Insulin On Cardiac Contractility Biology Essay

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It is expressed by Nelson and Cox in Principles of Biochemistry Nelson and Cox 2008 that people with Type I diabetes mellitus inject themselves with insulin everyday in order to decrease glucose levels since their bodies are not able to produce insulin by itself. The discovery that insulin injection can lead to a healthy normal life in diabetics was accidental. In the late 1800's, a young assistant by the name of Oskar Minkowski was working in a lab and began to study the importance of the pancreas. He removed the pancreas from a dog and noticed that the dog was urinating more than normal, and the urine contained high glucose levels. It was not until the 1920's when Frederick Banting found that there were cells in the pancreas that contained an element that decreased glucose levels. This element came to be known as insulin. (Nelson and Cox 2008)

Insulin Structure, its Synthesis, and Release

Nelson and Cox describe in Principles of Biochemistry (Nelson and Cox 2008) that insulin is a small protein with two amino acid chains (α and ß) linked by disulfide bonds. It is produced by the beta cells of the pancreas (islets of Langerhans) and synthesized first from preproinsulin. Preproinsulin is then proteolytically cleaved to form proinsulin, and three disulfide bonds are formed. The polypeptide chain is cut to make two chains and the connecting peptide (C peptide) is removed from proinsulin to form mature insulin by the action of particular proteases. Active insulin is released from the vesicles by exocytosis. (Nelson and Cox 2008)

Insulin Receptor

Insulin binding and its phosphorylation is described by Nelson and Cox. (Nelson and Cox 2008) Insulin binds to its receptor protein (INS-R), which consists of two alpha chains and two beta chains. The alpha chain is entirely extracellular and binds to insulin, while the beta chain is a transmembrane protein and a tyrosine kinase. When insulin binds to the alpha chain, autophosphorylation of the beta chain occurs on the tyrosine residues. The major actions of insulin are followed by activation of the intracellular protein, IRS-1 (insulin receptor substrate-1), which plays a major role in the activation of other proteins. (Nelson and Cox 2008)

Another key signaling pathway explained by Nelson and Cox (Nelson and Cox 2008) includes proteins containing SH2 domains (Src homology 2). SH2 domains are similar to SRC proteins, which is protein Tyr kinase. Activation of IRS-1 directs to the activation of PI3 kinase, which converts PIP2 to PIP3. A cascade of signals becomes activated and ultimately leads to the translocation of recycling vesicles consisting Glut4 to the cell membrane. After Glut4 reaches the plasma membrane, it brings glucose inside the cell. (Nelson and Cox 2008)

Second Messenger Activation

In the study reported by Zhang and Hancox (Zhang and Hancox 2003), it was found that a specific phospholipase C inhibitor decreased an insulin induced current. Phospholipase C is a second messenger system that causes the production of 1,4,5-triphosphate (IP3) and DAG. IP3 and DAG cause the release of calcium from the endoplasmic reticulum and extracellular fluid. Thus, when a phospholipase C inhibitor is present, IP3 and DAG cannot be produced and the release of calcium is inhibited. This can cause a decrease in contractility of heart muscle cells. (Zhang and Hancox 2003)

Zhang and Hancox also report (Zhang and Hancox 2003) that phosphatidylinositol 3-kinase (PI3-kinase) activates the phosphorylation of phosphoinositides and is involved in the activation of phospholipase C and other signaling pathways. Since PI3-kinase activates phospholipase C, it can increase the formation of IP3 and DAG, which ultimately increases the release of calcium. This leads to an increase in contraction of cardiac muscle cells. (Zhang and Hancox 2003)

Insulin Function

According to Hiraoka (Hiraoka 2003), the main function of insulin is to lower blood glucose levels, but insulin also has an influence on protein and fat metabolism, gene transcription, and regulation of ion channels in different cells. In a study conducted by Zhang and Hancox (Zhang and Hancox 2003), insulin activated a voltage-dependent nonselective cation current in cardiac cells. The insulin-activated nonselective cation current carried a current flow, which affected the activity of the Na+-Ca2+ exchanger and ultimately increased Ca2+ entry into myocardial cells. This process caused an increase in heart muscle contraction. Therefore, Zhang and Hancox found that insulin increased the contractility of the heart by activating a current and increasing the Ca2+ levels in myocardial cells. (Zhang and Hancox 2003)

