Insulin Resistance, Metabolic Syndrome, and Diabetes Mellitus Type 1 and Type 2: Physiology, Pathophysiology, Metabolic Considerations, and Clinical Presentation
Filomena Trindade, MD, MPH, ABOIM, IFMCP, FAARM, ABFM
Introduction
Diabetes mellitus (both type 1 and type 2) is rapidly emerging as one of the biggest health concerns in the United States as well as worldwide. Diabetes mellitus affects more than 180 million people around the world, and this number is anticipated to increase to 300 million by 2025.1 Recent statistics indicate that the prevalence of diabetes in adults has increased since 1980 in virtually every country of the world with close to a quadrupling of the number of adults worldwide with diabetes.2 This is particularly significant because the prevalence is especially increasing in countries where the prevalence of common risk factors such as obesity is low. Diabetes is associated with profound implications for disability, mortality, and health care costs. The rates of diabetes have been increasing at alarming rates and correlate with the changes in the nutrient density and quality of our food, our increasing sedentary lifestyle, and changes in our gut microbiome. In addition, global industrialization with the production of plastics, pesticides, synthetic fertilizers, heavy metals, electronic waste, food additives, and endocrine-disrupting chemicals in the environment has drastically altered our food chain.3 At the root of type 2 diabetes is insulin resistance, which presents as a continuum that should be evaluated in every patient.
Forty percent of children are overweight (meaning a body mass index or BMI of 25 or more and less than 30) and 2 million are morbidly obese (BMI of 30 or greater), exceeding the 99th percentile for weight.4 The numbers of “adult onset” or type 2 diabetes in children have also climbed astronomically. Over the last two decades there has been over 1000% increase in type 2 diabetes in children.5 Fifteen years ago 3% of new cases of diabetes in children were type 2 diabetes; now it is 50%.6 The first study to estimate trends in newly diagnosed cases of type 1 and type 2 diabetes in youth under the age of 20, from the five major racial/ethnic groups in the United States (non-Hispanic whites, non-Hispanic blacks, Hispanics, Asian Americans/Pacific Islanders), and Native Americans found that the combined triggers for the development of type 2 DM were genetic predisposition and environmental factors that result in an immune reaction that destroys pancreatic beta cells.7 In this study, they noted a significant annual increase in the incidence of type 1 and type 2 diabetes in all racial and ethnic groups except non-Hispanic whites in the period studied from 2002 to 2012.7
The causes of type 2 diabetes and insulin resistance are mostly due to environmental and lifestyle factors; meaning it is completely curable and preventable. Even when considering changes in the gut microbiota as the root cause of insulin resistance or diabetes type 1, it is environmental and lifestyle factors that can affect the gut microbiota. Dr Barbara Corkey proposed a model that environmentally induced elevated background levels of insulin, superimposed on a susceptible genetic background, or basal hyperinsulinemia is the root cause of insulin resistance, obesity, and diabetes.8 Dr David Ludwig has discussed how ubiquitous junk food marketing, lack of opportunities for physically active recreation, and other aspects of modern society promote unhealthful lifestyles in children. Furthermore, he points to how inadequate or unskilled parental supervision can leave children vulnerable to the obesogenic environmental influences in our food. He also discussed the emotional distress and depression, or other psychological problems arising from abuse and neglect that may exacerbate this situation by leading to disordered
eating and withdrawal from sports and other social activities which compounds the problem even further.9
eating and withdrawal from sports and other social activities which compounds the problem even further.9
Dr David Kessler, the former Food and Drug Administration (FDA) director, has described the science of how food is made into drugs leading to neurochemical addiction in his book, The End of Overeating. Our children are most susceptible to advertising schemes accounting for one of the reasons for obese children being nutritionally deficient.10 Another cause of the childhood obesity epidemic is the consumption of energy-rich sugar and high-fructose sweetened drinks.11
The focus of this chapter is on early detection and diagnosis of diabetes type 1 and insulin resistance (before insulin resistance progresses to prediabetes or diabetes type 2). We will also review the causes and the physiology of insulin resistance and diabetes type 1 as well as discuss and review treatment options. I hope to provide tools to help clinicians to better diagnose, treat, and hopefully reverse the progression to type 2 diabetes.
