What is Type 2 diabetes mellitus?

Image taken from: https://www.health.harvard.edu/staying-healthy/the-importance-of-exercise-when-you-have-diabetes

Background

Type 2 diabetes mellitus (T2DM) is described as insulin resistance and characterized by elevated levels of blood glucose (BG); hyperglycemia. At least 90% of all diabetes mellitus cases are T2DM ^[1][3]. It is suggested that this is due to preferential lifestyle changes towards a more Western lifestyle which involves ‘high diet with reduced physical activity’ ^[3]. However, genetic predisposition was also proven to cause T2DM.  There is a >50%  risk of developing diabetes in mono-zygotic twins, by individual, if their parents are diabetics showing a strong genetically inheriting factor ^[5] . Base on epigenetic theory , exposure to certain environmental stimuli  influences or even changes gene expression; genes switch on and off. Thus, T2DM can be classified as a multi-factorial disorder ^[2] i.e. genetic and environmental factors contribute to its cause. Thus, are genetically predisposed T2DM patients more susceptible to lifestyle changes and to what extent? (Figure 2&3)

Figure 2. Multifactorial causes of T2DM characterized by obstructed insulin secretion and insulin resistance . Genetic factors relate to mutations of insulin receptors, insulin resistance and impaired insulin production. Environmental factors include diet, lack of exercise, stress and aging. Information to create the flowchart was taken from Kohei K., 2010 and Ozougwu J.C.,2013 ^[2][3].

Symptoms

Symptoms of T2DM are subtle as production of insulin declines over time, thus someone with T2DM will be diagnosed during the more developed stages of the disorder. Symptoms may include ^[1][4]:

• Excessive thirst
• Excessive urination
• Excessive eating
• Dry mouth
• Fatigue
• Blurred vision
• Headaches
• Longer time for wounds to heal
• Frequent infections

The above are often accompanied with unexpected weight-loss because of breakdown of fats and proteins as an alternative fuel for energy^[1].

Pre-diabetic signs

Pre-diabetes is characterized by impaired glucose regulation but BG levels are not high enough for official T2DM diagnosis. At such stage, impaired glucose tolerance (IGT) and elevated levels of insulin are detected.  All types of diabetes are diagnosed ‘when fasting plasma glucose is more than 7mmol/L on at least two occasions’ ^[6]. An oral glucose tolerance test (OGTT) is one way to determine T2DM along with other criteria (Table 1 and 2).

Table 1. Diagnostic BG concentrations (mmol/L) used in OGTT. Data taken from Marshal W.J, 2017 ^[5]

mmol/L; millimoles per litre

Figure 3. BG levels in obese children during an OGTT. Data is in mean± standard deviation and BG concentration is measured in mg/dL. OGTT test was undertaken in obese children with T2DM, IGT  and normal glucose tolerance . It is observed that BG concentration in T2DM children are significantly higher than the IGT ones and the normal glucose tolerance ones. From Spagnuolo M.I et. al., 2010^[7]

Table 2. Criteria to diagnose all types of diabetes. Information taken from Mohammed H. , 2016 ^[6]

mmol/mol; millimoles per mole, mmol/L;
 millimoles per litre, mol/L; moles per litre, g; grams , 
WHO; World Health Organization,ADA; American Diabetes Association

Why is this a problem?

Pathophysiology

Under normal physiological conditions (Table 2), insulin regulates glucose homeostasis by stimulating BG uptake into the cells preventing hyperglycemia (Figure 4). Regardless of the constant fluctuation in glucose concentration, a tight regulation of glucose exists and a ‘dynamic interaction between tissue sensitivity to insulin (especially in the liver) and insulin secretion’ ^[10]. However, T2DM impairs this regulation as cells no longer respond to it causing changes in metabolism ^[10].

Figure 4. Under normal physiological conditions, insulin stimulates the uptake glucose into cells to prevent hyperglycemia. This is done by the activation of the GLUT-2 transport protein channel which facilitates the movement of glucose molecules down their concentration gradient. Once glucose enters the cell , immediate phosphorylation of glucose to glucose-6-phosphate (G-6-P) occurs. The reaction is catalyzed by the enzyme hexokinase and ATP is required. This immediate conversion to G-6-P allows a concentration gradient to be maintained so the cell can still be uptake glucose. In T2DM as cells do not respond to insulin this process is impaired caused hyperglycemia and further metabolic complications. Image from austincc.edu ^[11].

Insulin resistance

In T2DM, cells are insulin resistant, thus BG is unable to be up-taken and used for energy production. Consequently, glucagon secretion is promoted; hormone antagonistic to insulin ^[5] which favors gluconeogenesis; use of non-carbohydrate sources to create glucose, and glycogen breakdown. Glycogenesis and glycolysis are inhibited ^{[5] [10]}.  There is a decline in BG utilization while fatty acids (FA) and ketones are preferentially metabolized as energy substrates, increasing their concentration in blood as lipolysis rates increase and further contributing to hyperglycaemia (Figure 5). Ketogenesis is promoted by the high glucagon:insulin ratio ^[5]. High FA and ketones run the risk of ketoacidosis which can be problematic. Table 3 presents features associated with insulin resistance.

Table 3. Characteristics associated with insulin resistance, their effect on various mechanisms and link to any diseases. Information extracted from Freyn K.N , 2009 ^[10]

TAG; triacylglycerol, CHD; coronary heart disease, 
HDL; high density lipoprotein, LDL;low density lipoprotein

Diabetic complications

T2DM is strongly linked with macro and microvascular complications, thus considered a vascular disease ^[17]. Untreated, it can cause organ and tissue damage (Figure 5), changes in structure, anatomy and function of organs, leading to multi-organ dysfunction ^[15]. Since T2DM has a progressive nature the complications worsen over time^[1][2] .

