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4.6: Diabetes- Type 1 and Type 2 - Biology


An important example of negative feedback is the control of blood sugar.

  1. After a meal, the small intestine absorbs glucose from digested food. Blood glucose levels rise.
  2. Increased blood glucose levels stimulate beta cells in the pancreas to produce insulin.
  3. Insulin triggers liver, muscle, and fat tissue cells to absorb glucose, where it is stored. As glucose is absorbed, blood glucose levels fall.
  4. Once glucose levels drop below a threshold, there is no longer a sufficient stimulus for insulin release, and the beta cells stop releasing insulin.

Due to synchronization of insulin release among the beta cells, basal insulin concentration oscillates in the blood following a meal. The oscillations are clinically important, since they are believed to help maintain sensitivity of insulin receptors in target cells. This loss of sensitivity is the basis for insulin resistance. Thus, failure of the negative feedback mechanism can result in high blood glucose levels, which have a variety of negative health effects.

Let’s take a closer look at diabetes. In particular, we will discuss diabetes type 1 and type 2. Diabetes can be caused by too little insulin, resistance to insulin, or both.

Type 1 Diabetesoccurs when the pancreatic beta cells are destroyed by an immune-mediated process. Because the pancreatic beta cells sense plasma glucose levels and respond by releasing insulin, individuals with type 1 diabetes have a complete lack of insulin. In this disease, daily injections of insulin are needed.

Also affected are those who lose their pancreas. Once the pancreas has been removed (because of cancer, for example), diabetes type 1 is always present.

Type 2 Diabetes is far more common than type 1. It makes up most of diabetes cases. It usually occurs in adulthood, but young people are increasingly being diagnosed with this disease. In type 2 diabetes, the pancreas still makes insulin, but the tissues do not respond effectively to normal levels of insulin, a condition termed insulin resistance. Over many years the pancreas will decrease the levels of insulin it secretes, but that is not the main problem when the disease initiates. Many people with type 2 diabetes do not know they have it, although it is a serious condition. Type 2 diabetes is becoming more common due to increasing obesity and failure to exercise, both of which contribute to insulin resistance.


Diabetes

Diabetes mellitus (DM), commonly known as just diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. [11] Symptoms often include frequent urination, increased thirst and increased appetite. [2] If left untreated, diabetes can cause many health complications. [2] Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. [3] Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment. [2] [5]

Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced. [12] There are three main types of diabetes mellitus: [2]

    results from failure of the pancreas to produce enough insulin due to loss of beta cells. [2] This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". [2] The loss of beta cells is caused by an autoimmune response. [13] The cause of this autoimmune response is unknown. [2] begins with insulin resistance, a condition in which cells fail to respond to insulin properly. [2] As the disease progresses, a lack of insulin may also develop. [14] This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". [2] The most common cause is a combination of excessive body weight and insufficient exercise. [2] is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels. [2]

Type 1 diabetes must be managed with insulin injections. [2] Prevention and treatment of type 2 diabetes involves maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco. [2] Type 2 diabetes may be treated with medications such as insulin sensitizers with or without insulin. [15] Control of blood pressure and maintaining proper foot and eye care are important for people with the disease. [2] Insulin and some oral medications can cause low blood sugar. [16] Weight loss surgery in those with obesity is sometimes an effective measure in those with type 2 diabetes. [17] Gestational diabetes usually resolves after the birth of the baby. [18]

As of 2019 [update] , an estimated 463 million people had diabetes worldwide (8.8% of the adult population), with type 2 diabetes making up about 90% of the cases. [10] Rates are similar in women and men. [19] Trends suggest that rates will continue to rise. [10] Diabetes at least doubles a person's risk of early death. [2] In 2019, diabetes resulted in approximately 4.2 million deaths. [10] It is the 7th leading cause of death globally. [20] [21] The global economic cost of diabetes-related health expenditure in 2017 was estimated at US$727 billion. [10] In the United States, diabetes cost nearly US$327 billion in 2017. [22] Average medical expenditures among people with diabetes are about 2.3 times higher. [23]


