Diabetes Mellitus (DM) is a chronic disease that is highly prevalent and growing in prevalence around the world, associated with high morbidity and mortality, as well as a significant decrease in quality of life for people suffering from it (Murray, Vos, Lozano et al., 2012).
DM has become one of the most serious health problems of our time. This is a pathology that may become, in addition to obesity, one of the largest epidemics of the 21st century.
246 million people are currently estimated to be affected by this disease around the world. If this figure continues to grow at its current rate, it may reach 380 million in 2025.
In Spain, following the natural course of the disease, around 4.6 million people over the age of 18 suffer from Diabetes Mellitus Type 2 (DMT2).
Due to its complications, DM is one of the leading causes of blindness, amputations, and end-stage renal disease in developed societies, while it is one of the leading risk factors for suffering from cardiovascular disease (ADA, 2013).
Considering all of the costs (direct medical costs, personal care, professionals, transport, lost productive capacity), the total cost per patient suffering from DM vacillates between €873 and €13,584 per year (American Diabetes Association, 2012).
In Spain, DM entails a total direct cost of €5.89 billion, entailing 8.2% of total medical costs, a figure highly impactful on the domestic economy (Crespo, Brisa, Soria, López, and Soria, 2013).
However, in order to understand DM, one must understand the mechanisms generated by this disease. The role of insulin, then, must be discussed.
Insulin is a hormone released by beta cells in the pancreas, which is responsible for storing and releasing energy while eating and fasting, functions that are essential to the development and survival of human beings.
This hormone is secreted in response to high levels of nutrients in the blood, controlling critical energy functions such as glucose and lipid metabolism.
Once the insulin is been secreted, it will bond with the glucose molecules and use them to be transported so that they can be used as a cellular energy source (Illustration 1).
There are several reasons why insulin may not be able to do its job:
- It is not present in the body.
- It is in the body, but in an insufficient amount (a common effect of the aging process).
- The body is not able to use it correctly, despite having a sufficient amount.
This inability to use insulin for whatever reason is the basis for the pathology known as DM.
So, what is DM?
Echoing the definition provided by the WHO in 1999, DM is a metabolic disorder of multiple aetiology characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both.
There are diseases that only have a local effect, but there are others with a more general effect on the system, compromising the body as a whole.
DM is one of the greatest exponents of this kind of disease.
Are all DM types equal?
According to the classification made by the American Diabetes Association in 2014, DM can be classified into four clinical categories:
- Type 1 Diabetes
- Type 2 Diabetes
- Gestational Diabetes Mellitus
- Diabetes due to other causes
Despite not being the most frequent type of DM (only 5% to 10% of cases), it is a chronic pathology with a great deal of short and long term implications, mainly due to its early onset compared to DMT2 (Danese, 2006).
DMT1 involves a destruction of beta cells in the pancreas, leading to an insulin deficiency.
There are, in turn, two types of DMT1: autoimmune and idiopathic.
This type makes up 90-95% of cases of DM. It affects individuals who show either insulin resistance or a relative deficiency (Dabelea, Mayer Davis et al., 2014).
As can be noted, in this type of DM there is no destruction of beta cells, especially at the beginning. However, some patients do not require additional insulin to control their diabetes. That is why DMT2 was recognized as non-insulin-dependent diabetes (ADA, 2016).
The risk of having DMT2 increases with age, obesity, and sedentary lifestyle. It is also correlated with people with hypertension and dyslipidemia.
Developing DM2 seems to involve a large number of mechanisms, many of them still unknown, but it does seem that the basis of this pathology is insulin resistance in peripheral tissues along with a gradual reduction of the function of pancreatic beta cells, which lead to the secretion of deteriorated insulin and to hyperglycemia, the distinctive characteristic of DM2, among other metabolic conditions.
This is defined as any level of glucose intolerance whose first symptoms appear during pregnancy, regardless of whether or not they persist afterward (7 Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997).
