The Pathophysiology of Type 2 Diabetes is one of the central topics in medicine. Understanding the mechanisms that lead to insulin resistance and subsequent hyperglycemia may seem complex. But in this article, I will show you the key aspects of the pathophysiology of Type 2 Diabetes.
General aspects of Type 2 Diabetes
Type 2 Diabetes Mellitus is a multifactorial disease with polygenic and environmental aspects that interact in a complex context. The final result, however, is the presence of hyperglycemia.
It is indisputable that there are 2 main factors involved in the pathogenesis of Type 2 Diabetes, and these are:
- Insulin resistance or deficient action of it
- Deficient insulin secretion
On multiple occasions, the pathophysiology is the result of the combination of these 2 factors or elements.
Pathophysiology of Type 2 Diabetes Mellitus
To better understand this article, we recommend having read the Physiology of glucose uptake
As we have mentioned, glucose interacts with multiple receptors when it enters the body. At the level of the beta cells of the pancreas, the ones responsible for capturing glucose are GLUT2. When the threshold of 70 mg/dL is exceeded, the release of the hormone insulin is induced.
Unlike GLUT2 (which do not require insulin), GLUT4 receptors are hidden within the cells of peripheral tissues. In this scenario, insulin is essential.
Insulin must bind to insulin receptors (IRS) and carry out a series of signaling mediated by second messengers such as cAMP. The final result is the translocation or exocytosis of GLUT4, which will allow glucose uptake in the cells of peripheral tissues.
In type 2 diabetes, the problem lies in the sensitivity with which insulin receptors (IRS) capture insulin. In other words, insulin resistance has developed. This is partly attributed to obesity; however, it is multifactorial. The pathophysiological process may also present deficiencies in insulin synthesis and/or secretion.
Pathophysiology of insulin resistance
Insulin resistance is one of the pillars in the pathophysiology of type 2 diabetes. The process by which this so-called "resistance" develops is complex and responds to several pathways.
Inflammation and insulin resistance
In a physiological scenario, inflammation is a process that accompanies an immune response whose ultimate goal is the defense of the organism. However, in the pathophysiology of type 2 diabetes, there is a chronic inflammatory process.
Multiple studies agree that obesity is a clearly involved factor in this chronic inflammatory process. In patients with obesity, a greater number of inflammatory markers have been detected, supporting this hypothesis.
Part of this inflammatory process is mediated by an increased number of macrophages that infiltrate adipose tissue and consequently induce a greater number of pro-inflammatory cytokines such as Interleukins 6, 18, 1B, and Tumor Necrosis Factor (TNF).
These pro-inflammatory cytokines induce an overactivation of a kinase complex known as Ser/Thr. The hyperphosphorylation of the insulin receptor due to this hyperactivity leads to a reduced interaction with second messengers such as phosphoinositide-3-kinase (PIK3). Additionally, this hyperactivity also increases the degradation of insulin receptors.
The final result is then a lower number of insulin receptors (due to increased degradation) and less functional receptors (due to reduced cellular signaling by second messengers).
Obesity and Type 2 Diabetes
The greater the degree of obesity, the greater the accumulation of fatty acids and lipids, and therefore the greater the hypertrophy of adipocytes. This leads to an alteration at the level of adipokines and pro-inflammatory cytokines.
Both free fatty acids and pro-inflammatory cytokines will act at the level of hepatic and peripheral tissue (such as muscle). This partly contributes to the pathophysiology of Metabolic Syndrome.
Obesity and these alterations that lead to aberrant lipids also induce a greater infiltration of macrophages in adipose tissue. This is simply understood as increased immunological activity and consequently a greater inflammatory response.
The inflammatory response secondary to obesity has been shown to increase the levels of Toll-like receptors (TLR), especially types 2 and 4 (TLR2 and TLR4).
TLR4 has been shown to be significantly increased at the level of muscle cells and adipose tissue in patients with obesity.The problem then arises because these TLR4 are agonists of Saturated Fatty Acids (SFA).
It is this combination of factors that ultimately leads to chronic inflammatory processes and subsequent impairment of insulin receptors.
