The Continuum of Insulin Resistance

by Filomena Trindade, MD, MPH

Insulin resistance, or an increasing lack of sensitivity to the hormone insulin, is the common underpinning among many serious health concerns we see today. To name a few: we see heart disease, premature death, cancer, and dementia all as a consequence of insulin resistance. What’s more, insulin resistance is a major cause of pre-mature aging and death in both the developed and developing worlds. It is arguably our biggest global health epidemic.

In my practice I see a new patient with insulin resistance every day. Insulin resistance has many faces. It does not always present the same way in every patient. For instance, one patient could present with cardiovascular disease, another with inflammation and yet another with obesity – all with the common cause being insulin resistance. In short, the consequences of insulin resistance can prevent us from living a long healthy life.

Never before in human history have we seen the numbers of new cases of type 2 diabetes that we are currently diagnosing today – particularly in children. The diagnosis of “adult onset,” or type 2 diabetes in children has climbed astronomically. Over the last two decades there has been over a 1000% increase in type 2 diabetes in children.¹ A mere 15 years ago, only 3% of all cases of diabetes in children were type 2 diabetes; now that number has climbed to 50%.⁽⁾Furthermore, what is shocking is that,40% of children are now overweight and 2 million are morbidly obese (exceeding the 99th percentile for weight). ⁾ The good news, however, is that the causes of type 2 diabetes, metabolic syndrome, and insulin resistance are all completely curable and preventable.!This is possible because these diseases are primarily caused by preventable environmental and lifestyle factors.

This article will focus on what I refer to as “the continuum of insulin resistance,” with particular attention to early detection of insulin resistance and tools to reverse it in order to avoid the consequences as well as the progression to diabetes. My goal is to provide tools to help clinicians become better detectives with a high index of suspicion as we look for signs and symptoms of insulin resistance in our patients.

Insulin Resistance: The Bigger Picture

Insulin resistance is part of a bigger picture. That bigger picture is obesity, inflammation, and cardiovascular disease. The relationship between obesity and insulin resistance has been studied by countless researchers who maintain that one of the main reasons for the increase in diabetes and insulin resistance is obesity. I would actually say the opposite is true; that the reason we see such a big increase in obesity is because of insulin resistance. I am not disputing the fact that obesity can lead to insulin resistance; I am saying that a major cause of obesity is due to insulin resistance. Therefore, through my clinical experience and research, I believe that the major cause of weight gain is undiagnosed insulin resistance.

We know that people with diabetes suffer vascular disease at much higher rates. It is estimated that diabetics are four times more likely to die of heart disease than their nondiabetic counterpart. Furthermore, the rate of cerebrovascular accidents (CVAs) is 3 to 4 times higher in diabetics. These risks apply not only for the fully diabetic patient, however. They also encompass those who are “prediabetic.” Patients with prediabetes are 4 times more likely to die of heart disease and have a 21% higher risk of stroke. Therefore, the prefix pre– in prediabetes is arguably not really “pre” any disease at all! People with prediabetes are already in a disease state because of such a high level of insulin resistance in their bodies. Therefore, it is not the diagnosis of diabetes alone that renders higher risk for major life-threatening diseases, but rather a patient’s state of insulin resistance. This is the real problem and where our focus should be as clinicians.

As clinicians we need to ascertain why and how a patient became insulin resistant. How and where do we start? How do we identify insulin resistance, and how do we treat it? What is the root cause? Why is a person insulin resistant? Applying functional medicine principles to search for the answers to these questions is an objective of this article.

Definitions: Insulin Resistance Continuum

It is an almost everyday occurrence that I hear practitioners refer to metabolic syndrome and insulin resistance in the same sentence, almost as if they were synonymous. On the contrary, they are quite different, and this difference needs to be understood. Insulin resistance, impaired glucose tolerance, prediabetes and diabetes mellitus type 2 are all part of a progressive continuum of dysfunction and it is important to know the definition of each in order to properly diagnose and treat patients. Thus, depending upon where the patient falls in this spectrum, clinicians can determine how aggressive the course and type of treatment must be. In any case, our main aim as clinicians should be to preserve pancreatic function as much as possible and reverse insulin resistance.