However, this definition is not entirely accurate given the amount of excess weight and obesity and the increase in the percentage of undiagnosed DMT2. Therefore, DM testing should be carried out on women who show DMT2 risk factors when they go to a consultation about a potential pregnancy (Lawrence, Contreras, Chen, and Sacks).
Other forms of DM
There are other less common forms of DM such as:
- Monogenic diabetes: Caused by beta cell dysfunction, these forms of diabetes are characterized by the presence of hyperglycemia before the age of 25 (neonatal diabetes and diabetes in children), representing 5% of patients with diabetes (Rubio Cabezas et al., 2014).
- Cystic fibrosis-related diabetes: This involves greater comorbidity for patients suffering from cystic fibrosis, affecting 20% of adolescents and 40-50% who have it (Moran et al., 2010).
How do I know if I have diabetes?
Common symptoms of chronic hyperglycemia include:
- Polyuria (frequent urination)
- Polydipsia (feeling thirsty all the time)
In some cases, polyphagia (feeling hungry all the time)
Can DMT2 be prevented?
There are two types of risk factors that can influence the appearance of DMT2: Non-modifiable and modifiable.
Non-modifiable risk factors.
- Age: Especially after 50, the prevalence of DMT2 increases and it exceeds 20% at age 80 (Paulweber et al., 2010).
- Race: Caucasian people have the lowest risk, while Hispanic, Asian, and Black people are at higher risk, in addition to seeing faster development of the disease (Mediavilla, 2001).
- Family history in first-degree relatives: If one parent has the disease, the patient is 2.5 times more likely to get it; this increases to 5-6 times if both parents have it (McCulloch and Robertson, 2015).
- History of Gestational DM: These women have a risk seven times greater than women who showed normal levels of glucose during pregnancy (Bellamy, Casas, and Williams, 2009).
- Polycystic ovary syndrome. An estimated 40% of women who have this condition show glucose regulation alterations (Lua, How, and King, 2018).
- Modifiable risk factors.
- Obesity and excess weight: These increase the risk of developing glucose intolerance and DMT2 at all ages, as they provoke an increase in insulin resistance. Over 80% of DMT2 cases are attributed to these factors. In fact, a decrease in obesity and excess weight causes improved glucose control in diabetic patients (McLaughlin et al., 2018).
- Sedentary lifestyle: This causes a decrease in energy expenditure and weight gain. Moderate physical activity decreases the appearance of new cases of DMT2.
- Recent studies indicate that both obesity and physical inactivity contribute separately to the development of DM2 (Hamman et al., 2006).
- Smoking: Smoking, both actively and passively, causes an increased risk of having DMT2. It should be noted that in order to have the same risk of having DM as a non-smoker, a smoker must have quit smoking 20 years prior (Pan et al., 2015).
- Eating habits: High consumption of red and processed meats, sweetened drinks, sweets, and high-fat dairy products is associated with a higher incidence of DMT2 compared to diets based on vegetables, fruit, fish, poultry, and whole grains (McCulloch et al., 2015).
- Heart disease: Like high blood pressure, coronary disease, stroke, and advanced heart failure increase the risk of having DMT2.
- Use of medication: Such as atypical antipsychotics, glucocorticoids, and oral contraceptive pills, among others.
- Other factors: Having a high or low birth weight and being born prematurely are linked to greater risk of DMT2 throughout life, while breastfeeding is considered a protective factor (Kaul et al., 2018).
What will happen if it goes untreated?
There are two types of complications: acute and chronic.
- Acute complications of DM.
- There are different disease entities that involve an acute complication in cases of diabetes:
- Hypoglycemia: This is the most common complication affecting diabetics with both type 1 and insulin-dependent type 2 (ADA, 2014). This involves a concentration of glucose in venous blood below 60 mg/dL or below 50 mg/dL in capillary blood. Depending on the degree, symptoms may vary from anxiety, restlessness, tachycardia, sweating, hunger, blurred vision, and dizziness in light hypoglycemia to confusion, inappropriate behavior, or even loss of consciousness in more advanced phases.
