Insulin Resistance

Dr Thanh-Tam Pham - 7/3/2021

Insulin is a hormone produced by the pancreas to help glucose enter the cells in muscle, fat and liver where it is used for energy. Therefore Insulin regulates the storage or usage of energy.

There is Insulin resistance when the cells in muscles, fat and liver do not respond well to Insulin and they cannot take up glucose easily from the blood. As a result, the pancreas makes more insulin to help glucose to enter the cells so there is a state of hyperinsulinaemia. As long as the pancreas can make enough insulin to overcome the weak response of the cells to Insulin, the blood glucose level will stay in the normal range. When the secretion of Insulin cannot keep up to lower the blood glucose level, diabetes type 2 will develop.

People can have Insulin Resistance for years without knowing it as there are no noticeable symptoms. There are risk factors for the possibility of Insulin resistance and with proper lifestyle modification we can prevent the development of diabetes and other serious illnesses.

-       Overweight: excess of weight especially around abdomen, waistline >94cm in men and >80cm in women even if BMI is normal

-       High triglyceride

-       Physical inactivity

-       Gestational diabetes

-       Age over 45

-       Hypertension and high cholesterol

-       Fatty liver

-       Polycystic Ovarian syndrome

-       Heart disease or stroke

-       Sleep apnoea

-       Symptoms of low blood glucose due to hyperinsulinaemia: feeling of weakness, hunger, sweatiness and these symptoms resolve after taking carbohydrate. This leads to sugar cravings.

-       Drugs: glucocorticosteroids, antipsychotics

-       Acanthosis Nigricans: dark velvety patches on back of neck, groins and armpits or small skin tags in those areas. Some believe a build up of Insulin within skin cells may cause Acanthosis nigricans.

-       Some people can have diabetic retinopathy before having diabetes

-       HbA1C measurements: HbA1C <5.7% normal, HbA1C 5.7-6.4% pre diabetes, HbA1C over or equal to 6.5% diabetes.

Dr Benjamin Bikman, PhD, in his book “Why We Get Sick” gives a very comprehensive discussion about insulin resistance. Insulin resistance is the hidden epidemic that is at the root of most chronic diseases.

Cardiovascular disease

Commonly known factors for heart disease are cigarette smoking, alcohol, dietary cholesterol, lack of exercise and too much belly fat. But it is now proven that Insulin resistance and cardiovascular disorders are almost inseparable. The physician-scientist Joseph Kraft declared “Those with cardiovascular disease not identified with diabetes (ie insulin resistance) are simply undiagnosed”.

1-    Hypertension

-       Salt and water retention: Insulin increases aldosterone levels in the body that signals the kidneys to hold onto sodium and reabsorb it into the blood causing water retention

-       Thicker blood vessels: insulin is an anabolic hormone, signalling cells to grow bigger including the endothelial cells. With excess of insulin the vessel wall cells grow, the endothelium thickens and blood vessels begin to narrow.

-       Blood vessels cannot dilate: normally insulin activates the production of Nitric Oxide (NO) which makes the blood vessels to dilate to increase blood flow and nutrients to various tissues. With insulin resistance, it has now less effect

and blood pressure stays elevated.

-       Unhealthy changes in blood lipids: 

The main lipids are Triglycerides (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL). LDL has 2 patterns: pattern A refers to LDL that is larger and less dense, pattern B refers to LDL being smaller and denser.  LDL B being smaller can pass from the blood into the blood vessel wall to cause problem. TG/HDL ratio <2 corresponds to LDL A predominates, TG/HDL >2 LDL B predominates. Insulin resistance selectively drives the production of LDL B from the liver.

2-    Atherosclerosis is the most essential process in the development of heart disease. Insulin resistance with high insulin level seems to increase oxidative stress and oxidative stress also increases insulin resistance.

When cholesterol enters the blood vessel wall, it only causes problems when it is oxidised and macrophages came to engulf the oxidised lipid known as an inflammatory response. When cholesterol is oxidized, it is being bound to a polyunsaturated fat called Linoleic acid (very common in seed oils such as soybean oil, canola oil…).

