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The Interconnectedness of Type 2 Diabetes, Coronary Artery Disease, and Obesity

Connie L. Zeller

School of Nursing, James Madison University

NSG 461: Pathophysiology and Pharmacology

Dr. Robinson

April 1, 2021
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The Interconnectedness of Type 2 Diabetes, Coronary Artery Disease, and Obesity

The incidence of type 2 diabetes mellitus, coronary artery disease, and obesity is on the

rise. As these conditions lead to rising mortality rates and comorbidities, understanding them is

imperative to managing patient care. This paper aims to explore the pathophysiological causes

of each condition and overlapping processes, pharmacological treatment of each condition, and

relevant nursing implications in the care of these patients.

Disease Information

Pathophysiology (6 paragraphs max)

Type 2 diabetes mellitus results from the body’s impaired ability to respond to and

produce insulin leading to chronic hyperglycemia. Many factors and hormones contribute to

insulin resistance. Genetics, age, inactivity, and obesity all play a part in the development of the

disease, however obesity is especially related. McCance and Huether (2019) write obesity

creates an overabundance of white adipose tissue (WAT) which is responsible for the creation of

adipokine hormones adiponectin and leptin. However with obesity the creation of adiponectin

decreases while leptin increases. Adiponectin is an anti-inflammatory hormone which works on

the liver and muscle by increasing their insulin sensitivity (Forney-Gemano et al., 2018). With

lower levels of adiponectin, inflammation and insulin resistance rises. Leptin has been found to

lower the secretion and creation of insulin in pancreatic beta cells (Paz-Fihlo et al., 2012).

Thereby increased WAT reduces both insulin sensitivity and the beta-cells’ production and

secretion. During obesity, excessive free fatty acids build up in non-adispose tissue. This build

up between the cells causes insulin resistance and reduced insulin signaling (McCance &

Huether, 2019). According to Engin (2017), the fatty acid buildup in non-adipose tissue, like
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beta-cells, can cause lipotoxicity which leads to further beta-cell dysfunction and apotosis. Free

fatty acids are not the only elements released from adipocytes. McCance and Huether (2019)

write cytokines are released from WAT when macrophages infiltrate it. These cytokines cause

further systemic inflammation and interfere with insulin’s post-receptor mechanism and increase

resistance to it. Elevated levels of insulin resistance cause the beta-cells to work harder to meet

the body’s demands which leads to hyperinsulinemia and then beta cell exhaustion (McCance &

Huether 2019). The overworked beta-cells decrease in size and function as time goes on which

leads to reduced insulin production and exacerbates the problem. McCance and Huether (2019)

go on to explain how beta-cell dysfunction further exacerbates diabetes; the reduction in beta cell

function also reduces the amount of beta-cell hormone amylin. Amylin is responsible for

suppressing glucagon release. As it dwindles, the increased release of glucagon stimulates the

liver to break glycogen into glucose and contributes to hyperglycemia. Beta-cells also become

less responsive to the gastrointestinal incretins which are also involved in increasing the

production and secretion of insulin.

Systemically, the hyperglycemia and inflammation of type 2 diabetes create multiple

complications. The chronic overabundance of glucose causes damage to the kidney, nerves,

vasculature, and eye in several ways: oxidative stress with overproduction of free radicals,

permanent binding of glucose in irreversible glycation which produces damaging byproducts,

and sorbitol production. The nerves, kidneys, blood vessels, red blood cells, and parts of the eye

are all able to take in glucose without insulin; with hyperglycemia, these cells get overrun with

glucose (McCance & Huether, 2019). The cells turn to the polyol pathway as a means to process

the extra sugar resulting in sorbitol creation. Sorbitol causes swelling in tissues as osmotic

pressure draws water to it. This leads to vision problems with the shifting pressures. Sorbitol is
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responsible for causing diabetic neuropathies by Schwann cells, causing damage and

demyelination of the nerves, and disrupting conduction. This leads to the diabetic tingling and

loss of sensation as well as autonomic neuropathies (e.g. gastroparesis). Advanced glycation end

products (AGEs) also lead to systemic problems. When extra glucose permanently binds to

cells, blood vessels, and proteins, byproducts called AGEs are formed (McCance & Huether,