- Hyperglycemia: This involves glucose levels above 200 mg/dL. Not identifying the causes may trigger more serious diseases, such as diabetic ketoacidosis or hyperosmolar hyperglycemic state (SEMERGEN, 2001).
- Diabetic ketoacidosis: This is a complication that generally affects DMT1 patients and is usually brought on by infectious diseases or errors in insulin administration. It occurs as a result of hyperglycemia above 300 mg/dL, ketonemia with a total presence of ketone bodies in the blood above 3 mmol/l, acidosis with a pH below 7.3 and a serum bicarbonate below 15 mEq/l (SEMERGEN, 2001). Its onset is usually less than 24 hours and gradual, showing a large number of symptoms at the systemic level that range from polyuria (abundant excretion of urine), polydipsia (thirst), weight loss, anemia, ketotic breath, nausea, vomiting, deep and rapid breathing (Kussmaul), dehydration and even shock, head ache, lethargy, stupor, leading to coma.
- Hyperosmolar hyperglycemic nonketotic syndrome: This is a syndrome characterized by severe hyperglycemia, hyperosmolarity, and dehydration in the absence of ketoacidosis. This is the most severe form of insulin resistance, causing the underutilization of glucose and a resulting excess formation thereof (Remuñán and Álvarez, 2001). This is a rare pathological state mainly affecting DMT2 patients, and it has a mortality rate 10 times higher than ketoacidosis.
- Lactic acidosis: Rare condition resulting from the accumulation of lactate and protons in bodily fluids as a result of hypoxia.
Chronic complications of DM.
Chronic complications of DM are classified as:
- Macrovascular: These complications mainly affect the arteries. It is equivalent to atherosclerosis causing, among other things, coronary heart disease, cerbrovascular disease, and peripheral arterial disease. Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct costs of diabetes (ADA, 2016).
- Microvascular: With age, glycosylated proteins build up in everyone. These proteins appear especially frequently in diabetic patients and especially in those with chronic hyperglycemia. They accumulate in the crystalline lens of the eye, retinal and glomerular capillaries, and in the protein component of the myelin in the peripheral nervous system, causing, among other things, ertinopathy, nephropathy, and neuropathy.
- Diabetic foot: More than a condition itself, this is a product of neuropathy (nerve damage) and vascular affectation of macroangiopathic origin. In 1997, SEMERGEN defined diabetic foot as “an ethopathogenic neuropathic clinical alteration induced by chronic hyperglycemia that causes an injury and/or ulcer in the foot, with or without the coexistence of ischemia or prior traumatic trigger.” For many patients this entails large wounds on their feet and long recoveries, and in many cases the amputation of the affected foot.
Can it be treated?
Insulin is the pharmacological treatment used on patients with diabetes mellitus type 1. The following should be considered in the use of said medication as they influence expected results, such as normoglycemia.
These considerations include the form of administration (subcutaneous injection), the right selection of needles and syringes for administration, the right places for injection, the combination of insulins, and the right dose.
All of these factors will influence the appearance of chronic hypoglycemia, despite the attempts made by healthcare professionals who work hand in hand with patients to streamline all of the aspects involved in the treatment of diabetes and ensure the best possible control of blood sugar.
- Despite the pharmacological developments in insulin, the appearance of the above-mentioned complications resulting from insufficient and non-physiological control of hyperglycemia cannot be fully prevented.
- There are several types of insulins. Rapid-acting, short-acting, intermediate-acting, and long-acting insulins are available.
- Insulin lispro: Rapid-acting or ultra-short insulin. It has a faster-acting onset (<15 minutes), an earlier peak in blood sugar reduction (30 to 60 minutes), and a shorter duration (3 to 4 hours). This means that lispro should be administered 15 minutes before eating.