Mitochondrial Dysfunction.
It is important to remember that the Mitochondria is an essential element in the cell. It is the organelle responsible for the production of most ATP and participates in the metabolism and degradation of glucose and fatty acids.
In patients with Type 2 Diabetes, there is a decrease in the number of Mitochondria. The reason why there is a decrease in the number or function of mitochondria is still not entirely clear and remains a point of debate.
In patients who present Obesity, as mentioned, there is an increase in the concentration of fatty acids. This consequently leads to an increase in Beta Oxidation. Under normal conditions, this increases the availability of energy in the muscle and liver tissue cells.
However, when the threshold of ATP produced cannot be released as heat and exceeds the allowed threshold, a negative feedback is generated. This inactivates a protein called AMP-activated kinase. This reduces glucose uptake induced by Insulin.
Thus, insulin resistance actually functions as a protective mechanism at the cellular level. It seeks to prevent damage induced by ATP stress at the muscle and liver tissue level.
Reactive oxygen species (ROS) seem to be increasingly linked to the pathophysiology of Type 2 Diabetes. Stressed mitochondria mistakenly release electrons that generate ROS.
These ROS cause the activation of pro-inflammatory Kinases, among which are Ser/Thr, IKK-B, JNK, and PKC.
The kinases IKK-B, JNK, and PKC induce greater phosphorylation of "Ser," which, as we mentioned, accelerates the degradation of insulin receptors and interferes with their signaling. Consequently, this explains the development of what is called "Insulin Resistance" in the pathophysiology of type 2 diabetes.
Pathophysiology of deficient insulin secretion
As we have already mentioned, the pathophysiology of type 2 diabetes essentially consists of 2 events: insulin resistance and impaired insulin secretion.
At the onset of type 2 diabetes, most patients will have hyperinsulinemia. However, as the disease progresses, the pancreas is unable to sustain insulin secretion. In these patients, there may be hypoinsulinemia.
Patients who progress to hypoinsulinemia have been shown in autopsies to have lost more than 50% of the pancreatic beta cell mass. This explains why over time some patients with type 2 diabetes also require the use of insulin.
The loss of beta cells and subsequent decrease in insulin secretion is multifactorial..
Amylin Deposits
One of the most controversial theories regarding the loss of beta cells is the deposits of amyloid or amylin.
As previously mentioned, the beta cells of the pancreas have GLUT2 receptors to capture circulating glucose and initiate insulin secretion. Amylin is a peptide that is also synthesized at the level of these cells and is co-secreted along with insulin.
In patients with type 2 diabetes, chronic hypersecretion of amylin has been identified.It is then this accumulation or deposits of Amylin that seems to cause a precipitation within the beta cells of the pancreas.
The exact mechanism by which amyloid deposits lead to a decrease in insulin secretion is still a controversial and uncertain topic. One explanation for this phenomenon is that amylin or amyloid (IAPP) deposits accelerate the death of beta cells.
Recent studies have shown that IAPP has the ability to generate a direct cytotoxic effect on beta cells. This effect can occur both through interaction with second messengers and through direct action on the cell membrane.
Additionally, IAPP also has the ability to induce the activation of macrophages and subsequent release of cytokines (IL-1b, IL-6, TNF) that can also lead to the destruction of beta cells.
Other theories explaining the poor secretion of insulin include fat accumulation at the level of pancreatic beta cells. Additionally, some studies suggest that the decrease in glucagon-like peptide (GLP-1) is a key piece in the pathophysiology of type 2 diabetes.
Pathophysiology of Hyperglycemia
The final result of the molecular changes at the level of insulin receptors is Hyperglycemia.
The normal blood glucose value in an adult is a range of 70 to 110 mg/dL.
Values above 110 mg/dL are considered Hyperglycemia. However, not all Hyperglycemias are synonymous with Diabetes Mellitus. It is perfectly normal for blood glucose levels to rise after caloric intake.
The problem arises when the value remains chronically high as occurs in insulin resistance in Type 2 diabetes.