In another study conducted by Lee and Downing (Lee and Downing 1976), animals were used to study the effects of insulin on heart contraction. The hearts of the animals were removed and a papillary muscle was taken from the right ventricles of the hearts. Changes in contractile force were measured. A dose of 1 U/ml of insulin was added in the papillary muscles. Even though a previous study showed that in dogs only around 100 mU/ml of insulin is needed for a response to be detected, the authors of this study added 1U/ml of insulin because it has been shown that the binding of insulin to cells is a reversible process. After insulin was added to the bath containing the papillary muscles, the force on the muscles increased, but quickly declined reaching the same level as before the insulin was added. This suggests that insulin does not affect the force on the muscles in the heart. (Lee and Downing 1976)

To study the effect of insulin on the contraction of the heart, Lee and Downing (Lee and Downing 1976) looked at the tension and rate of tension of the papillary muscles as time progressed after the infusion of insulin. They found that in all of the animals, both tension and the rate of tension increased after insulin was added with slight variations among the animals. This result showed that the increase in the tension of the heart caused an increase in contraction. Overall, the results showed that insulin increased the contraction of the heart due to the addition of insulin and is not dependent on glucose levels. Lee and Downing also suggested that insulin can affect other metabolic function which can affect the contraction of the heart. (Lee and Downing 1976)

Target tissues of Insulin

As stated in the article by Brownsey (Brownsey et al. 1997), the main target tissues of insulin are skeletal muscle, adipose tissue, and liver cells. There are other tissues that are also affected by insulin, including the heart. When insulin is deficient, there is an increase in gluconeogenesis and breakdown of protein into amino acids. The amino acids and glucose that are formed are supplied to the heart muscles. This shows that if insulin was present, it would inhibit gluconeogenesis and inhibit the breakdown of protein. Therefore, insulin can be used to regulate the amount of substrates that go to the heart and can be used to maintain the heart's activity. (Brownsey et al. 1997)

Brownsey (Brownsey et al. 1997) also states that in the heart, there must be a rate of 40-80 cycles/min of calcium release in order for insulin to be released. This means that the release of insulin to the heart depends on the amount of calcium released. If there is not enough calcium being released, insulin will not affect the heart. This effect is not in the case in other parts of the body, including the liver and adipose tissue, as small concentrations of calcium are sufficient enough for insulin release. (Brownsey et al. 1997),

Effect of insulin on myocardial blood flow

In the study performed by Sundell (Sundell et al. 2001), the myocardial flow of 10 healthy men was studied after the infusion of insulin. These men were non-smokers and took a physical examination to be certain that they were not on any medication. They had normal blood glucose levels and electrolytes. The results showed that insulin was able to increase their myocardial flow, but it depended on the dose. When a dose of 5 mU kg-1 min-1 was given to the men, glucose uptake increased by 120% compared to a dose of 1 mU kg-1 min-1. Insulin also caused vasodilation of the coronary arteries. (Sundell et al. 2001)

Another study was done by Sundell (Sundell et al. 2002) where the effects of insulin on myocardial blood flow of young men with Type I diabetes mellitus was studied. The short-term effects of insulin were additionally studied. 9 non-smoking males with Type I diabetes mellitus were injected with insulin at a rate of 1 mU kg-1 min-1 for one hour. The men were analyzed using positron emission tomography (PET). The results showed that insulin had similar results on the coronary arteries in the diabetic patients compared to the healthy individuals. However, short term injections of insulin did not affect the myocardial blood flow in the Type I diabetics. Therefore, insulin caused the vasodilation of coronary arteries in both healthy and Type I diabetes mellitus individuals. Myocardial blood flow increased as the amount of insulin increased in the healthy individuals, but did not affect the patients with Type I diabetes mellitus. (Sundell et al. 2002)

Role of Diet and Insulin to Maintain Normal Heart Conditions

Chess and Stanley (Chess and Stanley 2008) studied the effects of diet on the heart. They state that the heart takes up fatty acids and the amount of fatty acids produced depends on the rate of lipolysis. This rate increases in cases where people are stressed. When insulin levels are low in the body, the concentration of free fatty acids increases. This suggests that insulin can increase lipolysis or decreases the concentration of free fatty acids. Regulation of the concentration of free fatty acids is a complicated process. When free fatty acids enter the cytosol, they are esterified into fatty acyl-CoA, which means that oxidation of the fatty acids takes place. The oxidation of free fatty acids reduces the heart activity and efficiency since the heart's rate of contraction increases. (Chess and Stanley 2008)