Etiology

DM is broadly classified into three types by etiology and clinical presentation, type 1 diabetes, type 2 diabetes, and gestational diabetes (GDM). Some other less common types of diabetes include monogenic diabetes and secondary diabetes.[2][3][4][5]

Type 1 Diabetes Mellitus (T1DM)

Type 1 diabetes mellitus (T1DM)򠫌ounts for 5% to 10% of DM and is characterized by autoimmune destruction of insulin-producing beta cells in the islets of the pancreas. As a result, there is an absolute deficiency of insulin. A combination of genetic susceptivity and environmental factors such as viral infection, toxins, or some dietary factors have been implicated as triggers for autoimmunity. T1DM is most commonly seen in children and adolescents though it can develop at any age.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) accounts for around 90% of all cases of diabetes. In T2DM, the response to insulin is diminished, and this is defined as insulin resistance. During this state, insulin is ineffective and is initially countered by an increase in insulin production to maintain glucose homeostasis, but over time, insulin production decreases, resulting in T2DM. T2DM is most commonly seen in persons older than 45 years. Still, it is increasingly seen in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets.

Gestational Diabetes Mellitus

Hyperglycaemia, which is first detected during pregnancy, is classified as gestational diabetes mellitus (GDM), also known as hyperglycemia in pregnancy. Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.

GDM can be complicated by hypertension, preeclampsia, and hydramnios and may also lead to increased operative interventions. The fetus can have increased weight and size (macrosomia) or congenital anomalies. Even after birth, such infants may have respiratory distress syndrome, and subsequent childhood and adolescent obesity. Older age, obesity, excessive gestational weight gain, history of congenital anomalies in previous children, or stillbirth, or a family history of diabetes are risk factors for GDM.

A single genetic mutation in an autosomal dominant geneꃊuses this type of diabetes. Examples of monogenic diabetes include conditions like neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY). Around 1% to 5% of all diabetes cases are due to monogenic diabetes. MODY is a familial disorder and usually presents under the age of 25 years.

Secondary diabetes is caused due to the complication of other diseases affecting pancreas (for example, pancreatitis), hormone disturbances (for example, Cushing’s disease), or due to drugs (for example, corticosteroids).


Type 2 Diabetes at the Cellular Level

In order to better understand Type 2 diabetes and how it works, it is important to understand what is going on at the cellular level — especially if you want to understand how to defeat it.

For example, the key cells that are affected when Type 2 diabetes initially develops (due to hyperglycemia and hyperinsulinemia) are not the pancreatic beta cells, although pancreatic beta cell dysfunction is discussed in detail as a major factor of Type 2 diabetes pathology and pathogenesis.

The key cells that are directly affected by Type 2 diabetes include the red blood cells and tissue cells of the muscle, fat, and liver . These tissue cells are designed to take glucose (sugar) out of the blood, pull it into the cells and convert it to energy (ATP) — this is known as carbohydrate metabolism.

These cells require insulin (as a key) to trigger the glucose transports to pull in glucose from the blood. When these cells fail to respond adequately to circulating insulin, the glucose remains in the blood and these cells lose their sensitivity to insulin (a condition known as insulin resistance ). This, in turn, causes blood glucose levels to rise.

The body responds to this situation (of rising blood glucose levels) by signaling the pancreas to produce more insulin, causing insulin levels in the blood to become too high. This condition is known as hyperinsulinemia.

High insulin levels increase fat storage and inhibit fat metabolism — that is, you gain more weight and you’re unable to burn or metabolize the fat, which, in turn, makes you even fatter!

The cells in the liver also become insulin resistant and respond by making too much blood glucose. Because blood glucose is not absorbed by the cells, it stays in the blood, causing blood glucose levels to rise even further. This condition is known as hyperglycemia.

High glucose levels prevent your cells from being able to convert the glucose to energy (ATP) causing poor glucose metabolism and a reduction in energy, which, in turn, leads to mental and physical fatigue. [This is why most diabetics feel tired!]

Red blood cells are damaged due to the high glucose levels, as sugar molecules are attached (glycated) to the exterior part of the red blood cells, forming a crystalline (coarse) crust.