Medical Consequences of Metabolic Dysfunction
Cardiovascular disease and diabetes be it type 1 or type 2 are linked to each other through obesity, insulin resistance, inflammation, oxidative stress, and immune dysfunction. 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 including coronary heart disease (CHD), myocardial infarction (MI), and congestive heart failure. The rate of cerebrovascular accidents (CVAs) is three to four times higher in diabetics. Patients with prediabetes are also four times more likely to die of heart disease. So “pre” is not really “pre” at all. Consequently, it is the insulin resistance that is the real problem and where our focus should be as clinicians.
The close association of insulin resistance, obesity, inflammation, oxidative stress, and immune dysfunction allows the clinician to diagnose vascular dysfunction early. Appropriate laboratory testing and noninvasive cardiovascular testing gives us the opportunity to diagnose vascular dysfunction in this “pre” stage so we can initiate aggressive prevention and treatment.9,12
It has been said over and over again by many researchers that one of the main reasons for the increase in diabetes and insulin resistance is obesity. In my opinion based on clinical review I believe that the opposite is true; that the reason we see such a big increase in obesity is due to 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. I believe the major cause of weight gain is undiagnosed insulin resistance. As clinicians we need to ascertain why and how a patient became insulin resistant, or if they have diabetes type 1 what was the trigger? 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 medical principles and cutting edge scientific research, it is important to get to the “genesis” of these diseases and answer these questions. This is one of the major objectives in this chapter.
According to Dr Barbara Corkey, insulin resistance actually starts with damage to the pancreatic beta cells leading to hyperinsulinemia and causing insulin resistance.8 In a publication in 2014, Dr Corkey discusses the role of beta cell toxicity inducing insulin resistance.13 In this article, she identifies many toxins including food additives, contaminants such as persistent organic pollutants, noncaloric sweeteners, and high-dose nutrients, to name a few, as potential causes of beta cell damage.13 Hyperinsulinemia and hyperlipidemia are early indicators of metabolic dysfunction, and treating and reversing these abnormalities may prevent the development of more serious metabolic diseases.14 In my opinion, based on her work and that of other researchers, I firmly believe that undiagnosed insulin resistance in many cases can be the cause of obesity and not the reverse. Obesity can lead to insulin resistance, but one of the main reasons for such high rates of diabetes type 2 may be undiagnosed insulin resistance. The continuum of insulin resistance must be understood, diagnosed, and properly treated and addressed.
The Continuum of Insulin Resistance and Diabetes Type 2
Diabetes Type 2 Exists on a Continuum of Insulin Resistance
Insulin resistance is a condition where insulin becomes less effective at lowering blood sugar. It is the inability of insulin to facilitate glucose uptake into the cell due to poor insulin binding at the insulin receptors. Insulin is unable to be transported to the interior of the cell, which results in increased pancreatic insulin production and hyperinsulinemia well above the normal range. Initially the excess insulin is able to keep serum glucose in the normal range.
Impaired Glucose Tolerance
Impaired glucose tolerance occurs when glucose rises above the normal range as the pancreas continues to overproduce insulin. The rise can be seen after meals or in the fasting state. In many patients, the fasting glucose may be normal, but there is an elevated glucose level after a meal or after a high glycemic load challenge. Serum glucose is elevated but not enough to qualify the patient as prediabetic. These are the patients who have an elevated HgbA1c but may have a normal fasting glucose. This implies that the pancreas is no longer able to keep blood glucose normal after a glucose challenge.
