Type 2 Diabetes Mellitus (T2DM) denotes a metabolic disorder typified by hyperglycemia attributed to inadequate insulin production and insulin resistance. T2DM accounts for 90 percent of diabetes incidence and is especially prevalent among the older. In the US alone, approximately 27 million have been diagnosed with T2DM whereas an additional 87 million have abnormal blood glucose that is not high enough to be considered as diabetes (pre-diabetes). This paper discusses the pathophysiology of T2DM, genomic issues associated with the disease, and treatment options.
Pathophysiology of T2DM
T2DM is typified by either the body producing insufficient hormone insulin (inadequate/impaired insulin secretion) or the bodily cells being unable to respond to insulin (insulin resistance). Understanding the pathophysiology of T2DM requires understanding the process of normal blood sugar regulation. Glucose is a crucial energy source for the human body. Carbohydrates are the primary source of glucose, which is often broken down into glucose for use by various bodily cells. Moreover, the glycogen stores found in the liver can also produce glucose. In a healthy individual, an increase in the level of blood sugar following a meal causes the secretion of insulin by the beta cells in the pancreas. In turn, insulin triggers the uptake of blood glucose by bodily cells. Besides, insulin helps in glucose conversion to glycolysis to discharge energy, converse surplus glucose for storage in the form of glycogen, and facilitate the uptake as well as a synthesis of fat, proteins, and amino acids.
In T2DM, impaired insulin secretion and insulin resistance work jointly to create pathophysiological conditions necessary for the disease to develop. Impaired insulin secretion is characterized by a decline in the responsiveness of glucose, which often precedes the clinical manifestation of T2DM. Impaired insulin secretion often progresses resulting in lipo-toxicity as well as glucose toxicity, which in turn leads to an impairment of the pancreatic cell function. As a result, the long-term control of blood glucose is affected. Whereas patients during early T2DM stages exhibit an increase in blood glucose due to high levels of insulin resistance and reduced insulin secretion, the gradual worsening of the pancreatic cell function results in a permanent increase in the levels of blood glucose.
Insulin resistance is typified by insufficient insulin action relative to the blood sugar concentration. The impaired insulin action in body organs like muscles and liver is a typical pathophysiological attribute of T2DM. Insulin resistance usually develops and increases before the clinical onset of T2DM. The combined effect of insulin resistance and impaired insulin secretion is an increase in blood glucose levels. In addition, there is a significant reduction in glycogen stores, resulting in less glucose being available for secretion when required. With the increase in blood sugar levels, the beta cells in the pancreas are supposed to produce more insulin; however, since they are impaired, they are unable to discharge adequate insulin to satisfy the demands of the body.
The age continuum also has implications for T2DM. In this regard, the risk for T2DM increases with an increase in age. Although the primary mechanisms through which diabetes increases with aging is not precisely understood, it has been suggested that aging results in an increase in insulin resistance because of the decrease in lean muscle mass, lower physical activity, an increase in adiposity, and alterations in dietary behavior. Nevertheless, it has been reported that these aforementioned factors alone do not explain the age-related impaired insulin secretion and glucose intolerance. One of the possible reasons suggested for age-related T2DM is the reduced proliferation of the beta cells as well as the increased apoptosis of the beta cells. The mechanisms that can be used to explain the reduced proliferation of beta cells include the increase in the aggregation of amylin, the reduced expression of pdxl, the increase in the expression of the cell cycle inhibitors, and the reduced expression of activators of cell cycles. It is evident that aging is associated with T2DM because it worsens pathophysiological conditions associated with the disease.
Genomic Issues Inherent for T2DM
Although it is well-known that T2DM has a significant genetic component, only a few particular genes have been recognized as playing a role in the development of the disease. Nevertheless, several genes have been suggested as potential candidates. Moreover, little is known regarding the number of genes that take part in the development of T2DM. Few research groups have suggested the potential gene regions that play a role in the genetic risk of T2DM in diverse populations. Studies have shown that in the Western world the lifetime risk for the disease is about 10 percent, first degree relatives of diabetic individuals have a risk of about 20-40 percent, whereas the risk for identical twins ranges about 57-90 percent among male twins. Progress in genotyping techniques, as well as the availability of large cohorts of patients, has been instrumental in identifying common genetic variants associated with T2DM via the genome-wide association studies (GWAS). As of 2012, at least 36 genes were established to increase the T2DM risk. However, all these genes combinations explain only 10 percent of the total genetic aspect of T2DM. GWAS studies have outlined some genetic variants linked to insulin resistance and the function of beta cells. Some of the genetic variants include TCF7L2, which lowers the responsiveness of beta cells; GCK, DGKB, FADS1, and MTNR1B, which lower the release of insulin; and FSADS1, which alters the metabolism of fatty acids. Other genetic variants linked to T2DM include WFS1, SCL30A8, HHEX, KCNJ11, PPARG, IGF2BP2, and FTO among others.
