Hypothyroidism as a Precursor for Other Metabolic Associated Disease
Joyce Brown
North Carolina Central University
Dr. Dayami Lopez
October 15, 2018

Insulin Resistance and Thyroid Disorders
Underactive thyroid (hypothyroidism), is a condition in which the thyroid gland has difficulty producing enough T3 (triiodothyronine) and T4 (thyroxine). These hormones are needed to control the body’s metabolism. When there are fluctuations in these levels, the pituitary responds to this by either increasing/decreasing the production of thyroid stimulating hormone (TSH). If there are abnormally high levels of TSH, it could mean that a person has an underactive thyroid. The problem with this condition is that it could be preliminary to other metabolic disorders. In the scientific community, there’s a lot of controversy towards insulin resistance as a causative condition of hypothyroidism or if an individual must first have an underactive thyroid to develop insulin resistance. I would like to argue that hypothyroidism leads to insulin resistance.

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Does Hypothyroidism Cause Insulin Resistance?
Thyroid disorders, including hypothyroidism, have been associated with insulin resistance. Hypothyroidism has also been linked to decreased insulin sensitivity (Brenta, 2011), meaning larger amounts of insulin are required to lower blood glucose. This suggest that an individual may at first be in an insulin resistant state before developing hypothyroidism. Insulin resistance is an indication that cells are unable to absorb secreted insulin. The pancreas releases insulin which in turn lowers blood glucose to maintain homeostasis. Excess insulin in the blood causes the body to absorb too much glucose, causing the liver to release less. This causes the condition hypoglycemia; a condition of extremely low blood glucose. There has been increasing evidence suggesting that this pituitary dysfunction may be a cause of hypothyroidism (Kalra, 2014).
However, hypothyroidism does not directly impact blood sugar levels; but, it has been shown that hypothyroidism can cause variations in blood sugar levels, leading to insulin resistance. There have even been studies that have shown insulin resistance is associated with low levels of T3 and T4 respectively in non-diabetic subjects (Wang, 2018). These are hormones, that when the thyroid is functioning properly, are at optimal levels. This suggests that altered thyroid state (due to underactive thyroid) can lead to insulin resistance. Pancreatic function was significantly reduced in patients with hypothyroidism in comparison to healthy subjects (Gullo, 1991). Glucose and insulin levels were also elevated in hypothyroid patients when compared to control groups (Upadya, 2015).
There are various instances of hypothyroidism that aren’t associated with insulin. Inadequate consumption of iodine, medication and pituitary disorders can all lead to hypothyroidism. This provides evidence that this condition doesn’t rely solely on insulin resistance alone. Insulin resistance however is causative of improper thyroid function, which can be a result of reduced insulin clearance and decreased absorption of glucose (Kumar, 2015); conditions seen in individuals with hypothyroidism.
Statins: Nuisance or Necessity?
Statins are a class of drugs whose primary function is to help lower cholesterol. They are usually the first-line of defense for individuals at risk of cardiovascular disease, making it one of the most widely prescribed drugs. Statins accomplish this task by working on enzymes involved in the production of cholesterol in the liver. They halt the production of cholesterol by competing with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which in turn reduces cholesterol synthesis. The reduction of cholesterol increases the amount of low-density lipoprotein present in the bloodstream. Low-density lipoproteins (The “Bad” Cholesterol) are carriers of cholesterol.
Once an excess of lipoprotein is present in the blood, most specialized receptors on the cell surface that bind LDL become occupied. The lack of receptors reduces the uptake of cholesterol, leaving the remaining cholesterol in the blood. This in turn leads to hypercholesterolemia, a high blood cholesterol lipid disorder. In addition to this increase, statins are also responsible for raising blood sugar levels. After the body has utilized enough glucose to produce energy, the excess glucose is stored as cholesterol or triglycerides in the liver. Over a prolonged period, the accumulation of glucose molecules compromises LDL particles. In return, LDL loses its efficiency, causing an elevation in serum cholesterol levels. The elevation in bad serum cholesterol increases the risk for heart disease and stroke. This condition is best described as diabetic dyslipidemia.
In a 2010 clinical study, insulin sensitivity was evaluated in 213 individuals placed on increasing doses of atorvastatin (10-30 mg/day). After a 2-month period, it was shown that atorvastatin decreased insulin sensitivity (Suazo, 2014). The JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial reported an increase incidence of diabetes in the rosuvastatin group when compared to the control (Ridker, 2008). In more recent studies, a meta-analysis demonstrated that statin therapy is associated with the risk of developing diabetes mellitus due to the insufficient reduction of cholesterol (Preiss, 2011). In vitro studies demonstrated how atorvastatin inhibits the maturation of adipocytes and impairs insulin signaling (Nakata, 2006). Considering the reviewed evidence, I wouldn’t recommend statins to treat diabetic hypercholesterolemia. All statins appear to produce a slight risk of developing diabetes. In my opinion, the risk of developing diabetes outweighs the cardiovascular benefits. A more pressing issue to address with statin usage is what happens when the body becomes statin intolerant?
Statin Intolerance: What are the Alternatives?
Statin intolerance occurs when an individual develops adverse effects from statin usage, with one of the primary downfalls being the limitations it places on the effectiveness of treatments. When an individual is statin intolerant, standard doses of statins that are required to reduce LDL’s are intolerable which can lead to abnormal liver and muscle functions (Banach, 2015). Statin intolerance is seen primarily in the elderly (over 75-80 years of age), in those having a small body frame, having pre-existing medical conditions (e.g., liver and kidney disease), and taking other medications. Most instances of statin intolerance have been managed with a regimen consisting of low doses of statin in combination with non-statin therapy or dietary intervention (Raju, 2013). But, to manage statin intolerance, its it important to consider all possible solutions.

Bile-Acid Resins
A large portion of bile is made primarily from cholesterol, making bile acid resins an alternative. Bile-acid binding resins are used to bind bile rich in cholesterol that has traveled from the liver to the gastrointestinal tract. The binding of bile-acid prevents their reabsorption from the gut, which decrease the body’s supply of cholesterol. This generates an upregulation of hepatic LDL receptors and increases the removal of LDL from plasma. Unfortunately, this method of treatment is ineffective in individuals with homozygous familial hypercholesterolemia (WebMD).
Fibric Acid Derivatives
Fibrates can be used as a single treatment to decrease the likeliness of a heart attack in individuals with high cholesterol. Fibrates are a class of medication that lowers blood triglyceride levels by reducing the amount of VLDL (very low-density lipoprotein) produced by the liver and decreasing the secretion of blood fats. The usage of fibrates tends to increase plasma HDL-C (high-density lipoprotein cholesterol) which frees the body of bad cholesterol. However, the use of fibrates in conjunction with statins are generally avoided due to the high risk of muscle damage.
PCSK9 Inhibitors
The PCSK9 (proprotein convertase subtilisin/kexin type 9) gene offers an alternative approach for the treatment of hypercholesterolemia. PCSK9 is responsible for degrading LDL receptors found on the surface of the plasma membrane. Downregulation of LDL receptors, via PCSK9, allows hepatic lipoproteins to dispose its contents in peripheral tissues instead of the liver. Mutations in this gene can cause familial hypercholesterolemia (FH), preventing the removal of bad cholesterol from the blood. Monoclonal antibodies have been designed to interfere with PCSK9 binding to LDL receptor which in turn reduces PCSK9 production. Inhibition of the PCSK9 gene intensify the effectiveness of some statins and in other cases, eliminates the need for it all together.


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