-       Inflammation:  insulin elicits anti-inflammatory actions in an insulin-sensitive person (with normal levels of insulin), insulin activates inflammation in insulin- resistant people with high levels of insulin. By increasing inflammation, it increases the likelihood of blood vessel damage by promoting the ongoing infiltration of the blood vessel with macrophages.

3-    Cardiomyopathy:  insulin resistance has been associated with cardiomyopathy as it compromises the heart’s ability to take in and use glucose. Chronically elevated insulin drives the growth of the myocardium and makes it too thick to allow the chambers to fill with blood.

The Brain and Neurological disorders

Insulin stimulates the brain to take up glucose for fuel and helps the brain cells grow and survive. It also plays a role in regulating appetite as when the brain senses an increase insulin level after a meal, our appetite will wane. Less responsive to insulin may lead us to overeat, contributing to weight gain. Insulin also plays an important role in learning and memory formation.

-       Alzheimer’s disease: it is becoming increasing clear that insulin resistance is contributing to the disease giving rise to the new term for Alzheimer”s as “type 3 diabetes”. In early stages of the disease, the 2 main features are accumulation of plaques and tangles in the brain. Insulin may contribute directly to amyloid plaques accumulation in the spaces between the nerves in the brain. Tau is a protein that acts to maintain normal nerve structure. In Alzheimer’s, Tau is overactive and instead of maintaining nerve structure, Tau now twists the nerve, creating neurofibrillary tangles. Normal insulin level inhibits the activity of tau. With insulin resistance, tau becomes overactive, potentially leading to neurofibrillary tangles.

The brain has a tremendous energy demands at several times more than muscle and is very sensitive to energy deprivation. As the brain becomes progressively insulin resistant, it becomes less able to obtain enough glucose to meet its energy demands and this leads to compromised brain function.

-       Vascular dementia: it is the second most common form of dementia. Vascular dementia occurs because the brain suffers from insufficient blood flow from atherosclerosis.

-       Parkinson’s disease: up to 30% of patients with Parkinson’s have type 2 diabetes and possibly up to 80% having insulin resistance (or prediabetes).

-       Migraine headaches: a study found that insulin levels were significantly higher in people with migraines.

-       Neuropathy: it is commonly associated with type 2 diabetes but the problem appears to start before blood glucose is elevated when insulin is high in insulin resistance.

Reproductive Health

1-    Insulin and Women’s reproductive health:

-       Gestational diabetes: in pregnancy physiological insulin resistance can be normal as the pregnant body needs to grow and insulin helps that process. But when the insulin resistance cannot keep the control of blood glucose, it becomes pathological. Gestational diabetes increases seven fold higher the likelihood of developing diabetes later in life.

-       Preeclampsia: if not treated can lead to liver or kidney failure and future heart issues for the mother.

-       Over and underweight Babies: they are at increasing risk to develop obesity and metabolic disorders later in life.

-       Low breast milk supply

-       Polycystic Ovarian Syndrome (PCOS) is the most common cause of female infertility. Aromatase converts androgens into oestrogens in ovaries. Too much insulin inhibits aromatase. The hypothalamus in the brain sends signal to the pituitary gland to secrete FSH for the follicles in the ovary to develop into mature eggs. As the follicles mature, oestrogen increases in the ovaries and the pituitary releases LH surge for ovulation to occur. Insulin may directly act on the brain to block normal LH surge production which may disrupt normal fertility. In PCOS, the ovaries become burdened with cysts resulting in painful ovaries that grow to several times their normal size.

2-    Insulin and Men’s Reproductive health:

-       Sperm production: men with high body fat tend to have less testosterone. Aromatase also exists in fat tissue so fat tissue can act like an ovary. Excess fat tissue increases circulating oestrogens in men.

-       Erectile dysfunction (ED): scientists recently stated in a research article that “insulin resistance may be the underlying pathogenesis of ED in young patients without a well known etiology”.  Blood vessels must dilate dramatically to develop and sustain an erection. When the endothelial cells are insulin resistant, they produce less Nitric oxide which deprives the blood vessels of a strong dilating signal. ED could be one of the earliest signs of insulin resistance.

