Diabetes Mellitus (DM) is a metabolic disease characterized by an increase in blood glucose (hyperglycemia). Considered by some as a pandemic of the 21st century, due to the complications and mortality associated, it is in fact a worldwide problem, making this pathology a huge challenge for health systems. Genetic predisposition, and the increase in the average life expectancy of the population, combined with the adoption of an unhealthy lifestyle, seem to be the factors that have been promoting the increase in its prevalence and incidence.


Diabetes Mellitus (DM) is a complex disease resulting from a set of metabolic alterations that are characterized by permanent hyperglycemia caused by defects in insulin secretion, its action or both. Insulin is a hormone produced by pancreatic β cells and is responsible for controlling blood glucose, allowing glucose to enter muscle and adipose tissue where it is converted into energy. If insulin production is altered then the dynamics of blood glucose will also change. Thus, if insulin production is insufficient, glucose entry into cells will also be conditioned, resulting in hyperglycemia; in case there is the correct secretion, but not a correct use by the target cells, the result will be the same. It is this chronic maintenance of hyperglycaemia that is associated with long-term damage, such as dysfunction and failure in different organs, especially the eyes, kidneys, nerves, heart and blood vessels.


However, despite having no cure, clinical evidence indicates that controlling hyperglycemia can significantly reduce the incidence of complications, so it is important to keep glucose levels under control, adopting healthy lifestyle habits and the practice of physical exercise to that, only as a last resort, pharmacological measures are used.



Although it does not seem very serious, due to its slow progression, the truth is that diabetes currently affects more than 386 million people worldwide and according to the International Diabetes Federation (IDF) forecasts point to 592 million in 2035. What is worrying is that 46.3% of cases remain undiagnosed and it is estimated that in 2014 alone, diabetes led to 4.9 million deaths. In Portugal, the picture is no different and 13% of the population aged between 20 and 79 years, that is, about 1 million, also have diabetes, with only 7.3% of cases diagnosed. It is also verified that the male population is more affected than the female population, 15.6% against 10.7%, respectively, and in both cases its incidence increases with age.





Any individual is subject to daily fluctuations in plasma glucose concentration, as glycemic levels tend to increase after a meal, then progressively decrease during the interval between meals. Despite the fluctuations in concentration, the body has a complex system of regulation and counter-regulation, based on hormones that prevent extreme situations, maintaining an adequate concentration of glucose and ensuring the body's homeostasis. The following figure summarizes this homeostatic system:


Figure 1 – Dynamic interaction between pancreas and liver in maintaining blood glucose homeostasis


When the blood glucose level rises (for example, after a meal), insulin secretion by β cells also increases. This increase will stimulate glycogenesis and glycolysis with consequent production of glycogen and pyruvate respectively. On the other hand, when the plasma glucose level decreases, in addition to developing a series of warning symptoms, counterregulatory mechanisms are triggered that involve different hormonal responses. Initially, insulin secretion by β cells decreases, but if the glycemic level continues to decrease to more critical levels, an increase in secretion of the counterregulatory hormone glucagon by pancreatic α cells begins. Glucagon then stimulates hepatic glucose production via glycogenolysis (breakdown of glycogen) and via gluconeogenesis (conversion of lactic acid, amino acids and glycerol). When this regulation fails, DM situations arise.



Types of Diabetes


Assigning a specific type of diabetes most often depends on when the diagnosis is made, so more important than the type is understanding the pathogenesis of hyperglycemia and treating it effectively. However, 4 main subtypes can be considered: Diabetes type 1, type 2, gestational, and other special types.





It represents 5 to 10% of all cases. This specific type can be further divided into the more common immune-mediated DM and the rarer idiopathic DM. In both cases there is destruction of the β cells of the pancreas. In the autoimmune form, markers of immunological destruction of β cells can be found clinically, including autoantibodies against the islet of Langerhands cells, anti-insulin, against a glutamate decarboxylase (GAD65) and against tyrosine phosphatases (IA-2 and IA-2β). . It is also associated with human leukocyte antigen (HLA) and the genes involved in its encoding. It is more typical in children and adolescents and ketoacidosis can be the first manifestation of the disease. It can also appear in adults, called LADA (Latent Autoimmune Diabetes in Adults) but as in these cases the β cells retain some residual activity, ketoacidosis can be masked for years. In either case, there is a progressive destruction of these cells that usually leads to absolute endogenous insulin deficiency. In the idiopathic form, the etiology is unknown. It is known that African and Asian ethnicities are the most affected and that these patients suffer from episodic ketoacidosis, exhibiting variable insulin deficits but without any autoimmune process.






