Causes of Different Types of Diabetes Mellitus

Theoretically, diabetes mellitus (DM) can be divided into primary and secondary types.

The primary types include type 1 (insulin-dependent DM, IDDM), type 2 (non-insulin-dependent DM, NIDDM), and gestational DM.

The secondary types of DM are the disorders, which secondarily give rise to DM.

This article will be discussing the causes for primary types first, followed by a briefing on secondary types. DM, in general possesses a multifactorial basis.

Causes of Type 1 DM

Environmental and Genetic Causes

The environmental trigger is an autoimmune phenomenon (i.e. a condition where your immune/defensive system recognizes your body’s own healthy cells as being foreign to the body and starts attacking these healthy cells) via producing autoantibodies.

Simply put, normally, antibodies develop in response to a foreign organism, such as a virus or bacterium, and function to defend your body against that invader. However, an autoantibody will destroy your own tissues, instead of slaying the foreign organism.

Probably, this autoimmune reaction in type 1 DM is the result of a viral trigger, most commonly the coxsackievirus B (CVB) (1).

Studies reveal that when women encounter this infection during pregnancy, their children develop autoantibodies to the β-cells of the pancreas (2). Since these cells secrete insulin that tends to lower the blood glucose levels, the autoantibody-induced destruction of β-cells ends up in early-onset DM (also called as juvenile or childhood-onset DM).

This viral-provoked damage to the cells of pancreas specifically occurs in genetically susceptible children (3).

What is genetic susceptibility by the way? Think of the genes, which are hereditary units transferred from one generation to another. For instance, if you inherit a gene from one or either of your parents, who carry a mutation (i.e. an altered or damaged gene), this confers an amplified probability of developing a disease.

These susceptibility genes/proteins are Human Leukocyte Antigens (HLA), and type 1 DM has an increased association with the HLA genes (4, 5). They reside on the surface of white blood cells.

The HLA genes also function to differentiate self-proteins from proteins belonging to the foreign invaders.

Cutting to the chase, studies reveal that if both parents are diabetic, the child has a 30% chance of inheriting the disease. But bear in mind, it isn’t only the genetic inheritance that plays its role here; it’s both genetic and environmental (6,7).

From the above-listed discussion, we conclude that type 1 DM has a multifactorial causality.

CAUSES OF TYPE 2 DM (T2D)

Type 2 DM also occurs because of an interaction of genetic and environmental factors, nonetheless, the environmental causes differ in that it has no viral association.

Genetic factors

Family history is established as a cause for type 2 DM, as opposed to type 1 DM, where family history is not so commonly allied. The estimated risk of developing diabetes is 70% when both parents are diabetic (8). Likewise, the probability increases to about 3 times with a first-degree diabetic relative (8).

Additionally, if an identical twin has diabetes, the risk is about 70% (9).

Type 2 DM has a strong hereditary component (10).

I won’t go into the detail of the genes associated with type 2 DM as this could become complex, nonetheless, would just take an example of one or two genes and try to explain that how does gene mutation or alteration cause this type of diabetes.

Let us take a gene called insulin receptor substrate-1/IRS-1 (11). This gene is vital for the function of insulin. To be concise, most of the genes involved in the disease mechanism of type 2 DM either have a link to insulin function, or secretion, or the β-cell function. Development of DM attributes to the failure of any of these mechanisms.

The influx of zinc (a trace element) into the β-cells also affects the insulin synthesis and release (12). So, if there’s any genetic mutation affecting zinc, T2D is inevitable.

Environmental Factors

Chronic Inflammation, Obesity, and Insulin Resistance

Type 2 DM has a link to obesity, which decreases the synthesis of the insulin receptor. Hence, insulin cannot bind to its receptor to exert its effects, called as insulin resistance in the medical world.

It is, however, important to note that it is not merely insulin resistance (IR) that is a prominent feature in type 2 DM, impaired beta-cell function, and insulin secretion is as essential as IR in the progression to T2D (13).

What instigates this obesity-induced IR is actually a low-grade chronic inflammation of the white fatty tissue (which stores fats) which mediates the obesity-induced insulin resistance (14, 15).

Besides, studies show that the genes that confer the risk for obesity also increase the risk for type 2 DM (11).

As a matter of fact, not all obese persons develop T2D. Hence, studies demonstrate various mechanisms via which obesity causes type 2 DM. For instance, there appears to be a relationship between adipokine dysregulation (a cell-signalling protein associated with obesity) and type 2 DM (16). Obese people who have this type of genetic variation will acquire diabetes.

There are numerous other genetic defects common to both obesity and T2D. A study conducted by the Nature Clinical Practice Endocrinology and Metabolism identified another gene common to both obesity and type 2 DM (17).