2019). When AGEs attach to receptors on the eye, kidney, and vessels they initiate damage in

many ways: influencing macrophages to release cytokines increasing inflammation, creating

oxidative stress through lipid oxidation, encouraging platelet clumping, fibrosis, and increased

cell production in the blood vessels thickening vessel basement membranes (McCance and

Huether, 2019). As they thicken, blood pressure in these small vessels of the eye, kidney, and

capillaries rises as they become occluded. Tissues become ischemic. Vascular damage is not

limited to the small vessels; the larger arteries and vessels are also damaged as these AGEs bind

to vessel wall receptors and encourage inflammation, thrombosis, and plaque formation.

Obesity is caused when excess adipose tissue accumulates in the body as calorie intake

exceeds what is required. As adipose tissue increases, hormone levels become imbalanced and

dysfunctional. As hormone levels imbalance, hunger, satiety, and metabolism centers in the

hypothalamus signaling loops stop working properly. As discussed, white adipose tissue (WAT)

produces and secretes adipokines which consist of cytokines and hormones (i.e. leptin and

adiponectin). As WAT increases, leptin increases and adiponectin decreases. Leptin levels serve

to balance appetite and energy usage. McCance and Huether (2019) describe the leptin and

neural signaling system; when levels are high and individual has fed, leptin works on the pro-

opiomelanocortin-producing peptide and cocaine-and-amphetamine-regulated transcript

(POMC/CART) neurons to signal the hypothalamus to lower appetite and spend more energy.
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When a person has not eaten and leptin levels are low, leptin instead works on the agouti-related

protein and neuropeptide Y (AgRP/NPY) neurons to conversely reduce energy spending and

increase appetite. With high levels of WAT, leptin levels are continuously elevated and the

signaling pathway becomes muddled and ineffective. This resistance to the high levels of leptin

causes the AgRP/NPY neural pathway to continue rather than turn off, increasing weight gain

and eating (McCance & Huether, 2019). Chronically high levels of leptin creates a state of

chronic inflammation, oxidative stress, insulin resistance, hypertension, the formation of

thrombosis (Gomes et al., 2010). Glucagon-like peptide 1 and peptide YY are both lowered

during obesity; these peptides are secreted from intestinal endocrine cells and lower appetite,

slows gastric motility. GLP-1 also increases energy use and stimulates insulin secretion.

Obesity leads to systemic changes in inflammation as the abundance of WAT is infiltrated by

macrophages and cause the release of cytokines. Low levels of adiponectin allows inflammation

to rise, reduces vascular protection, and leads to plaque formation. This atherosclerosis leads to

CAD, stroke, and hypertension. Excess amounts of fats circulating in the obese also leads to

fatty liver disease and dyslipidemia (McCance and Huether, 2019).

Coronary artery disease involves the narrowing and buildup of fatty plaques in the

arteries responsible for perfusing the heart muscle. If plaques build up to cause blockages,

myocardial ischemic occurs. According to Gomes et al. (2010), endothelial dysfunction marks

the beginning of coronary arteriosclerosis. This, once again, is influenced by adipokines and

inflammation. The adipokine tumor necrosis factor alpha (TNF-a) encourages endothelial

dysfunction by reducing cells’ ability to interact with nitric oxide. Nitric oxide allows

vasodilation; the inability to properly use it results in the vessel being unable to relax. Adipokine

angiotensinogen is a building block of angiotensin II (McCance & Huether, 2019). Angiotensin