- Regular insulin: Short-acting insulin. This is the only insulin that can be administered intravenously; the other types are suspensions and may be harmful if administered this way. Used to start treatment of newly-diagnosed cases of DMT1, and in combination with intermediate-acting insulins to better control blood sugar.
- Intermediate and long-acting insulins: The onset, peak, and duration of the insulin can be modified by adding acetate and protamine buffers. Zinc and protamine are added to NPH insulin to prolong its duration (Figure 1).
- Insulin glargine: It is similar to human insulin with a long-acting duration of 24 hours administered subcutaneously once per day, generally when the patient is going to bed, in order to treat patients with both DMT1 and DMT2. It has a relatively constant effect, i.e., it does not peak (Lemon, 2009).
The treatment objective for patients with DMT2 is metabolic control allowing complications to be controlled in the short and long term and to maintain quality of life, based on three fundamental aspects:
1) Pharmacological treatment
2) Physical activity
3) Healthy diet (ADA, 2011)
Particularly with regard to pharmacological treatment, it has been identified that initial medical treatment is based on monotherapy with oral hypoglycemic drugs. However, metabolic control is seldom achieved (Sánchez-Millagón, 2011).
There is currently a wide range of treatment options for DMT2 patients, including metformin, sulfonylureas, glitinides, thiazolidinediones, disaccharidase inhibitor (IDPP-4), and glucagon-like peptide 1 receptor antagonists (GLP1), which along with insulin may be used in monotherapy or in association.
These medicines must be used after reviewing their respective fact sheets. The choice depends on the consideration of a number of aspects with regard to the patient’s characteristics, the strength of the medicine to achieve the therapeutic objective, the complications or associated illnesses, the risk of adverse effects, tolerance, and cost (Menéndez Torre et al., 2010).
This scenario has favored the combination of hypoglycemics, without achieving the desired results, a situation that increases the likelihood of developing chronic complications. (García, 2011). Nevertheless, scientific evidence has demonstrated that treatment based on insulin is the best option for achieving metabolic control. There are reports indicating this (López, 2011).
Other than pharmacological treatment, complementary treatment focused on physical activity and diet must be explored to help to maintain and control blood sugar levels. As a result, healthcare professionals must have good diabetes education.
Diet is one of the key elements to ensuring good metabolic control.
It should provide the energy and nutrients necessary to maintain an appropriate body mass index.
It should prevent the appearance of hypoglycemia and hyperglycemia. Insulin must be adapted to the appetite and habits of the patient.
The patient’s cultural, ethnic, and family characteristics must be respected. Healthcare professionals should not lose sight of the objective of maintaining and preserving the patient’s quality of life and environment.
There are no prohibited foods for diabetics. Some foods, such as sweetened drinks, should be consumed sparingly and they should be considered when calculating insulin units. Others should be eaten frequently so as to consume foods rich in fat and protein to slow gastric emptying.
One should avoid being excessively dogmatic or trying to impose a method that is too difficult for the patient and their day to day life. Metabolic control allows us to confirm the success of the method used.
Offering advice on how to reduce consumption of processed foods and encouraging patients to learn to cook with fresh ingredients is important.
The distribution of nutrients is practically the same as that recommended for any adult:
- Carbohydrates: 50-55%
- Fats: 30-35%
o Less than 10% saturated fat and trans fat
o Less than 10% polyunsaturated fat
o Less than 10% monounsaturated fat (up to 20% of total energy intake)
- Proteins: 10-15%
- Fiber: 3 g/250 kcal of total daily energy intake (between 15 and 30 g/day)
Healthy foods like wholewheat bread, grains, legumes, fruit, vegetables, and skim or low-fat dairy products. Moderate consumption of sucrose (up to 10% of total).
Another important point in good blood sugar control is physical exercise, as it has positive health impacts such as reducing cardiovascular risk, contributing to weight control, and providing a feeling of well-being.