-       Insulin and puberty: insulin can play a role in puberty. Insulin stimulates Leptin production from fat cells which then activates precursor sex hormones in the brain, then the gonads. Our metabolic health and our nutrition have a strong influence on when puberty begins.

-       Overnutrition and early puberty: there is a connection between obesity and precocious puberty. Excess Insulin drives excess leptin production leading to early puberty.

-       Undernutrition and delayed puberty: in female gymnast or anorexia nervosa patients.


Cancers have different possible causes such as genetic mutations or gene damage or from metabolism. Regardless of its specific cause, cancer is a disease of cellular growth, and cells begin to multiply uncontrollably. Almost 100 years ago, Otto Heinrich Warburg discovered that cancer cells have an almost total reliance on glucose as their metabolic fuel. But instead of using their mitochondria to break down the glucose, they do so outside the mitochondria without the need of oxygen (anaerobic glycolysis). This “Warburg effect” allows cancer cells to grow rapidly everywhere in the body, including locations that might not have adequate blood flow. Insulin’s main action is to cause cells to grow and high insulin level also works to increase the growth of cancer cells. Any cancer cells that have mutated to be more sensitive to insulin are growing far more rapidly than fat cells.

1-    Breast cancer:

Breast cancer is perhaps the most commonly linked to Insulin resistance. Women with highest fasting insulin level are those with the worst breast cancer outcomes. The average breast cancer tumour has over 6 times more insulin receptors than non cancerous breast tissue. There is a link between insulin resistance and obesity and excess body fat increases circulating oestrogens. Breast tissue is sensitive to oestrogens and the breast tissue is more likely to grow excessively increasing the risk of developing breast cancer.

2-    Prostate cancer.

A man with insulin resistance is about 2 to 3 times more likely to have an enlarged prostate. Men with a high degree of insulin resistance may be up to 250% more likely to develop prostate cancer.

3-    Colorectal cancer

Insulin resistance is associated with increased risk of colorectal cancer and it also is associated with the cancer to be more lethal.


Aging, the Skin, Muscles and Bones

1-    Insulin resistance and the skin:

- Acanthosis Nigricans: this involves overactive melanocytes producing melanin pigment. Darkening occurs most often where the skin rubs together such as the neck, armpits and groins.

- Skin tags: hyperinsulinaemia stimulates the growth of keratinocytes.

- Psoriasis: the cause of psoriasis is unknown but people with psoriasis are almost 3 times more likely to have insulin resistance.

- Acne:  people with acne have higher levels of insulin in the blood.

- Insulin resistance and the ear function. There is a connection between Meniere’s disease (vertigo), tinnitus and hearing loss especially hearing lower tones

2- Insulin and muscle function: insulin resistance compromises healthy muscle function, contributing to muscle loss, reduced muscle capacity and decreased performance. .

-Muscle loss: Sarcopenia is muscle loss that accompanies aging and we lose about 1% of our muscle each year after middle age. People with insulin resistance, outside of the effects of aging, have a relative increase in muscle protein breakdown.

-Fibromyalgia is one of the most common generalised pain disorders. There is a widespread muscle pain accompanied by fatigue, memory problems and mood issues.

3- Insulin and the Bones and Joints:

Like a muscle, with its high protein need, proper bone health requires bone matrix turnover: the bone is constantly degrading and rebuilding its contents, and calcium and other minerals are being added and taken from the bone. Insulin stimulates osteoblast activity promoting bone growth and inhibits osteoclast action reducing bone degradation. Ostoblasts also secrete a hormone called osteocalcin with the presence of vitamin D. Osteocalcin improves insulin resistance so it explains that vitamin D is linked to insulin sensitivity.

- Reduces bone mass

- Osteoarthritis: The loss of joint cartilage was once considered as a disease of excessive wear and tear, however it is increasingly considered as a metabolic disease. The main cells in cartilage are chondrocytes that are insulin responsive and with insulin resistance, they cannot maintain that matrix and the cartilage weakens. Synovial fluid in the joint is made from synoviocytes. When synoviocytes are exposed to high levels of insulin, they experience an invasion of immune cells that promotes inflammation in the joint.