Insulin Resistance

Simply put, insulin resistance is a condition where insulin becomes less effective at lowering blood sugar. In other words, it is the inability of insulin to facilitate glucose uptake from the blood into the cell (because of poor insulin binding at the receptor cells). The body responds to this by stimulating the pancreas to produce more insulin so that some glucose can leave the blood stream and enter the cells. Initially, the body’s response is effective in that the excess insulin is able to keep blood sugar in the normal range. However, the first sign of imbalance lies in the above normal levels of insulin production.

Impaired Glucose Tolerance

Impaired glucose tolerance occurs when glucose rises above the normal range in spite of the pancreas continuing to overproduce insulin. The rise can be seen after meals or in the fasting state. In many patients at this stage along the continuum, fasting glucose may be normal but you will see an elevated glucose level after a meal or after a high glycemic load. Levels are elevated but not enough to qualify the patient as prediabetic. These are the patients where you see an elevated hemoglobin A1c (HgbA1c) despite a normal fasting glucose. Simply put, impaired glucose tolerance is when the pancreas is no longer able to keep blood sugar normal after a glucose challenge.

Prediabetes

As the pancreas continues to over produce insulin it is not longer able to keep fasting blood sugar in the normal range. By definition it is a fasting blood sugar over 100mg/dL to 125mg/dL. As you can see this is a severe and advanced state of disease. Close behind is prediabetes is the end of the continuum. Therefore, prediabetes is clearly a state of major dysfunction and it is not “pre” any disease! It is a disease in and of itself.

Diabetes Mellitus Type 2

Fasting blood sugar of 126mg/dL or higher, or a random blood sugar of over 200mg/dL on more than one occasion.

Metabolic Syndrome vs. Insulin Resistance

The synergistic, aggragate effects of insulin resistance, obesity, hypertension (HTN) and dyslipidemia all form a construct called metabolic syndrome⁾.⁴ This name was established through the recognition by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) 2004 update, of the importance of cardiovascular disease (CVD) risk factors. Metabolic syndrome was initially coined “syndrome X” by Gerald Reaven, as “a constellation of lipid and non-lipid risk factors of metabolic origin⁾.” ⁵. Risk factors for metabolic syndrome include visceral adiposity, high body mass index (BMI), insulin resistance, and high insulin. In order to have metabolic syndrome, a patient must have 3 out of 5 of the following characteristics present: increased waist circumference; greater than 40 inches for men and 35 inches for women), hypertension (blood pressure greater than 130/85mmHg), elevated triglycerides (greater than 150mg/dL), elevated fasting blood sugar (greater than 100mg/dL), and decreased HDL (40mg/dL in men and 50mg/dL in women).

Focus has recently shifted to insulin resistance as the dominant and independent predictor of age-related diseases. By definition, a normal blood sugar level is less than 100mg/dL. However, we know that risks extend below that threshold. Studies have shown that a blood sugar greater than 87 mg/dL equals a progressive increase of diabetes type 2. Further, the lowest risk of progression from insulin resistance to diabetes type 2 is a fasting blood sugar less than 81 mg/dL ⁶.

In the US we have seen rises in obesity in epidemic proportions in the last 20 years⁾.⁷ Among the American adults who are simply overweight, over 70% of them already have “prediabetes.” Thus, as a consequence of undiagnosed and untreated insulin resistance, the American overweight have significant risks of cardiovascular disease and even death. The unfortunate piece is that most of these people don’t even know they have this problem and remain at risk. The issue is further aggravated by the fact that there are no current national screening guidelines and no reimbursement to health care providers for diagnosing or treating anything but full-blown diabetes. Doctors are not trained or paid to properly diagnose, or treat the biggest chronic disease in the US – insulin resistance. In sum, it is a well known fact that obesity increases insulin resistance and thus diabetes risk. However, as I stated above, the reverse is also true. The most important cause of obesity is increasing insulin resistance. Once insulin resistance has been established, physicians next have to find out why a person developed insulin resistance in the first place.