Prediabetes
As the pancreas continues to overproduce insulin, it is no longer able to keep fasting blood glucose in the normal range. This new range needs to be redefined based on new data. However, according to most laboratories and the ADA this is presently defined as fasting blood glucose over 100 mg/dL but less than 126 mg/dL. However, data from NHS about the relationship of fasting blood sugar (FBS) to CHD and MI suggest that risk starts at about 80 mg/dL. If we analyze the
data further, several studies have shown that fasting blood sugar (FBG) over 75 is where cardiovascular risk starts, and for each 1 mg% increase in FBG starting at 75 mg%, there is a 1% increase in CV events. Also, for 2-hour oral glucose tolerance test (OGTT), there is a 2% increase in CV events per 1 mg% increase in glucose starting at 110 mg%.15,16,17
data further, several studies have shown that fasting blood sugar (FBG) over 75 is where cardiovascular risk starts, and for each 1 mg% increase in FBG starting at 75 mg%, there is a 1% increase in CV events. Also, for 2-hour oral glucose tolerance test (OGTT), there is a 2% increase in CV events per 1 mg% increase in glucose starting at 110 mg%.15,16,17
Diabetes Mellitus Type 2
Diabetes type 2 is still being defined by most laboratory reference ranges as an FBS of 126 mg/dL or higher, or a random blood sugar of over 200 mg/dL on more than one occasion. However, these values need to be redefined. According to multiple studies, postprandial risk starts at 110 mg/dL and should not be more than 140 mg/dL. Postprandial hyperglycemia predicts CHD better than FBS in both diabetic and normal individuals. Mean amplitude of glucose excursions (MAGE) predicts glucose instability between peaks and nadirs and is the best predictor of CVD.18 Post challenge hyperglycemia predicts early vascular damage better than fasting glucose and HgbA1C. The 2-hour OGTT is superior to FBG and HgbA1C in predicting vascular disease early in obese and high-risk patients without DM. Also 2-hour OGTT correlates better with carotid IMT and arterial stiffness.19
What are the Causes of Diabetes Type 1 and Insulin Resistance
The following is a list I copyrighted and have used to look for the underlying root cause(s) of insulin resistance and diabetes type 1. I also ask the question: How did this person develop insulin resistance, impaired glucose tolerance, prediabetes, diabetes type 2, or diabetes type 1?
Consider the following causes of Insulin Resistance:
Food allergies and/or sensitivities
Dysbiosis, leaky gut and gut microbiota
Food additives or excesses
Digestive insufficiencies
Oxidative stress and/or mitochondrial dysfunction
EMF, dirty electricity
Toxins (heavy metals, endocrine disruptors, volatile solvents, etc)
Obesity
Stress or adrenal fatigue/dysfunction
Lack of sleep
Hormone imbalances
Infections (especially occult-dental, fungal, parasitic, bacterial, viral)
Nutrient deficiencies/excesses
Rx drugs (statins and DM, PPIs)
Genetic predispositions/SNPs
More than one cause?
We apply this to each patient and personalize our approach. You first ask the question: How did this particular person develop insulin resistance or type 1 diabetes? Remembering that there may be more than one cause. Also, some of the potential causes on the list may contribute in more than one way. For example, obesity can cause insulin resistance because of increased inflammation and oxidative stress, but it may also cause insulin resistance by changing the gut microbiome.
In diabetes type 1 we know patients have a genetic predisposition, but in order for them to develop the disease they need an environmental trigger and increased permeability in the gut. Basically, the trigger interacts with the genetic predisposition, and in the presence of increased gut permeability they develop the autoimmune disease. There may exist a trio of causes where the genetic predisposition, an environmental trigger, and leaky small intestine act together to develop the autoimmune condition according to Dr Alessio Fasano.20 Dr Fasano was initially talking about celiac disease but has published articles describing that this is basically what you see in most autoimmune conditions. Consequently, whether we are talking about insulin resistance, type 1 or type 2 diabetes, we need to identify the trigger to get to the root cause. In order to find the root cause or causes we must take a thorough history, perform a complete physical exam as well as obtain the appropriate laboratory evaluations.
Complete History and Physical Examination
Glean as much as you can from the history and physical examination. Chronic conditions from a patient’s past medical history can also give you clues. Conditions such as hypertension, polycystic ovarian syndrome, nonalcoholic fatty liver disease (NAFLD), obstructive sleep apnea, elevated uric acid levels, infertility, elevated liver function tests, and breast cancer, to name a few, can be associated with insulin resistance. The higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signaling leading to insulin resistance, hyperinsulinemia, and increased concentrations of endogenous estrogen and androgen. Overall adiposity in women may adversely affect breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous estrogen.21 Consequently, overall adiposity in women does affect their breast cancer risk, but visceral obesity as measured with body composition analysis is preferred as physical habitus and BMI may not accurately reflect body fat.