Autoimmune Linkage of T2d

Contrary to the earlier assumptions, new research indicates that type 2 DM also has an autoimmune association (18), called as latent autoimmune diabetes of the adult/LADA (19, 20).

Pregnancy and Type 2 DM

During pregnancy, poor nutrition can also affect the glucose-insulin metabolism in the baby, who later goes on to suffer from obesity and type 2 diabetes (21).

Causes of Secondary DM

As aforementioned, there are conditions that secondarily give rise to diabetes. A few common ones are as under:

Risk Factors for Diabetes Mellitus

The risk factors for DM can be divided into modifiable versus non-modifiable risk factors:

Modifiable Risk Factors

These factors are reversible if one pays close attention. They are as follows:

Obesity (for type 2 DM): A body mass index (BMI) of ≥30 defines obesity (22).
Cigarette smoking: According to CDC, cigarette smoking puts you at a significant risk of acquiring diabetes, approximately a 30-40% chance of than non-smokers.
Sedentary lifestyle: Combining physical activity with a healthy diet attenuates the incidence of DM (23). Noteworthy is the fact that physical inactivity leads to obesity, and obesity per se is one of the greatest risk factors for T2D (24).
Diet (for T2D):
Unwholesome, junk foods like chips, French fries, sugary (25,26) or high-carb or high GI (glycemic index) diet, like white bread, white rice, and so on so forth. GI is a measure of how a carbohydrate-containing food will raise the blood sugar levels.
High-fat (saturated or trans fat) such as in red meat, hydrogenated vegetable oil
Low-fiber diet The high-fiber diet actually hastens insulin response after a meal, curbs appetite, and keeps you full for longer (27, 28).
Hypertension (high blood pressure): This is attributable to the fact that hypertension and DM both possess similar features like obesity and sedentary lifestyle (29).
Dyslipidemia (deranged lipid profile such as raised LDL/bad cholesterol, raised triglycerides, or low HDL/good cholesterol).
Prediabetes: Prediabetes is another risk factor for acquiring diabetes sooner or later.
Gestational diabetes: Children born to diabetic mothers have a strong inclination to develop type 2 diabetes later in life (30).
Medication-induced DM: Glucocorticoids, diuretics, β-blockers cause DM via various mechanisms.
Insulin resistance serves as another risk factor for prediabetes, which can progress to type 2 DM.
Sleep apnea: A sleeping disorder manifests as interrupted breathing during sleep. Sleep apnea alters glucose metabolism, enhancing the risk for type 2 diabetes (31).
Polycystic ovarian syndrome: This is a condition strongly associated with insulin resistance, obesity, and type 2 DM.

Non-modifiable Risk Factors

These are inherited, genetic, or developmental features that are irreversible and are not modifiable by dietary or other lifestyle changes.

Family history: There is a fourfold increase risk of prediabetes if your parents are diabetic (32). Likewise, if a first-degree relative has type 2 diabetes, the chances of developing diabetes amplify (33).
Race: People of varying ethnic origins have an increased prevalence of developing type 2 DM. According to ADA, among all the Americans, the African Americans, Mexicans, American Indians, and Pacific Islanders are more prone to develop diabetes than other populations.
Age: Aging calls for a high risk of hypertension, diabetes, cardiac diseases, and stroke. You cannot reverse the age-related changes, however, you can get yourself into the groove by adopting healthy lifestyles, such as eating healthy, exercising, watching out your weight, and monitoring the blood glucose levels at timely intervals (34). According to a survey conducted in 2011, CDC detected that 16% of Americans were diagnosed with diabetes at 18-39 years and 21% diagnosed at 65-79 years.
Gender: The prevalence of diabetes based on gender varies widely. A study showed that single women of 35-64 years were more prone to develop DM (35), whereas results from this study were almost equivocal (36).

Causes of Gestational DM (GDM)

GDM is diabetes that develops first time during pregnancy. As a rule of thumb, pregnant women have an increased propensity to develop insulin resistance and a variety of defects, including pancreatic β-cell function (37), leading to reduced insulin sensitivity (38).

The placenta supplying nutrients and oxygen to the baby produces a variety of hormones like estrogen, cortisol, and human placental lactogen, which can impede insulin action, culminating in GDM (39).

Moreover, consumption of high-calories in pregnancy worsens the insulin resistance and β-cell function (40).

Furthermore, GDM also has some autoimmune background with autoantibodies detected against the β-cells (41, 42).

Obesity also perpetuates GDM (43), just as a family history of having a first-degree relative with type 2 DM does (44).

References

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