Identifying Patients at Risk

It is not always as simple as looking at a patient’s stature to tell whether or not they have insulin resistance. According to the National Health and Nutrition Evaluation Survey (NHANES) correlation study from 1999-2004, up to 25% of normal weight patients (BMI less than 25) may be insulin resistant.⁸ Further, some patients can be insulin resistant and still have normal fasting insulin levels, normal HgbA1c and normal fasting glucose. So the question becomes, how do we identify the patients at risk? I believe this is best addressed by looking at the various factors that influence genes and metabolism – both of which underlie the abnormal patterns of function seen in hyperinsulinemia.

My Protocol

I have developed my own treatment protocol for insulin resistance which incorporates functional medicine principles. This includes a thorough and detailed history as well as a complete physical examination. In taking a history from a patient, I look for basic imbalances in digestion/absorption/barrier integrity, in detoxification, in hormone/neurotransmitter health, immune/inflammatory process or a mind/spirit equilibrium imbalance. The goal is to get to the underlying cause of illness. We want to connect the dots in the history and get to the root cause or the foundation of the dysfunction. So once I’ve investigated how each patient developed insulin resistance and I’ve established the underlying causes (Table 1), I stage patients, based on their symptoms, along the continuum of insulin resistance. I then individualize a treatment protocol that incorporates certain basic standards (see Table 1).

Staging the Patient

Staging allows us to determine where along the continuum of insulin resistance each patient lies. It is the stage that will determine the treatment. It will also determine how likely they are to progress to type 2 diabetes. In the continuum of insulin resistance, with illness on one end and wellness on the other, as we progress from insulin sensitive we become insulin resistant, then develop impaired glucose tolerance then comes prediabetes then finally diabetes.

There are three stages: stage 1 is when adiponectin (an adipose-derived protein) starts to decrease, in stage 2 insulin is already starting to increase and stage 3 the pro-insulin (the prohormone precursor to insulin) increases. Not everyone presents in precisely these stages. There may be variations. We also know that there may be some patients that fall between type 1 and type 2 and this is usually due to an underlying autoimmune disease.⁹ This is valuable because manifestations of insulin resistance and metabolic syndrome all reside along the continuum of insulin resistance, and each stage will direct proper treatment. For instance, if someone starts out with insulin resistance and hyperlipidemia, it is the insulin resistance that is increasing the progression to glucose intolerance and prediabetes, so we would treat that first and foremost.

Table 1:

Insulin Resistance Assessment Protocol

© 2013 Filomena Trindade, MD, MPH. All rights reserved. Reprinted with permission of the author.

Laboratory Evaluation

Not all insulin-resistant patients develop diabetes. However, insulin resistance is the underlying problem to a variety of health concerns. For example, it constitutes increases in cardiovascular risk. Consequently, we see again that it is very important to identify the people with insulin resistance and promptly treat them in order to halt and reverse disease progression. Laboratory evaluations are another tool to help guide us in our assessment of our patient’s status along the continuum of insulin resistance.

Most conventional ranges for laboratory results are very broad because we are looking at disease ranges and not functional ranges. A general guideline is that normal functional medicine ranges are in the middle to upper three quarters of conventional ranges. This helps when analyzing results for patients who can only do conventional labs.

Hemoglobin A1C

Hemoglobin A1C (HgbA1C) was developed to see if diabetic patients were being compliant with their medication. Put simply, it measures the amount of glucose that is bound to our hemoglobin. It was not developed as a screening tool although it is being used as one nowadays. So what does it mean if a HgbA1C is elevated? Where does that place the patient on the continuum? The answer is that if a HgbA1C is 5.4 or higher, the patient has impaired glucose tolerance. If their HgbA1C has changed, the patient already has hyperglycemia. However, it might be only postprandial and not in the fasting state, so we need to have patients check the postprandial blood sugars at home.