Chess and Stanley (Chess and Stanley 2008) state that if the free fatty acids in the body are reduced with diet or drugs, the oxidation of the fatty acids can decrease; thus, decreasing the rate of contraction of the heart. This, in turn, brings the contraction to a normal level. It is also stated that in order to prevent heart failure, low levels of insulin should be present in the body. This is probably due to the fact that insulin increases the contraction of the heart, and thus by decreasing insulin levels, the contraction decreases. Thus the heart does not work as hard, and heart failure can be prevented. Of course, there should be normal levels of glucose and free fatty acids present since an increase in either can also overwork the heart. Overall, in order to prevent an increase in heart contraction, which can lead to heart failure, one should maintain a low fat and low carbohydrate diet, as well as physically exercise. (Chess and Stanley 2008)

Cardiovascular Effects of Insulin in Diabetes Mellitus

Cardiomyopathy in Diabetics

Fein (Fein 1990) studied the effects of diabetic cardiomyopathy on rats that were severely diabetic. The study showed that the diabetic rats had a decreased contraction of the heart. When insulin was used as a treatment, the rats showed an increase in contraction. The diabetic rats were compared to diabetic rats with hypertension. The rats with diabetes and hypertension showed an increase in myocardial dysfunction, and several of them died unexpectedly because of diabetic cardiomyopathy. According to Ren and Davidoff (Ren and Davidoff 1997), diabetic cardiomyopathy enhances mortality and impairs the contraction of the heart by prolonging contraction and relaxation periods. Therefore, insulin can increase the contraction of the heart in diabetics and prevent diabetic cardiomyopathy. Hypertension with diabetes causes more severe results, such as heart failure. (Ren and Davidoff 1997)

Increased glucose levels may contribute to diabetic cardiomyopathy, which can be controlled by insulin sensitizing agents, such as metformin. Metformin increases the effect of insulin and lowers blood pressure. In a study conducted by Ren (Ren et al. 1999), it was shown that increased glucose levels cause abnormalities in the heart muscle cells of diabetic rats. Metformin was used to study its effects. Ventricular myocytes were obtained and placed in a high glucose medium. The presence and absence of metformin were observed to see what differences metformin can make. It was found that metformin prevented any abnormality in relaxation that the myocytes had in the high glucose medium, even in the presence of insulin. This suggests that metformin can be used instead of insulin to decrease abnormalities of relaxation in the heart when high levels of glucose are present. (Ren et al. 1999)

Insulin and insulin-like growth factor I (IGF-1) are similar in structure and cellular function. Therefore, IGF-1 can replace insulin to control blood glucose levels in diabetics. In a study done by Ren (Ren et al. 1998), the affect of IGF-1 was studied in diabetic rats. IGF-1 normally stimulates cardiac growth and contraction, but did not show to stimulate contraction in the diabetic rats. This can be due to a change in intracellular Ca2+ levels or nitric oxide formation. (Ren et al. 1998)

Condition of Heart with Insulin-Dependent Diabetes Mellitus

In a study done by Kimball (Kimball et al. 1994), it was found that cardiac disabilities might be related to abnormal functions of the kidneys. 39 IDDM patients (boys and girls) and 40 healthy patients (boys and girls) were studied. None of the patients had coronary artery disease or any heart defects. The IDDM patients were given daily doses of insulin. All patients underwent an echocardiography. Blood pressure was measured in a resting state. Since blood pressure varies with age and sex, the systolic and diastolic readings were formulated. The urine samples of all of the IDDM patients and 18 healthy patients were collected. The samples were tested for creatinine, albumin, and hemoglobin levels. Contractility was measured in both the IDDM patients and the control group. (Kimball et al. 1994)

Kimball's results (Kimball et al. 1994) showed that in the diabetic patients, there was an increase in contractility of the left ventricle of the heart compared to the healthy individuals. There was also an increase in thickness of the left ventricle in the diabetic patients. These findings may show a cardiac condition. The study also showed that there was an increase in creatinine levels and microalbuminuria in the urine in the diabetic patients, which suggests a renal dysfunction, which can eventually lead to renal failure. This shows that the kidney filtration by the glomerulus is disrupted due to the increased left ventricular contraction of the heart and high blood pressure. This relationship between an increase in contractility of the heart and a renal dysfunction shows that the heart and kidney are related and any abnormality in one organ might cause an abnormality in the other. (Kimball et al. 1994)