Regular exercise is recommended for patients with diabetes as it reduces the risk of developing macrovascular complications. Exercise should be taken into account when calculating the amount of carbohydrates the patient will consume and the insulin they will administer because exercise increases their sensitivity to insulin, however it also increases the synthesis and release of counterregulatory hormones, which tends to reduce sensitivity to insulin.
Daily physical exercise is easier to manage and incorporate into habitual treatment routines. Ideally, aerobic exercise should be done daily with the same schedule and intensity. In order to control and, in fact, take advantage of the changes that exercise causes in the body, two things must be considered with regard to metabolic control: carbohydrate consumption and insulin administration, depending on the kind of exercise.
Especially when exercise is not regular, measuring blood sugar levels before and after exercising is helpful, as well as considering these levels when making new determinations in the following 12-24 hours, as they may also be affected by the exercise. Blood sugar levels may also need to be tested while exercising if the physical activity is prolonged or symptoms of hypoglycemia appear.
When levels are not tested and ketone bodies are present, exercise may increase blood sugar or accelerate ketoacidosis. Therefore, when blood sugar is very high (> 250 mg/dL), ketonic bodies should be tested for in the blood or urine. If the test result is positive, patients should not exercise; if it is negative, they may exercise if they are under the effect of previously taken insulin. (Carcavilla, 2009).
Can it ever be cured?
Surgery is another type of treatment. This option would take place once the disease has been established and islets have been fully destroyed. The only possibility of being cured would be by replacing the non-functioning cells.
There are two options: islet transplant and pancreas transplant, with the latter being carried out generally on patients with end stage kidney disease, at the same time as a kidney transplant or after it. Pancreas transplants are rarely performed in isolation. Simultaneous kidney-pancreas transplant is currently the option that achieves the best results with regard to transplant acceptance and functioning (80% insulin-independence after five years, compared to 10% after islet transplant).
However, there are side effects inherent to the chronic immunosuppression treatment that these patients require.
The initial enthusiasm provoked by the possibilities that islet transplants seemed to offer led to years of expectation that the majority of type 1 diabetes would be cured. This therapy, starting in animal models over 40 years ago, received a significant boost in 2000 with the use of the so-called Edmonton Protocol based on the use of steroid-free immunosuppression. Although the procedure is minimally invasive (infusion of islets in the liver of the recipient through portal vein cannulation by percutaneous transhepatic drainage), it currently poses difficulties in applicability. Moreover, the immunosuppression treatment does not always prevent the recurrence of the immune process in transplanted islets. This has significant undesired effects and does not prevent the sensitization that would make a future organ transplant more difficult, if necessary. In order to obtain the optimal number of islets two or even four donors are required (Barajas, 2008).
Islet transplants are therefore limited to a small number of patients and centers.
Considering the low number of islet donors compared to the incidence of DMT1, alternatives must be analyzed in order to make the application of this therapy feasible. The most promising of these alternatives is based on using stem cells.
The development of more sophisticated cell transplant methods combined with bioengineering techniques may notably improve the potential of stem cells.
Numerous research groups have shown that embryonic stem cells are able to differentiate themselves into insulin-producing cells in vitro.
Studies have also been published about the potential for differentiation of stems cells derived from bone marrow, which is changing the classical view of tissue-specific stem cells, such that some cell populations present in bone marrow are known to be able to abandon their characteristic cellular differentiation pattern and differentiate into typically non-hematopoietic tissues.
Recent studies show that it is possible to detect the expression of insulin in tissues where this does not usually take place, such as bone marrow, fatty tissue, and skeletal muscle. Other authors state that some cells present in bone marrow are able to transdifferentiate into functioning beta cells. Using the CreloxP system, Lanus and Col demonstrated that cells derived from bone marrow contribute approximately between 1.7% and 3% to the formation of new beta cells (Goñi, 2008).
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