Gout and high uric acid levels can be a common sign of insulin resistance secondary to high sugar intake and high-fructose corn syrup.22 NAFLD, the commonest liver problem in the Western world, can be seen in patients with insulin resistance, metabolic syndrome, and prediabetes. NAFLD is the most common cause of elevated liver function without clinical symptoms. Insulin resistance is the cause of NAFLD. One-third of NAFLD cases progress to nonalcoholic steatohepatitis (NASH) and 20% to 25% of NASH cases go on to cirrhosis.23,24
The history and physical exam are the first interactions with the patient. Consider how they interact with you and the office staff, but also look for signs of insulin resistance on physical exam such as acanthosis nigricans, which are dark skin folds in the neck, inguinal and axillary areas, and the elbows. Also look for skin pallor, skin coloration, hydration, and lesions. Skin tags or hirsutism even without obesity are also important observations consistent with insulin resistance. Examine the nails because they can give you clues to vitamin
and mineral status as well as gastrointestinal and digestion issues. White spots on the nail bed can be a sign of possible zinc deficiency. People with insulin resistance or impaired glucose tolerance or prediabetes can present with peripheral neuropathy. Look in the mouth and pay particular attention to the mucosa. What does the tongue look like? If there is papillary atrophy, it can be associated with riboflavin (B2) and other B vitamin deficiencies. Is there periodontal disease? Are there amalgams? Hidden chronic infections as well as amalgams and general oral health can give us clues to underlying processes and causes. Enhanced tongue fissures (longitudinal and lambda) can be a sign of upregulated gut-associated lymphoid tissue (GALT), which can be seen in both type 1 as well as type 2 diabetes and insulin resistance.25 The body shape (pear vs apple) in women can also give you an idea as to the underlying processes and root causes. An android body shape is more consistent with increased inflammation through adipocytokine communication and hyperinsulinemia and reduced adiponectin levels. Increased weight around the midsection can be a sign of autonomic dysfunction, anxiety, and elevated cortisol levels. Women who are gynoid can have more risks for hypothalamic-pituitary-thyroid-gonadal dysfunction and more detoxification abnormalities as well as gastrointestinal concerns and food sensitivities. In addition, the extreme gynoid can be associated with estrogen dominance and higher risk for estrogen-related conditions. You also want to look at muscle bulk, hair, and skin. Someone who is exercising regularly and has poor muscle bulk points to the probable existence of a catabolic state.
and mineral status as well as gastrointestinal and digestion issues. White spots on the nail bed can be a sign of possible zinc deficiency. People with insulin resistance or impaired glucose tolerance or prediabetes can present with peripheral neuropathy. Look in the mouth and pay particular attention to the mucosa. What does the tongue look like? If there is papillary atrophy, it can be associated with riboflavin (B2) and other B vitamin deficiencies. Is there periodontal disease? Are there amalgams? Hidden chronic infections as well as amalgams and general oral health can give us clues to underlying processes and causes. Enhanced tongue fissures (longitudinal and lambda) can be a sign of upregulated gut-associated lymphoid tissue (GALT), which can be seen in both type 1 as well as type 2 diabetes and insulin resistance.25 The body shape (pear vs apple) in women can also give you an idea as to the underlying processes and root causes. An android body shape is more consistent with increased inflammation through adipocytokine communication and hyperinsulinemia and reduced adiponectin levels. Increased weight around the midsection can be a sign of autonomic dysfunction, anxiety, and elevated cortisol levels. Women who are gynoid can have more risks for hypothalamic-pituitary-thyroid-gonadal dysfunction and more detoxification abnormalities as well as gastrointestinal concerns and food sensitivities. In addition, the extreme gynoid can be associated with estrogen dominance and higher risk for estrogen-related conditions. You also want to look at muscle bulk, hair, and skin. Someone who is exercising regularly and has poor muscle bulk points to the probable existence of a catabolic state.
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