At this point along the continuum, we want to preserve beta cell function and aggressively address the underlying cause. HgbA1c is an independent risk factor for cardiovascular mortality: “The predictive value of HgbA1c for total mortality was stronger than that documented for cholesterol concentration, body mass index and blood pressure.”¹⁰

HOMA-IR

HOMA-IR is a homeostatic model assessment for insulin resistance. It is a calculation based on plasma levels of fasting glucose and insulin. It is used to assess insulin sensitivity. I think there are better ways of assessing this and have thus provided more means below.

Adiponectin, Insulin and Pro-insulin: Staging the Progression of Insulin Resistance to Prediabetes and Diabetes Type 2

Adiponectin protects against atherosclerosis, moderates fat tissue, promotes insulin sensitivity, and decreases hepatic glucose and lipid production. Adiponectin decreases before insulin increases. It is a marker of insulin sensitivity. We can also look at insulin, pro-insulin, HgbA1C, fasting glucose, and 2-hour postprandial and also 30-minute insulin levels after a 75g glucose load. This can be done through any conventional laboratory as well as through functional labs. With a functional lab we get the results plotted on a colorful graph. With conventional labs we would have to plot the results on a graph to ascertain where the patient is. In optimal control, adiponectin will be normal, fasting insulin will be 5 to 7 (conventional laboratory value), HgbA1C would be 5.3 or less and fasting sugar should be less than 81mg/dL. The risk of diabetes significantly increases when the fasting blood glucose is greater than 87mg/dL.⁶

In stage 1, adiponectin is declining and fasting insulin is still normal. Postprandial insulin might be elevated, but our primary determining factor of stage 1 is a normal fasting insulin. Pro-insulin is normal. Glucose is normal too. Adiponectin is a key link that needs to be restored as much as possible because low adiponectin is a marker for insulin resistance, which means the patient is more at risk for dyslipidemia. With that, there is increased risk for vascular injury and increased risk of progression along the continuum toward type 2 diabetes. Plus decreasing adiponectin also tends to be associated with increasing inflammatory markers. At stage 1, we would see low adiponectin, normal HOMA-IR (although it could be slightly elevated), normal glucose, normal HgbA1C, normal insulin, and normal pro-insulin.

Treatment includes diet and lifestyle changes. Focus is on body composition and making sure patients are eating the most healthful diet possible. Many experts recommend a Mediterranean-type, low-glycemic-load diet, but I think that the diet needs to personalized to each individual.

Stage 2 progresses from stage 1. Adiponectin is decreasing, insulin is starting to increase, and pro-insulin is still normal. There could be early beta cell impairment. There will be a higher normal HOMA-IR, higher than normal insulin, even a high postprandial glucose, and fasting glucose can be borderline as well as average glucose possibly being mildly elevated (or not at all). Usually stage 2 treatment consists of lifestyle changes and supplementation. We do not start pharmacotherapy until early into stage 3, and even then we may be able to reverse it with diet, nutrition, lifestyle modification and nutraceutical support. Again it is case dependent.

In stage 3, pro-insulin is increasing. Elevated pro-insulin means that the pancreas is struggling to keep glucose normal. The pancreas is trying to send out insulin as fast as it can before the final cleavage has happened. In stage 3 there is low adiponectin, high HOMA-IR, high insulin, elevated pro-insulin, possibly high glucose, and high HgbA1C. There are some patients who can maintain normal or close to normal fasting glucose even with these numbers. However, the moment you challenge them with a glucose load, their postprandial level will be high. Elevated pro-insulin means the that final cleavage to produce insulin has not happened. They may not be diabetic. They might not even fulfill the full criteria for prediabetes (remember the ADA definition for prediabetes is a fasting glucose level of 100–125mg/dl). The number one treatment aim in a patient in stage 3 is to preserve beta cell function as much as possible. There may be a totally normal fasting glucose, but it most cases the postprandial glucose will increase the moment you challenge them with a high-glycemic-load meal. Having patients check postprandial glucose levels also helps them learn what particular foods increase their glucose level.