- Gout is an inflammatory joint disease where there is accumulation of uric acid in the joints commonly in feet (especially in big toe), ankles, fingers and wrists. Uric acid is normally excreted by the kidneys and with insulin resistance, the kidneys accrue uric acid rather than excrete it.


Gastrointestinal and Kidney Health

Our digestive and urinary tracts are involved in fundamental processes necessary to survival: absorbing nutrients into the body and eliminate the waste from digesting and metabolising these nutrients.

1- Reflux Oesophagitis: it is linked to visceral obesity and insulin resistance. Visceral obesity may compress the surrounding tissues including the stomach and this would increase stomach and relax the lower oesophageal sphincter.

2- Gastroparesis: it was thought that diabetes with excess of blood glucose damages the vagus nerve (neuropathy) and thus is less able to induce stomach contractions and peristalsis but in one study high levels of insulin can also have that effect.

3- Insulin and the Liver:

The liver may be one of the first organs to become insulin resistant. With the action of insulin, a healthy liver will take up glucose and convert it into glycogen and some to fat. Glycogen is held for reserve energy in the liver and muscles and when the body needs energy, glycogen is converted to glucose and released into the blood stream. With insulin resistance, even with high blood glucose and insulin, the liver begins to break down glycogen to release glucose further increasing glucose and driving up insulin. With insulin resistance, the excess insulin signals to the liver to create excess fat. This creates hyperlipidemia and fatty liver disease.

- Hyperlipidemia: it means the blood has too much fat often carried on lipoprotein (LDL).  When the liver produces fat from any source, it commonly produces a saturated fat called palmitic acid. It is potentially pathological by increasing inflammation and cardiovascular complications and exacerbating insulin resistance.

- Non alcoholic Fatty liver disease (NAFLD): The liver stores too much fat (5% to 10% of its body weight) and start to lose functionality. Historically, fatty liver was seen almost exclusively with excess alcohol consumption but now it is the most common liver disorder in Western countries.

Fructose is similar to alcohol and is metabolised by the liver. High fructose consumption is a high contributor to NAFLD as liver has very limited options for metabolising fructose and alcohol. In a study, glucose drinkers developed more subcutaneous fat while the fructose drinkers developed more visceral fat. Many people consider fruit juice as a healthy drink but all fruit juice is pure fructose. Eating whole fruit is different because of its fibre content and relatively lower fructose, it can improve diabetes risk.

While almost all obese people have NAFLD, if lean people is diagnosed with NAFLD, it is an almost certain sign the person has insulin resistance and will likely develop type 2 diabetes. One fifth of people with NAFLD will develop cirrhosis and then potential liver failure requiring liver transplant for survival. In some, it can develop into liver cancer.

- Insulin and the Gallbladder: gallstones can be formed in 2 ways with the liver producing too much cholesterol or the gallbladder may not be contracting enough to push bile into the intestines. Insulin resistance affects both of these functions. However, dietary fat is one of the best ways to prevent a gallstone from forming. Increased dietary fat raises gallbladder motility which helps prevent stone formation. People who adopt a low fat, low calorie diet for weight loss have an increased risk of gallstone formation. Insulin slows gallbladder motility. Pregnancy increases the risk of developing gallstones or a thicker bile termed “sludge”.

4- Kidney health:

- Kidney stones; high insulin increases the amount of blood calcium

- Kidney failure: type 2 diabetes is the most common cause. The most insulin resistant people have a 4 times greater risk of developing kidney failure. This happens even when glucose levels are still normal.


The Metabolic Syndrome and Obesity

The World Health Organization defines the metabolic syndrome by 2 main criteria: first the patient must have 2 of either factors high blood pressure, dyslipidemia, central obesity or low levels of protein in urine and second the patient must have insulin resistance.

 Obesity and insulin resistance:

Obesity and insulin resistance tend to occur together but the connection between them is complicated- it’s a chicken and egg question of which happens first. Excess body fat drives insulin resistance. There is now more evidence that high blood insulin precedes obesity as insulin directs nutrients toward being stored as fat even when the number of calories stays the same.


Causes of Insulin Resistance

Age and Genetics

1- Genetics: in children who have one parent with insulin resistance, fasting insulin levels are roughly 20% higher.