Figure 5. Potential mechanisms for T2DM-associated multi-organ and endothelial dysfunction. AGE: advanced glycation end products; FFA: free fatty acid PKC: protein kinase C; RAGE: receptors for AGE; ROS: reactive oxygen species; RAS: renin-angiotensin system ^[15]

Macrovascular complications

Cardiovascular disease (CVD)

Figure 6. Relationship between CDV and T2DM. Decreased circulating insulin and insulin resistance causes accumulation of BG leading to a domino effect of metabolic, microvascular and macrovascular complications. Image from Zhu H.A, 2016 ^[8]

CVD is the main cause of death in T2DM patients ^[15] (Figure 7) where 50% of T2DM patients die from it. Research suggests that CVD is associated with poor BG control leading to a domino-effect of micro and macrovascular complications ^[9][10][15] (Figures 6 & 8)

Figure 7. Relative risk of CVD in normal BG level (normoglycemia), pre-diabetes and T2DM. It is observed that people with T2DM are at a significant more risk to develop CVD than people with normoglucemia. From Laakso M., 2008 ^[9]

Microvascular complications

Figure 8.  Overview of T2DM complications associated with insulin resistance. FFA; free fatty acids, ROS; reaction oxygen species. Image from Laakso , M. ,2008 ^[9]

Diabetic retinopathy (DR)

DR is the primary cause of impaired vision (Figure 9). It is characterised by changes in retina blood vessels. Hyperglycaemia affects the peripheral retina, thus why T2DM patients are more likely to have DR ^[14](Figure 8). DR is also associated with higher BMI and hypertension ^[15].

Figure 9. DR is changes in the blood vessels of the retina. Chronic hyperglycaemia can damage the capillaries of the retina causing microaneurisms, capillary swelling (edema) and haemorrhages. Consequently, we have leakage and inadequate supply of blood (ischaemia) to the retina contributing to loss of vision. DR severity ranges from non-proliferative to pre-proliferate to more severe proliferative DR in which the new vessels are observed to grow abnormally. Image taken from ranueye.com ^[10]

The eye is considered to be one of the most metabolic active organs and extremely sensitive to nutrient imbalance and ischemia ^[15].

Figure 10. Pericytes are cells that elongate, contract and wrap around the endothelial cells of the retina. They provide control of endothelial growth and vascular stability. Their function is to assist in controlling capillary dilation, constriction and growth and protect endothelial cells against ROS. In T2DM patient’s loss of pericytes is observed due to hyperglycemia ^[15][16]. Image taken from McCollough et.al, 2017  ^[12]

Their absence causes chronic vessel dilation leading to increase permeability of endothelial cells and formation of micro-aneurysms ^[10][15]. Research suggests that this is linked to poor BG control; a characteristic of T2DM, and accumulation of sorbitol and ROS in the retina due to hyper glucaemia ^[10][15]. Sorbitol is an intermediate product of the polyol-pathway (Figure 11) and glucose is the main component used for sorbitol production , thus hyperglycemia increases the rates of the pathway ^[10][15]. This causes oxidative stress. and damage to the retinal endothelial cells,  causing poor vision. Retinal blood flow is impaired causing inflammation and inflammatory cells adhere to the retinal blood vessels blocking capillaries are blocked causing hypoxia ^[15].

Figure 11: The polyol-pathway for production fructose. Intermediate product is sorbitol. AR along with co-factor NADPH catalyses the production of sorbitol.  AR is present in a variety of tissues such as retina and nerve cells and has a high affinity for glucose [14]. Higher glucose concentration leads to higher the rate of glucose conversion to sorbitol. Accumulation of sorbitol along and NADPH can cause damage to these tissues ^[10]

Diabetic peripheral neuropathy (DPN)

[11]. Research suggest that the polyol pathway (Figure 11) and poor BG control may contribute to this ^[15].

Figure 12. Poor BG control and hyperglycemia can cause neuron and blood vessel damage causing DPN. DPN is the result of neurons that carry messages to and fro the central nervous system been damaged.  Image from fightdiabetes.com ^[11]

DPN can be categorized into ^[11][19]:

• Peripheral neuropathy; most common and affects the limps
• Autonomic neuropathy; affects internal nerves and sex drive. It may also affect blood pressure and heart
• Focal neuropathy; muscle weakness near an affected nerve
• Proximal neuropathy; weakness in the legs with pain in your lower body area

Diabetic nephropathy (DN)

Figure 13. DN is characterized by presence of albumin in urine; proteinuria, due to inadequate glomerulus filtration. Hyperglycaemia is a main cause of DN [14]. If untreated it can lead to chronic kidney injury and potentially kidney failure. Image taken from Jefferson J.A,2008^[20]

There is a direct link between T2DM, CVD and DN ^[15] (Figure 8). Albumin in urine is a diagnostic marker of DN ^[10][15]. Due to hyperglycemia, excess BG sticks onto the meningeal extracellular matrix thickening it causing glomerular hyper-filtration (Figure 13) ^[15][20] . Progressively proteinuria increases and glomerular filtration rates gradually decline, leading to tubular and glomerular sclerosis and potential renal failure.

How do you treat Type 2 diabetes mellitus?

Treating T2DM is more of a balancing act ^[14]. It focuses more on making some major lifestyle changes to maintain BG concentrations by changing ones diet to a keto base one and embracing new daily habits such as exercise more frequently.

Written by Lazaros Hadjiforados

References

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