Treatment: My Approach

Table 2 presents my approach for the treatment of insulin resistance. You will need to address these factors both at baseline and throughout the course of treatment.

Table 2: Insulin Resistance Treatment Protocol

Reprinted with permission of the author.

© Copyright 2012 Filomena Trindade MD, MPH. All rights reserved. Reprinted with permission of the author.

Dietary Management

Dietary management for the patient with insulin resistance includes decreasing insulin stimulation. Dietary modifications that decrease insulin release include exploring fiber, good and bad fats, and simple and complex carbohydrates, and taking the time to educate patients about the difference. It is important to make sure that they have protein at every meal and with every snack. Eliminate most inflammatory foods, including wheat, dairy, soy, corn, and nightshades. Give agents that increase cellular responsiveness to insulin, including chromium, alpha lipoic acid, magnesium, CoQ10, and protein kinase modulators, to name a few.

To summarize, their diet should be a low-carbohydrate, low-glycemic-load diet that incorporates healthful fats. This will help decrease inflammation. Include organic, fresh, whole, unprocessed, colorful food. Eliminate sugar, trans fats, some saturated fats, and food allergens. Address the areas of dysfunction or imbalance and prioritize. The elimination diet is helpful to identify and remove any dietary source of inflammation.

Phytochemicals

Many phytochemicals work as tissue specific kinase response modulators (SKRMs). Kinases are enzymes that facilitate insulin function. These are going to affect cellular communication and cellular signaling. Some dietary phytochemicals that modulate these pathways include berberine, cinnamon, ginseng, quercetin, resveratrol, green tea extract, and hops extract.

Nutrients known to modify insulin responsiveness at the cellular level include chromium, alpha-lipoic-acid, CoQ10, vitamin D, magnesium, vitamin C, vitamin E, omega-3 fatty acids, and chromium. A recent study on chromium and insulin resistance on children showed good results using 400 mcg chromium chloride.¹¹

Micronutrient Recommendations

• Chromium: Generally give 1000 mcg/daily if insulin resistant. Likely most effective if deficient, but difficult to test.

• Vitamin D: Test 25(OH)D and supplement as appropriate (or supplement 2000-5000) IU/daily. Vitamin D levels should be 50–80 ng/ml, depending on whether other medical conditions are present. A study showed a positive correlation of 25(OH)D concentration with insulin sensitivity and a negative effect of hypovitaminosis D on beta cell function. Subjects with hypovitaminosis D are at higher risk of insulin resistance and the metabolic syndrome. Increasing 25(OH)D from 10-30 ng/mL can improve insulin sensitivity by 60%.¹⁶

• CoQ10: Generally supplement in patients with metabolic syndrome, insulin resistance, hypertension, or mitochondrial dysfunction. COQ10 dose depends on functional levels: optimize to > 2 mcg/mL (plasma). In a patient with high oxidative stress or mitochondrial dysfunction, you may need to supplement at a much higher dose. We know that 120 mg/day of coenzyme Q10 improves glycemic control and blood pressure in NIDDM (non-insulin-dependent diabetes mellitus). 200mg of CoQ10 daily improved HgA1C and blood pressure in NIDDM patients.^12,13

• Alpha-lipoic acid: Doses of 600 to 1800 mg/day of alpha-lipoic acid (ALA) can improve insulin sensitivity in patients with type 2 diabetes. And 600-1200 mg/day of ALA may improve microcirculation and diabetic polyneuropathy.^14,15

• Magnesium: Epidemiological studies show that high daily Mg intake is predictive of a lower incidence of NIDDM. Poor intracellular Mg concentration is found in NIDDM and in hypertensive patients. Daily Mg administration in NIDDM and insulin-resistant patients restores intracellular Mg concentration and contributes to improve insulin sensitivity and glucose uptake.¹⁷ Magnesium supplementation has been shown to improve insulin sensitivity.¹⁸ Many patients have a hard time absorbing magnesium intracellularly. A buccal swab is the best way to assess intracellular magnesium. Patients with low magnesium are at a slightly higher risk for atrial fibrillation and arrhythmias. Many of these patients may also need potassium. I use magnesium glycinate because it is going to have less affects on the gut in terms of causing loose bowels and it is generally well absorbed. I generally start at 200–400 mg of a chelated magnesium and increase to bowel tolerance if normal kidney function is established.