2- Ethnicity: there are real facts that insulin resistance is becoming increasingly common among people who have been exposed more recently to a Western diet. The theory suggests that those of European descent have had more time to adapt to foods that can raise insulin and lead to diabetes. In USA, one study showed that the highest insulin resistant groups are in descending order Hispanic, Asian, African and Caucasian. Indigenous American people (Pima Indians) that were not included in that study have the highest prevalence of insulin resistance.

3- Age: the older we get, the more insulin resistant we generally become.

- Menopause increases insulin resistance: oestrogen helps maintain insulin sensitivity.

- The decrease in testosterone in men is linked to insulin resistance.

How Hormones cause Insulin Resistance.

1- Too much insulin causes insulin resistance:

If a muscle or liver cell is inundated with insulin, it can do nothing to directly reduce the insulin the pancreas is producing but it can alter itself to ensure insulin has a smaller effect and thus becomes resistant to insulin.

Many people with type 2 diabetes were given insulin to bring the blood glucose under control for a time but as insulin creates more insulin resistance, there is a demand for higher insulin doses.

2- The stress hormones: Epinephrine and Cortisol:

Cortisol raises blood glucose for energy for the fight and flight response and insulin is trying to reduce glucose. In chronic stress, cortisol makes the body resistant to insulin. Cortisol selectively makes visceral fat to grow more than subcutaneous fat, creating an unhealthy metabolic state.

3- Thyroid Hormone;

Hypothyroidism is a cause of Insulin resistance whereas hyperthyroidism improves insulin sensitivity.

Obesity and Insulin Resistance

1- Location of fat deposition:

The “gynecoid” fat pattern is typified by fat accumulating as subcutaneous fat on the hips and thighs, with less fat on the upper body and trunk. This is seen in women due to the action of oestrogen.

The “android” pattern may have both subcutaneous fat and visceral fat meaning fat inside the trunk of the body, surrounding the visceral organs (liver, kidneys, intestines and heart). This is typical male fat storage pattern.

It is well known that women have a better chance of living longer than men.

Waist to hip ratio: for men the ratio is ideally below 0.9 and for women the ratio should be below 0.8.

Excess body fat, especially visceral fat, increases 2 pathological conditions- it increases inflammation and causes oxidative stress.

2- Fat cell size matters.

Insulin sends a powerful signal to the fat cell to store fat and it inhibits the fat-shrinking process known as “lipolysis”. As we gain fat, our fat tissue can grow in 2 ways: via an increased number of fat cells “hyperplasia” or a growth in cell size “hypertrophy”. If fat cells can multiply via hyperplasia, they never reach their limit and maintain sensitivity. When a fat cell reaches its maximum dimensions through hypertrophy, it attempts to limit further growth by becoming resistant to Insulin. The person whose fat is growing via hypertrophy will stop gaining weight as the enlarged fat cells become insulin resistant, this person could be only moderately overweight yet be very insulin resistant. The person whose fat cells are multiplying will continue to gain weight and have a greater potential to be very overweight, yet likely to maintain a high degree of insulin sensitivity. The insulin resistant fat cell that is grown beyond its borders not only leak fat, but because it is too big, it also becomes inflamed, dumping inflammatory proteins into the blood, both of which drive insulin resistance.

The fat molecule that makes fat cell hypertrophy is called 4-hydroxynonenal (4-HNE) born from the union of a polyunsaturated fat (such as Omega-6 fat, linoleic acid) and reactive oxygen molecules (oxidative stress). Linoleic acid is the main fat in all processed and packaged foods. A second fat that disrupts fat cell growth forcing hypertrophy is called ceramide1- phosphate (C1P). Whereas 4-HNE is a consequence of oxidative stress, C1P can be considered more a consequence of inflammation.

3- Ectopic obesity.

When we store fat in the non fat tissue (ectopic fat), problems arise including insulin resistance.

- Fatty liver: once insulin resistant, the liver allows glycogen to break down resulting in blood glucose and insulin elevation.

- Fatty pancreas: those with fatty pancreas were almost 60% more likely to have insulin resistance.

