fat loss on a very low carbohydrate diet.
Insulin resistance and hyperinsulinemia can be detected with simple inexpensive lab tests (fasting insulin level, triglycerides, HDL-C, C-reactive protein) and reversed with these lifestyle changes and loss of excess body fat even before blood glucose begins to increase. Prediabetes and T2D can be detected with simple inexpensive lab tests (fasting glucose, glucose tolerance test, HbA1c). In those with prediabetes or T2D, reversal of insulin resistance, hyperinsulinemia, hyperglycemia, and most diabetic complications can be accomplished with these lifestyle changes and loss of excess body fat. In a small percentage of persons with T2D in whom lifestyle change and loss of excess body fat are not enough, insulin sensitizing medications including metformin and the glitazone class of medications can be useful and assist with body fat loss. Sulfonylureas and the meglitinides should be avoided and exogenous insulin used only in those few with T2D and severe beta-cell failure as mentioned above.
The above mentioned lifestyle habits have greatly improved my life as a person with T1D. So I can personally attest that what you think you might be missing out on by changing your lifestyle will be returned to you many times over with improved health and well-being. Over time you will no longer miss what you thought you could not live without!