Exploring Detoxification

Toxins can be another underlying problem causing insulin resistance. Toxic endocrine disruptors affect estrogen and estrogen metabolism (endocrine disruptors in the etiology of type 2 diabetes mellitus).¹⁹ The literature shows that even a GGTP in the high normal range is associated with insulin resistance. Start to monitor GGTP. Consider it high if it is 30IU/L or higher. If it is over 40 IU/L then glutathione production needs to be improved. Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes.²⁰ Metals may also be a problem and can contribute to insulin resistance.

Exercise

Exercise is extremely important. According to the WHO, adults aged 18 to 64 should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week or an equivalent combination of moderate and vigorous-intensity activity. Aerobic activity should be performed in bouts of at least 10 minutes duration. For additional health benefits, adults should increase their moderate-intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate and vigorous-intensity activity. Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week. Exercise alters skeletal muscle metabolism and improves glucose uptake, reduces low-density lipoprotein, raises HDL, lowers blood pressure, reduces inflammation and oxidative stress.²¹ In a Diabetes Prevention Program Research Group 2002 study, 3234 prediabetics were randomized to placebo, metformin, or lifestyle modification (≥7% weight loss and ≥150 min/week of physical activity) for 2.8 years. Compared with the placebo group, lifestyle intervention decreased incidence of type 2 diabetes by 58%. Metformin (850 mg b.i.d.) decreased type 2 diabetes mellitus by only 31%.²²

Assess how much a patient is moving his/her body and design a program that fits the patient. It is extremely important to devise an appropriate exercise regimen for each patient that incorporates aerobic and weight training and reevaluate at regular intervals and change as appropriate. Interval training has worked well for many of my patients. Generally, I review some of the published studies with patients and give them the choice between diet/lifestyle and physical activity versus medication including the potential side effects. Typically patients always choose diet and lifestyle. I inform them if they do not change their diet, lifestyle and stress reduction, I can pretty accurately predict what their outcome will be. Are they willing to take those risks? I have found that when I explain how diet, nutrition, exercise and lifestyle modification has been proven superior to prescription medications, patients are not only amazed but choose and succeed with the former.

Stress and Autonomic Dysfunction

The effect of stress on insulin resistance is very important to explore: Autonomic dysfunction contributes to heart disease and vascular disease. Autonomic dysfunction can be measured by heart rate variability. Lower heart rate variability is correlated with impaired pancreatic function in patients with coronary artery disease ²³. As your heart rate variability decreases, you progress from insulin resistance to impaired glucose tolerant to diabetes. Knowing this connection, the dysregulation of the autonomic nervous system can now be linked to visceral adiposity and insulin resistance. In a study of subjects with either a family history of DM or no family history, subjects genetically predisposed to NIDDM had more visceral fat and lower insulin sensitivity compared with controls. Visceral fat (not subcutaneous fat) was associated with lower heart rate variability.

Sleep

Sleep is extremely important. The average amount patients should be sleeping is 7 to 7½ hours per night. I encourage my patients to sleep at least 8 hours per night. What is the quality of their sleep? Are they waking up multiple times? Are they feeling rested when they wake up? Sleep deprivation may lead to insulin resistance and subsequently, to diabetes mellitus ²⁴. Lack of sleep can affect insulin resistance in several different ways. It can cause insulin resistance due to inflammation, changes in glucose metabolism, altered appetite, and HPA changes. Also, obstructive sleep apnea can affect insulin resistance, metabolic syndrome and disordered breathing so we need to have a high index of suspicion for this in our patients.