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II levels increase with the amount of adipose tissue. Elevated angiotensin II creates further

oxidative stress and inflammation, increasing atherosclerosis. Gomes et al. (2010) write the free

radicals associated with angiotensin II further decrease vascular tissue access to nitric oxide and

damages the vessels. These damaged and inflamed vessels have lesions that low density

lipoprotein binds to, becomes oxidized, and attracts large amounts of macrophages that form

streaks of fat (McCance & Huether, 2019). These macrophages then release more cytokines

inflaming and damaging the wall of the vessel and perpetuating the process. Gomes et al. (2010)

describe C-reactive protein as an adipokine that directly causes plaque formation. In a table

outlining the vascular complications caused by adipokines, C-reactive protein is shown to

increase smooth muscle cell numbers causing narrowing of the vessel’s diameter while also

increasing the accumulation of cholesterol to endothelial cells. The higher the amount of C-

reactive protein in the blood, the higher the inflammation and plaque formation (McCance &

Huether, 2019).

Analysis

These three conditions are interrelated by chronic inflammation causing cellular damage

and perpetuating further inflammation. This inflammation is caused by adipokine imbalances in

obesity, hyperglycemia, and oxidative stress. Inflammatory cytokines are released by

macrophages in infiltrated adipose tissue, macrophages bound by AGEs, high levels of leptin,

and cellular damage. AGEs also bind to lipids to increase lipid oxidation which in turn creates

oxidative stress, damage, and more inflammation. The polyol pathway of hyperglycemia

reduces antioxidant levels by degrading glutathione, contributing to more free radicals and

oxidative stress injuries in the tissues (McCance & Huether, 2019). Adiponectin’s anti-

inflammatory, vascular and cardiac protecting properties are lost in obesity due to decreased
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release of cytokines that reduce its production (Gomes et al., 2010). Chronic inflammation and

oxidative stress lead to the endothelial dysfunction, vascular lesions, and plaque formation which

increases the prevalence of CAD, stroke, and myocardial infarction.

Treatment of the Disease

Pharmacologic Treatment

The pharmacologic treatment for diabetes mellitus type 2 consists of oral antidiabetic

drugs and insulin. While there are multiple oral antidiabetics (biguanides, sulfonylureas, alpha-

glucosidase inhibitors, incretin mimetics/enhancers, thiazolidinediones, and meglitinides),

metformin is typically the first choice to treat type 2 diabetes (McCance and Huether, 2019).

Metformin is a biguanide antidiabetic with a threefold mechanism of action: increases tissue

insulin sensitivity, inhibits the liver’s glucose production, and lowers glucose absorption in the

intestines (Vallerand et. al, 2014). Typical dosage is 500mg twice a day; patients may

experience gastrointestinal upset. Metformin may be damaging to the kidneys, so monitoring of

kidney function is desired. If the patient is to have imaging done using contrast dye, metformin

must be held for 48 hours (Robinson, 2021). When oral antidiabetics fail, insulin is initiated.

Insulin is an antidiabetic that acts to transport glucose into the cells, lower blood glucose levels,

inhibits the liver’s breakdown of glycogen, and stimulates the synthesis of glycogen (Vallerand

et al., 2014). Dosing schedule will depend upon the type and duration of action: insulin lispro

(short duration and rapid acting), regular insulin (short duration and slower acting), neutral

protamine Hagedorn insulin (intermediate duration), and insulin glargine (long duration). Insulin

lispro and regular insulin are of short duration and used to control blood glucose spikes

following meals; these are typically administered with meals (Robinson, 2021). Longer-acting

insulin may only be used once a day. It is important to follow the physician’s direction. Adverse
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effects include hypoglycemia, so patients must be educated on monitoring their blood glucose

prior to administration.

Obesity is usually treated with diet and exercise, however there are a few medications in

use. McCance and Huether (2017) state that antidiabetic GLP-1 receptor analogs have been

shown to treat obesity as well as type 2 diabetes; these drugs suppress appetite, prolong gastric

emptying, and increase energy spending. The typical dosing schedule is 100mg daily; the most

prominent adverse effect is pancreatitis, and the patient should notify the physician of severe

abdominal pain (Vallerand et al., 2014).