It corresponds to about 90 to 95% of diabetes cases. It is the most common type of diabetes in adults, usually after the age of 40, but it can occur earlier, especially in populations with a high prevalence of the disease. However, it often goes unnoticed for years and its diagnosis is made only when complications arise or abnormal blood and urine glucose values are detected. Type 2 diabetes is associated with family history, aging, an unhealthy lifestyle such as lack of physical exercise, sedentary lifestyle and obesity, especially in the abdominal region. It is characterized by peripheral insulin resistance, especially in muscle cells, increased glucose production by the liver, and changes in pancreatic insulin secretion. Individuals initially have normal or slightly elevated fasting insulin levels but gradually reach disproportionately high concentrations relative to blood glucose levels. This leads to a progressive impairment of β cells until insulin is insufficient for the absorption of glucose by the cells and hepatic synthesis of glucose begins, increasing its blood concentration.






It is defined as a variable degree of glucose intolerance that begins or is recognized during pregnancy. It usually resolves postpartum, however these women should be reassessed in order to reclassify the type of diabetes, as they are more predisposed to developing type 2 diabetes.





There are several other types of diabetes, including genetic defects in β-cell function, called MODY (Maturity Onset Diabetes of the Young), in insulin action, diseases of the exocrine pancreas, endocrinopathies, drug-induced diabetes and infections, among others. less common.





There are several complications associated with this pathology that can manifest in the short or long term. The strict control of blood glucose, blood pressure, and lipids, as well as the most sensitive organs (eyes, kidneys, peripheral nerves and vascular system), should be carried out in order to minimize the damage resulting from permanent hyperglycemia.



Acute complications are related to faster metabolic changes, so immediate therapy can prevent them. These complications include hypoglycemia, ketoacidosis and non-keto hyperosmolarity. Chronic complications are mainly due to prolonged hyperglycemia leading to two major groups of lesions, microvascular and macrovascular. Microvascular lesions concern small blood vessels and are at the origin of neuropathy, retinopathy and nephropathy. In neuropathy, progressive degeneration of axons and nerve fibers occurs, leading to changes in the extremities of the arms and legs. This complication may be at the origin of the diabetic foot, which due to loss of sensitivity, the wounds progress without pain, and as the individual does not value them, there is a risk of necrosis with subsequent need for amputation. Retinopathy is a common but slowly progressive complication. Changes that occur in small vessels, such as hemorrhages and angiogenesis, lead to changes in retinal irrigation that potentially lead to blindness. Nephropathy can arise as a result of increased albumin elimination in the urine, increased arterial hypertension, and renal failure. Regarding macrovascular complications, they are characterized by damage to larger blood vessels, mainly due to the process of atherosclerosis. These complications are at the root of coronary artery disease, cerebrovascular disease and peripheral arterial disease.





The classic symptoms of diabetes are polyuria, polydipsia, polyphagia, and involuntary weight loss. Other symptoms that also lead to its suspicion are fatigue, weakness, lethargy, skin and vulvar itching, balanoposthitis and recurrent infections. Sometimes it is only diagnosed when its chronic complications are detected. However, as diabetes is asymptomatic in a large percentage of cases, clinical suspicion occurs only in the presence of risk factors or when abnormal blood glucose values are detected in routine exams. Currently, according to the General Directorate of Health, the diagnostic criteria for diabetes are as follows:

a) Fasting blood glucose ≥126 mg/dl (or ≥7.0 mmol/l), or

b) Classic symptoms + occasional blood glucose ≥200 mg/dl (or ≥11.1 mmol/l), or

c) Blood glucose ≥200 mg/dl (or ≥11.1 mmol/l) at 2 hours, in the oral glucose tolerance test (PTGO) with 75g of glucose; or

d) A1c glycated hemoglobin (HbA1c) ≥6.5%. Patients with impaired fasting blood glucose or impaired glucose tolerance are referred to as “prediabetic” and therefore have a higher risk of developing diabetes.



Included in this group are users with the following parameters:

a) Fasting blood glucose abnormality (FAG): fasting blood glucose ≥110 and <126 mg/dl (or ≥6.1 and <7.0 mmol/l);

b) Decreased Glucose Tolerance (TDG): 2-hour blood glucose at PTGO ≥140 and <200 mg/dl (or ≥7.8 and <11.1 mmol/l).

In any asymptomatic person no diagnosis can be made with just one determination so in these cases an analysis should be repeated after 1 or 2 weeks.





The maintenance of blood glucose levels as close as possible to the reference values, interspersed with the control of the lipid profile and hypertension are the primary objectives for minimizing short- or long-term decompensations.



The initial treatment of diabetes involves an adjustment of the diet and the practice of physical activity and only later should oral medication and/or insulin be used. The need to resort to oral antidiabetic therapy aims to increase insulin production, increase the body's sensitivity to its use, and reduce the concentration of glucose in the body. This control can be obtained in monotherapy or by combining drugs with complementary mechanisms of action. When the type 2 diabetic still does not achieve good metabolic control, insulin administration alone or in combination with oral antidiabetics is necessary.


In Portugal, eight different classes of drugs are approved for the control of DM: insulin (human), sulfonylureas, meglitinides (glinides), biguanides, thiazolidinediones, α-glucosidases inhibitors, incretin modulators and, more recently, sodium and glucose 2 (SGLT2).


in Ivo Barreiros - University of Coimbra (Review of Diabetes Pathophysiology and Treatment)