Conclusion

We have established that insulin resistance is a disease within and of itself contributing to numerous chronic and life threatening conditions and effecting countless undiagnosed patients. However, once again, the good news is that insulin resistance as well as the progression to diabetes cannot only be prevented but it can be treated and reversed as well. Therefore, it is our responsibility as clinicians to track down early cases of insulin resistance before they advance into later stages along the continuum and to reverse the damage that has incurred. Likewise, it is our duty to offer an effective protocol to those who already suffer from a clinical diagnosis of diabetes or prediabetes.

Functional medicine tools help us identify the underlying dysfunctions and the root causes in a personalized manner. Using our clinical evaluation as well as laboratory measurements including adiponectin, fasting insulin, pro-insulin, HgbA1c, postprandial insulin and glucose we can assess where the patient lies along the continuum of insulin resistance. Then, once the stage of insulin resistance has been identified, we can personally tailor a treatment plan in order to prevent further progression to diabetes and reverse beta cell dysfunction. As needed, treatment options may address any of the following areas of a patient’s life: diet, sleep, stress, exposure to toxins and ability to detoxify, exercise and/or micronutrient consumption. In conclusion, by way of acknowledging the role of insulin resistance in the bigger picture of obesity, diabetes and cardiovascular disease, we are able to recognize how vitally important it is to incorporate the effective diagnosis and treatment of insulin resistance into clinical practice.

Notes

1. Ludwig DS, Ebbeling CB. Type 2 diabetes mellitus in children: primary care and public health considerations. JAMA. 2001 Sep 26;286(12):1427–1430.

2. Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr. 2005;146:693–700.

3. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002 Dec 4;288(21):2709–2716.

4. Vitaliano PP, Scanlan JM, Zhang J, Savage MV, Hirsch IB, Siegler IC. A path model of chronic stress, the metabolic syndrome, and coronary heart disease. Psychosom Med. 2002 May–Jun;64(3):418–435.

5. Reaven GM. Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. Panminerva Med. 2005 Dec;47(4):201–210.

6. Tirosh A et al. Normal fasting plasma glucose levels and type 2 diabetes in young men. N Engl J Med. 2005;353:1454–1462

   .

7. Hyman M. The Blood Sugar Solution. Little, Brown; 2012

8. Wildman RP et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med. 2008 Aug 11;168(15):1617–1624.

9. Gabriel CL, Smith PB, Mendez-Fernandez YV, Wilhelm AJ, Ye AM, Major AS. Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus. Am J Physiol Endocrinol Metab. 2012 Oct 2.

10. Khaw KT et al. Glycated hemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322(7277):15–18.

11. Kim CW et al. Effects of short-term chromium supplementation on insulin sensitivity and body composition in overweight children: randomized, double blind, placebo-controlled study. J Nutr Biochem. 2011 Nov;22(11):1030–1034.

12. Singh RB et al. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens. 1999;13(3):203–208.

13. Hodgson JM et al. Coenzyme Q(10) improves blood pressure and glycemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr. 2002;56(11):1137–1142.

14. Jacob S et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo- controlled pilot trial. Free Radic Biol Med. 1999;27(3–4):309–314.

15. Haak E et al. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2000;108(3):168–174.

16. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004 May;79(5):820–825.

17. Barbagallo M et al. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspects Med. 2003;24(1–3): 39–52.

18. Guerrero-Romero F et al. Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial. Diabetes Metab. 2004;30:253–258.

19. Alonso-Magdalena P et al. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol. 2011 Jun;7(6):346–353.

20. Lee DH et al. Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dysplipidemia, and insulin resistance among people free of diabetes. PLoS One. 2011 Jan 26;6(1):e15977.

21. Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management through lifestyle modification for the prevention and management of Type 2 diabetes: rationale and strategies. A statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Am J Clin Nutr. 2004;80(2):257–263. Review.

22. Knowler WC. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.

23. Sayer JW, Marchant B, Gelding SV, Cooper JA, Timmis AD. Autonomic dysfunction is related to impaired pancreatic beta cell function in patients with coronary artery disease. Heart. 2000 Feb;83(2):210–216.

24. Aldabal L, Bahammam AS. Metabolic, endocrine and immune consequences of sleep deprivation. Open Respir Med J. 2011;5:31–43.