Coronary artery disease is typically treated with pharmacologic salicylates. Daily, low-

dose aspirin inhibits the production of prostaglandins reducing inflammation and decreases

platelet aggregation (Vallerand et al., 2014). Statins are HMG-CoA reductase inhibitors used to

lower cholesterol and inflammation (Goldfine & Shoelson, 2017). The drug inhibits the enzyme

HMG-CoA which is responsible for the beginning of cholesterol synthesis; atorvastatin is

regularly prescribed and usually is initiated at 10-20mg daily but may be increased up to 80mg if

needed (Vallerand et. al, 2014). Frequent adverse effects may include GI upset and muscle pain,

and the patient should be educated to notify their doctor if is accompanied by fever or malaise.

The shared pathophysiologic mechanism of inflammation is reduced across the board

while pharmacologically treating these three conditions. As outlined above, aspirin inhibits

prostaglandins which reduces inflammation. According to research by Goldfine and Shoelson

(2017), statin therapy implementation was shown to reduce C-reactive protein inflammation

markers by 13% to 50%. Metformin, Goldfine and Shoelson (2017) also write, is shown to

reduce inflammation and C-reactive protein in patients with type 2 diabetes. While these drugs
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are not likely to fully negate all inflammation, reduction will help slow pathogenesis and

complications.

Role of the Nurse

Nursing care for these patients should focus on education and assist the patient on a path

that is patient centered. Diabetic patients participating in religious fasts need to understand that

their medication dosages may need to be adjusted and glucose monitored more frequently.

Healthy diet that is low in sodium and unhealthy fats should be encouraged while remembering

possible religious accommodations to animal products. While assessing a female patient,

determine if she has the “apple” shaped central obesity rather than the more common peripheral

“pear” shape, and educate her on the increased risks associated with it. Across all genders, races,

and lifestyles, encourage exercise as appropriate for their fitness level. This is especially

important for black and Hispanic ethnicities with the highest percentages of obesity (McCance &

Huether, 2019).

Conclusion

As shown in this paper, these three conditions are interwoven by chronic inflammation.

The inflammation, caused by oxidative stress, imbalanced adipokines, activated cytokines,

hyperglycemia, hyperinsulinemia, and dyslipidemia found in obesity and type 2 diabetes

promotes vascular damage perpetuating to coronary artery disease. Pharmacologic treatment of

these conditions with has been found to lower inflammation and slow disease progression. As

obesity, diabetes, and CAD rates rise, particularly among minorities, nurses must stress the

importance of healthy diet, physical activity, and close monitoring to reduce comorbidities and

mortality.
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References

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Forny-Germano, L., De Felice, F., & Vieira, M. (2018). The Role of Leptin and Adiponectin in

Obesity-Associated Cognitive Decline and Alzheimer’s Disease. Frontiers in

Neuroscience, 12, 1027–1027. https://doi.org/10.3389/fnins.2018.01027

Gomes, F., Telo, D., Souza, H., Nicolau, J., Halpern, A., & Serrano, J. (2010). Obesity and

coronary artery disease: role of vascular inflammation. Arquivos Brasileiros de

Cardiologia, 94(2), 255–261.

McCance, K., & Huether, S. (2019). Study guide for pathophysiology: the biological basis for

disease in adults and children (8th ed.). Mosby.

Paz-Filho, G., Mastronardi, C., Wong, M. L., & Licinio, J. (2012). Leptin therapy, insulin

sensitivity, and glucose homeostasis. Indian Journal of Endocrinology and Metabolism,

16(Suppl 3), S549–S555. https://doi.org/10.4103/2230-8210.105571

Robinson, J. (2021). Alterations in endocrine [PowerPoint slides]. Canvas@JMU.

https://canvas.jmu.edu/courses/1777916/pages/endocrine?module_item_id=26713385

Vallerand, A., Sanoski, C., & Deglin, J. (2014). Davis’s Drug Guide for Nurses (14th ed.). F.A.

Davis Company.