The sources for the literature review have been obtained through a search of various electronic databases, including Google Scholar, Cumulative Index to Nursing and Allied Health (CINAHL), Global Health, GoPubMed, HubMed, MedlinePlus, PubMed, Pubget, Science Direct, and SpringerLink. A number of search phrases have been used, including “type 2 diabetes mellitus,”, “pathophysiology of type 2 diabetes mellitus,”, “treatment of diabetes mellitus type 2,”, “genetics of type 2 diabetes mellitus,” and “age-related type 2 diabetes mellitus”. In addition, a complimentary search of the web has been performed to locate any reports published by well-known professional organizations concerned with diabetes such as the American Diabetes Association. The search has yielded numerous peer-reviewed papers, after which they have been filtered to leave recent publications not older than seven years. The findings of the literature review are presented in the following subsections.
Basics of T2DM
T2DM comprises of numerous dysfunctions typified by hyperglycemia attributed to a combination of impaired insulin secretion, insulin resistance, and excessive secretion of glucagon. T2DM that is poorly managed usually results in veracious neuropathic complications affecting the peripheral and autonomic nerves; macro-vascular complications such as peripheral vascular and coronary artery disease; and micro-vascular complications such as renal and retinal disease. Contrary to patients having type 1 diabetes mellitus, patients with T2DM are not completely dependent on insulin in the course of their lifetime. Nevertheless, the majority of T2DM patients are eventually treated with insulin. Owing to the fact that T2DM patients have the ability to produce some amounts of endogenous insulin, they are perceived to need insulin although they are not dependent on insulin. Despite the fact that T2DM is prevalent in the adult population, the increasing prevalence of physical inactivity and obesity among children has resulted in the disease starting to occur at younger ages.
T2DM is a chronic illness that needs long-term medical care in order to prevent the patient from developing life-threatening conditions, as well as manage these conditions in the event that they occur. Moreover, T2DM is a relatively expensive disease with the direct medical costs of the disease in the US totaling about $116 billion annually. Statistics show that medical expenses for diabetic individuals are 2.3 times higher than for those who do not diabetes. Moreover, visits to emergency departments by diabetic individuals double expenses of people who are not diabetic. In other words, diabetes needs long-term costly care.
The etiology of T2DM entails multifaceted interactions between genetic and environmental variables. T2DM often develops following the superimposition of a diabetogenic lifestyle such as obesity, excessive calorie consumption, and inactivity on a predisposing genotype. Studies have identified various risk factors for T2DM. One of the risk factors associated with T2DM is obesity; in this respect, surveys have shown that 90 percent of people with T2DM have obesity. Low birth weight has also been identified as a risk factor for developing T2DM. Evidence shows that infant weight has an indirect impact on insulin resistance in the course of adulthood and this relationship is mediated through the effect of infant weight on waist circumference and body mass index (BMI). Aging is also a risk factor for developing T2DM. With regard to this, being older than 45 years is a risk factor for the disease; however, the incidence of T2DM is also increasing among the young population. Another risk factor for the disease is a family history, especially in the first degree relative such as a sibling or a relative. Individuals from some ethnicities such as Pacific Islanders, Asian Americans, African Americans, Native Americans, and Latinos have a higher predisposition to T2DM. Other risk factors include polycystic ovarian syndrome, previous gestational diabetes, delivery of a baby with a birth weight that exceeds 9 lb., previous impaired fasting glucose (IFG), previous impaired glucose tolerance (IGT), hypertension, and dyslipidemia. The following subsection discusses treatment approaches for T2DM.
Treatment of T2DM focuses on eliminating symptoms, as well as preventing and slowing down the development of potential complications associated with the disease. Although T2DM has no cure, it can be managed through three treatment approaches, which include lifestyle interventions, pharmacological approaches (medications), and surgery. These treatment approaches are described in the subsections below.