Overproduction of Hepatic Glucose
In a physiological scenario after carbohydrate intake and subsequent glycolysis, unused glucose is converted into adipose tissue at the liver. Lipogenesis is one of the pathways stimulated by insulin.
In a healthy person, when blood glucose levels decrease, glucagon secretion is activated. Glucagon stimulates gluconeogenesis and glycogenolysis. Both biochemical pathways cause the liver to produce glucose in order to maintain homeostasis.
Under normal conditions, insulin has a counter-regulatory effect on the receptors of the alpha cells of the pancreas. This means that when insulin is elevated, glucagon is decreased and vice versa.
Where is the problem? In a person with type 2 diabetes, high blood glucose levels keep insulin secretion stimulated, resulting in hyperinsulinemia. It would be logical to think that glucagon levels should be low. But they are not.
Just like the IRS in muscle, the receptors of the alpha cells of the pancreas have developed insulin resistance. This generates an aberrant behavior where both glucagon and insulin are present.
Glucagon will then stimulate hepatocytes to activate the glucose synthesis pathways. Glycogenolysis, in which glycogen reserves are degraded and converted into glucose that is released into the bloodstream, and gluconeogenesis, in which more glucose is synthesized from non-carbohydrate compounds.
The final result is an overproduction of glucose by the liver.
But the problem does not end there. It turns out that since insulin keeps the lipogenesis pathway active, all the extra glucose will enter the fatty acid synthesis process, which, as we described earlier, will have a toxic effect on insulin receptors, thus contributing to increased insulin resistance.
The excess fatty acids will also accumulate in tissues such as the liver, thereby contributing to the pathogenesis of hepatic steatosis or fatty liver disease.
That is why patients with type 2 diabetes usually have a profile of overweight and obesity.
Video Pathophysiology of Type 2 Diabetes
Clinical manifestations of Type 2 Diabetes
It is important to differentiate with the Pathophysiology of Type 1 Diabetes. The symptoms or clinical manifestations in Type 1 Diabetes usually appear suddenly; however, in Type 2 Diabetes, the onset of symptoms tends to be gradual.
Many patients with Type 2 Diabetes are asymptomatic or the symptoms may go unnoticed or be confused with other conditions.
Symptoms of Type 2 Diabetes
The symptoms that may present include:
- Polydipsia
- Polyuria
- Polyphagia
- Weight loss
- Fatigue
- Blurred vision
- Paresthesias in the upper and/or lower limbs
- Areas of darker skin (in the neck, armpits, or creases) known as Acanthosis Nigricans
- Frequent infections
Pathogenesis of Clinical Manifestations
Most clinical manifestations in Diabetes are directly related to Hyperglycemia.
Polyuria
The renal system is responsible for filtering the excess Glucose in the blood, expelling it through Urine. The Nephron, like other specialized cells, has GLUT2 receptors.
The renal threshold for glucose filtration is between 180 and 220 mg/dL. When the blood glucose level exceeds this figure, it begins to appear in the urine. This is known as Glucosuria.
Glycosuria is therefore a manifestation of Diabetes, although not exclusive to it.
Hyperglycemia acts as a diuretic. Its main action occurs at the level of the proximal convoluted tubule.
The relationship between blood glucose levels and the number of increased urinations appears to be directly proportional. Some patients experience episodes of urgency to urinate during sleep. This is known as nocturia.
Polydipsia
Polydipsia, or excessive thirst in patients with type 2 diabetes, responds almost simultaneously to polyuria.
The greater the level of dehydration caused by frequent urination, the greater the thirst generated to try to compensate.
This same dehydration can cause dry mucous membranes, which in turn can lead to cough in patients with type 2 diabetes.
Polyphagia
Although there is a high concentration of glucose in the blood, it cannot be utilized by the cells of peripheral tissue. This lack of energy leads to the activation of signaling pathways whose result is the expression of hunger.
Unfortunately, no matter how much is consumed, the energy deficit cannot be compensated. Most patients with type 2 diabetes tend to have some type of eating disorder related to increased carbohydrate consumption usually linked to an anxiety disorder.