- Fatty muscles: once fat is converted to ceramides in the muscle, they start to attack several proteins in the muscle that would normally respond to insulin.


Inflammation and Oxidative Stress

Inflammation and oxidative stress are 2 critical components of our immune system to help the body to defend against infections and to recover and heal when it has been damaged.

1- Inflammation is a cause of insulin resistance. It is most obvious when a person has an infection related illness such as infectious mononucleosis, periodontitis and autoimmune diseases ( rheumatoid arthritis, Lupus, Crohn’s disease).

Asthma: inhaled toxins as in cigarette smoke increase inflammation and certain people may develop respiratory sensitivities such as asthma. Asthma is highly linked to insulin resistance.

2- Obesity is also an inflammatory disorder. When the fat cells are too big, they can release inflammatory proteins called cytokines. Where inflammation is driving insulin resistance, it does so with the help of intermediates like ceramides.

3- Oxidative stress refers to the damage that harmful molecules cause to a cell. These dangerous molecules commonly originate from the mitochondria, the parts of the cell that use oxygen to break down glucose and fats to produce energy. One of these processes is to turn oxygen into water “metabolic water”. It is a complicated process and the problem arises when the oxygen only gets an electron without a hydrogen. This produces molecules called reactive oxygen species (ROS).

Lifestyle factors

1- Things we breathe: we breathe constantly taking roughly 20,000 breaths per day.

- Air pollution: particles up to 2.5 microns in size (PM 2.5) are so small that they can penetrate deeply into the lungs and are even capable of entering the blood. When these toxic molecules enter the lungs, immune cells (like macrophages) sense them and activate those pro-inflammatory proteins called cytokines.

- Cigarette smoke: causes insulin resistance. Even second hand smoke is enough to produce ceramides. Fat cells are one of the direct sites where nicotine acts to create insulin resistance.

2- Things we eat:

- Monosodium Glutamate (MSG): MSG increases insulin and every gram of MSG correlates with a 14%increased risk of developing insulin resistance.

- Petrochemicals: they are found in items we wear, lotions we apply and even food we eat or drink. The main petrochemical that causes insulin resistance is biphenol A (BPA). BPA is everywhere in soft plastic water bottles and jugs, baby bottles, plastic toys and the lining of canned foods.

- Pesticides

- Sugar and Artificial sweeteners

Artificial sweeteners can increase the risk of insulin resistance. In one study, people who drink a diet soda daily have a 36% greater chance of developing metabolic syndrome and a 67% higher risk of type 2 diabetes. A few theories explain that artificial sweeteners increase our craving for “real food”, trick us into thinking we can eat more later. It may cause a small insulin spike even though they provide no meaningful calories. This phenomenon is known as the cephalic phase insulin response (CPIR), and it is a natural reaction to sweet foods that helps prepare the body for a carbohydrate load.

- Too little salt: As salt consumption drops, the kidneys initiate a process to reabsorb as much salt as possible from the urine back into the blood through the actions of aldosterone.  Aldosterone antagonizes insulin, creating insulin resistance.

- Starvation: eating too little for too long can become harmful as in anorexia nervosa. If a fast continues to the point of muscle loss, fasting has turned into starvation.

3- Things we do

- Sleep: sleep deprivation can lead to insulin resistance. Specifically, being exposed to bright light may be the determining factor of whether or not a person develops insulin resistance with sleep deprivation. Exposure to light at night alters our levels of melatonin and importantly cortisol. Napping too much, more than one hour a day is more likely to develop insulin resistance

- Sedentary living: the less we move our body, the more insulin resistant it becomes. Many suspect physical inactivity is a main reason why insulin resistance tends to worsen with age. Just one week of being sedentary can increase insulin resistance sevenfold. Insulin resistance through disuse is mostly a result of our muscles: because we don’t use them, they respond less to insulin. If one leg is in a cast, that leg becomes half as insulin sensitive as the mobile leg within just days. The unused muscle experiences an increase in activity of inflammatory events which drives the insulin resistance. Even something as seemingly benign as sitting for too long, too often, is associated with greater insulin resistance.





Why We Get Sick – Dr Benjamin Bikman.