Lifestyle interventions place emphasis on physical activity, weight control, and diet. There is a widespread agreement in the literature that lifestyle modification is the foundation of diabetic treatment and care, especially physical exercise, which has been documented to yield better results. The core attributes associated with lifestyle interventions include eating a healthy balanced diet, losing weight for overweight diabetics, and regular physical activity. With regard to physical activity, aerobic exercise has been found to reduce the levels of glycated hemoglobin and result in significant improvements in insensitivity to insulin. Moreover, resistance training has also been found to be helpful for diabetic individuals. Evidence-based guidelines for physical activity recommend at least 30 minutes of aerobic exercise during most days of the week. Strength training and stretching are also recommended. Moreover, guidelines recommend combining exercises such as aerobic exercises (dancing, walking, and running) with resistance training (yoga and weight lifting). Combining exercises has been found to be more effective in controlling blood sugar levels as compared to using a single exercise type. Furthermore, since physical activity reduces the levels of blood sugar, it is a good practice to check one’s level of blood sugar before exercising.
A healthy diet plays an important role in losing weight. Although there is no specific diet for diabetic individuals, it is recommended to consume low-fat and high-fiber foods such as whole grains, vegetables, and fruits. The intake of animal products, sweets, and carbohydrates should be reduced. Studies have also shown that foods with low glycemic index and low carbs can enhance the control of blood sugar. If lifestyle interventions do not improve the levels of blood sugar within six weeks, the patient can consider medications. There is scant evidence suggesting that lifestyle interventions lower the mortality of diabetic individuals.
Pharmacological Approaches – Medicine and Insulin Therapy
Not all diabetic individuals can accomplish their target levels of blood sugar using lifestyle interventions. As such, insulin therapy or medications may be required. Numerous anti-diabetic medications exist in the market. The medication prescribed depends on the current level of blood sugar and the existing health conditions of the diabetic patient. The physician can prescribe a mix of medications from various classes to help control the level of blood sugar through various mechanisms. The first choice of medication is Metformin, which functions by enhancing insulin sensitivity in order to ensure the effective use of insulin by the body tissues. Moreover, Metformin reduces the amounts of glucose that the liver produces. This drug does not work in isolation and should be accompanied by physical activity and weight loss. Empirical evidence affirms to show that Metformin reduces mortality. Other medications can be prescribed in the event that Metformin is not effective in achieving the target blood sugar levels such as sulfonylureas, thiazolidinediones, meglitinides, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and insulin therapy. Surgical treatment is the next option in case medications do not work.
Bariatric (weight loss) surgery has been found to be an effective treatment for diabetes for those having excess weight. After surgery, many diabetic individuals are capable of controlling their blood sugar levels with little help from medications. Nevertheless, bariatric surgery has a short-term mortality risk of 1 percent. Moreover, the BMI threshold for surgery is yet to be established. This option is recommended as the last resort for those who are unable to control their blood sugar levels and weight.
The treatment choice for T2DM is lifestyle intervention. The rationale for this choice is the fact that physical activity and a healthy diet have been recognized as the cornerstone of diabetes treatment. Moreover, lifestyle interventions are the preferred treatment choice because of the crucial role it plays in alleviating risk factors such as obesity and hypertension. Other treatment options only target T2DM whereas lifestyle intervention focuses on risk factors, which makes this treatment approach an important aspect of primary prevention of T2DM.
Monitoring sugar levels is a crucial component of diabetes treatment. Since lifestyle interventions can be implemented in home settings, follow-up care helps in ensuring adherence to the treatment plan. The focus of the follow-up treatment should be on monitoring progress with regard to controlling blood sugar. A number of tests exist for monitoring blood sugar levels such as the HbA1c test, which is performed every 2-6 months. In addition, lifestyle interventions require the involvement of dieticians and physical exercise specialists in the treatment plan. In this regard, the patient is recommended to work closely with a physical exercise specialist and a dietician.
Insulin resistance and impaired insulin secretion work jointly to create pathophysiological conditions for the development of T2DM. GWAS has affirmed the crucial role that genetic markers play in the onset of T2DM together with environmental variables. With respect to treatment, the emphasis is on eliminating the symptoms, preventing, and slowing down the development of potential complications associated with the disease. In this respect, three treatment approaches exist, which include lifestyle interventions, pharmacological approaches (insulin therapy and medication), and bariatric surgery. Lifestyle interventions should be the first line of defense, being followed by pharmacological approaches and then surgery.