The activation of these stimuli at the brain level and excessive consumption is what is termed Polyphagia.
Weight loss
Initially, patients with type 2 diabetes tend to gain weight rather than lose it. This is because they still partially absorb glucose to some extent with Hyperinsulinemia. However, at some point, the remaining beta cells will suffer the toxic effects generated by Hyperglycemia and fatty acids, causing the pancreas to have a reduced capacity for insulin production.
With insufficient insulin, weight loss in patients with type 2 diabetes becomes more evident. Weight loss in diabetes initially occurs due to water loss secondary to Polyuria and subsequently due to increased biochemical pathways of Gluconeogenesis.
It is important to remember that the substrates that Gluconeogenesis can utilize are fatty acids and proteins. This essentially explains the weight loss.
Blurred Vision in Diabetes
Type 2 diabetes can affect vision and lead to blurred vision in affected individuals through 2 mechanisms.
The first is due to dehydration. When patients present with dehydration secondary to polyuria, this causes changes in the curvature of the lens. These changes can cause individuals with hyperopia to experience worsened vision during hyperglycemic crises.
The second mechanism corresponds to an enzymatic saturation process. The eyes, like other cells, require glucose for energy production. In the membrane of the ciliary epithelium, GLUT1 and GLUT2 receptors (which do not require insulin) are also present.
Under normal conditions, retinal and lens cells can perform glycolysis without issue. However, when blood glucose levels exceed 200 mg/dL, there is enzymatic saturation. This results in all remaining glucose needing to enter the alternative pathway of Aldose Reductase.
Aldose Reductase converts glucose into fructose and sorbitol. It is the latter that causes the problem. Sorbitol has a high osmolar weight, which causes water to enter the cortex of the lens, leading to increased opacity. In the patient, this translates to blurred vision.
Paresthesias in type 2 diabetes.
Paresthesias or "tingling sensation" can initially be caused by the loss of electrolytes. Patients with high blood glucose concentrations, which act as a diuretic, also experience considerable losses of electrolytes.
Potassium and sodium are usually the most involved electrolytes. However, it is important to mention that even in type 2 diabetes, as long as there is no significant renal functional impairment, the kidney is capable of compensating for the losses through sodium retention and buffering mechanisms.
Another explanation at the pathogenic level for paresthesias is the damage to the microvasculature that occurs in type 2 diabetes.
Chronic hyperglycemia generates mitochondrial stress as described at the beginning of this article, leading to oxidative stress. This, in turn, causes endothelial damage and vascular damage.
When this chronic hyperglycemia (which is usually defined as an HbA1c greater than 9%) is sustained, it causes damage at the level of nerve fibers, leading to a reduction in the speed of transmission and conduction of synaptic impulses. This is part of the basis of what is called Diabetic Neuropathy.
One of the most mentioned symptoms by patients with type 2 diabetes, which is part of the pathophysiological process of Diabetic Polyneuropathy, is the "burning sensation in the soles of the feet" which is usually greater at night.
Acanthosis Nigricans
The hyperpigmentation and thickening of the skin with dark coloration is a response to hyperinsulinemia.
Insulin stimulates a specific receptor called insulin-like growth factor type 1. This is responsible for promoting an increase in the synthesis of keratinocytes and dermal fibroblasts, which generates hyperpigmentation and thickening.
Usually, the most affected areas are skin folds such as the neck, armpits, genital area, submammary region, nipples, and labial commissures.
Algorithm of clinical correlation and pathophysiology of type 2 diabetes
Below is a summary of the pathophysiology of type 2 diabetes and its respective clinical correlation:
1. Type 2 diabetes is a multifactorial disease 2. It is very closely related to overweight and obesity 3. The pathophysiology of type 2 diabetes is due to insulin resistance secondary to an increase in the degradation of IRS and blockage of signaling. ⚕️ 4. At the onset of type 2 diabetes, there are no symptoms due to the existence of compensatory mechanisms. 5. The longer the duration of chronic hyperglycemia, the greater the damage to various organs.
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