Insulin Resistance and Action of Leptin on Heart

In an article by Hintz (Hintz et al. 2003), the effect of prediabetic insulin resistance on leptin levels were studied. The heart's response to leptin was also considered. Leptin is an obese gene that is produced by adipose cells. Leptin decreases the amount of food taken, which reduces body weight. It plays a role in diabetes. In this study, rats were divided into two groups: one that was fed a sucrose diet and the other one were fed a cornstarch diet. The animals were killed and their hearts were removed to examine the ventricular myocytes. The results showed that there was a dysfunction of cardiac contractility due to leptin. Unresponsiveness to insulin can cause abnormal cardiovascular function and an increase in blood pressure. So a change in one's diet and regular physical activity plays an important role in improving cardiac function and decreasing blood pressure. (Hintz et al. 2003)

Insulin's Effect on Cardiac Muscle Contraction throughout Canine Shock

The effects of insulin on the heart during endotoxin shock were studied in an experiment done by Law (Law et al. 1988). 22 mongrel dogs were used to study the effect of endotoxin shock on myocardial blood flow and contractility using an electromagnetic flow probe. The shock was induced through Salmonella typhimurium and caused a decrease in myocardial activity and an increase in contractility. In the control group, the myocardial glucose uptake increased, while there was no elevation in glucose uptake in the dogs with the endotoxin shock. The decreased responsiveness of the heart suggests that there is an insulin resistant state. A reason as to why insulin did not increase the heart's contractility during the shock can be that its response had already reached its highest potential. Another explanation can be due insulin interacting with agents, such as glucagon or catecholamines. Therefore, during endotoxin shock, the heart is not stimulated by insulin and glucose uptake decreases. (Law et al. 1988)

Potassium Channels, Cardiac Function, and Insulin Release

The review article by Sandhiya and Dkhar (Sandhiya and Dkhar 2009) explains that potassium channels have a vital function in cellular activity, smooth muscle contraction, hormone secretion, cardiac repolarization, and the release of insulin. An irregulation of potassium channels can cause cardiac problems associated with long QT syndrome and type 2 diabetes mellitus. There are potassium ATP channels in the heart that increase vasodilation, thus increasing blood flow to the heart. These potassium ATP channels are activated by substances such as nitric oxide and cGMP, and cause smooth muscle relaxation due to vasodilation of the heart. Thus, potassium channels are important in that they help in releasing insulin and increase blood flow to the heart. Scientists are studying to find effective drugs to cure various diseases which can occur because of any irregularity in potassium channels. (Sandhiya and Dkhar 2009)


Overall in reviewing all the studies and articles, insulin increases the contractility of the heart. Phospholipase C inhibitors can decrease any effect of insulin and thus decrease the heart's contractility. It was found that insulin activates a current flow that increases Ca2+ concentrations. This also causes an increase in contraction of the heart. Insulin was found to regulate the amount of substrates that reach the heart, and therefore affects the heart's activity. In healthy individuals, insulin increases myocardial flow, but does not affect individuals with Type I diabetes mellitus.

The role of diet showed a major effect of insulin, which ultimately affects the heart. Insulin decreases the concentration of free fatty acids, which prevents oxidation and an increase in heart contraction. Thus, the heart does not overwork and heart failure can be prevented. A diet with low fat and carbohydrate concentration is recommended. Increased glucose levels may cause diabetic cardiomyopathy, which can be controlled by insulin and insulin sensitizing agents, such as metformin. Another study showed that the heart and kidney are related and thus if the heart has any abnormalities, such as an increase in contractility, the kidneys can also be affected. Insulin can help prevent an increase in heart contraction, and thus can prevent any damage to the kidneys.

When an endotoxin shock was given to dogs, the action of insulin seemed to decrease. Thus, the heart was not able to increase its contraction. There were a couple explanations as to why this is the case. Finally, potassium channels in the heart play an important role and help to release insulin. If insulin is released, it can help to increase the contraction of the heart.