These coarse red blood cells cause damage as they circulate throughout your circulatory system, damaging arteries and capillaries.

This liver tries to repair this damage by producing cholesterol to be used like spackle to repair the damaged blood vessels.

But, the excess oxidation, glycation and inflammation in combination with the extra cholesterol produced by the liver, leads to arterial plaque formation — all triggered by an inflammatory immune response.

These coarse red blood cells cause greater damage in dense capillary areas such as the hands and feet, and fragile capillaries such as those that feed the kidneys and eyes.

As depicted in the following diagram, diabetes affects and causes damage to many different types of cells.

And, all of this cell damage leads to several diabetic complications that eventually leads to blindness, kidney failure, amputation, heart attack and stroke.

Other health issues that may occur include high blood pressure, high cholesterol, high inflammation markers, periodontal disease, and erectile dysfunction.


Total number of people with diabetes reaches 4.6 million

Almost nine in ten people diagnosed with diabetes have Type 2, and it is estimated that there are nearly 1 million people currently living with the condition who don’t know they have it because they haven’t been diagnosed. Counting this undiagnosed population, the total number of people living with diabetes reaches 4.6 million.

While Type 1 diabetes isn’t currently preventable, three in five cases of Type 2 diabetes can be prevented or delayed by making healthier choices, by helping people understand their own risk of developing the condition − and how to reduce it – and by securing early diagnosis for those known to be at high risk.

There are an estimated 12.3 million people at increased risk of Type 2 diabetes in the UK, and obesity is the leading cause in the majority of preventable cases.

Three in five women (59 per cent) and two in three men (68 per cent) are overweight or obese. More than one in five children (22 per cent) are overweight or obese in their first year of primary school in England. This increases to more than one in three (34 per cent) by the time they leave primary school.


Symptoms of type 1 and type 2

Type 1 and type 2 diabetes share common symptoms. They are:

  • going to the toilet a lot, especially at night
  • being really thirsty
  • feeling more tired than usual
  • losing weight without trying to
  • genital itching or thrush
  • cuts and wounds take longer to heal
  • blurred vision.

But where type 1 and type 2 diabetes are different in symptom is how they appear. Type 1 can often appear quite quickly. That makes them harder to ignore. This is important because symptoms that are ignored can lead to diabetic ketoacidosis (DKA).

But type 2 diabetes can be easier to miss. This is because it develops more slowly, especially in the early stages. That makes it harder to spot the symptoms. That is why it is important to know your risk of developing type 2 diabetes. Some people have diabetes and don’t know it. They can have it for up to 10 years without knowing.


More information on genetics

If you would like to learn more about the genetics of all forms of diabetes, the National Institutes of Health has published The Genetic Landscape of Diabetes . This free online book provides an overview of the current knowledge about the genetics of type 1 and type 2 diabetes, as well other less common forms of diabetes. The book is written for health care professionals and for people with diabetes interested in learning more about the disease.


Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A., Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society, 3(3), 643–654.


Chronic Inflammation

As previously mentioned, high glucose levels leads to damaged insulin receptors and dysfunctional glucose transporters (GLUT4) , insulin resistance and an increase in fatty acids, which leads to an increase in visceral or belly fat.

And, this leads to an increase in oxidative stress and glycation, causing the (glycated) red blood cells to cause damage to the inner walls of the arteries.

This, in turn, triggers an immune response of cellular inflammation in order to release repair agents and chemicals to repair the damage to the arterial walls, which leads to an increase in inflammation.

Normally, inflammation is the first stage of cellular repair, but, in this scenario, the inflammation is ongoing and leads to cell and tissue damage.

This ongoing inflammation is known as chronic inflammation, which fuels insulin resistance and your diabetes. [Ref: PubMed, NIH]

This creates a vicious cycle where the inflammation causes more insulin resistance which causes more hyperglycemia and hyperinsulinemia and cellular damage to additional cells and tissues. And, when these additional cells and tissues become damaged, they trigger another inflammatory immune response to try to repair the damaged cells and tissues.

This, in turn, triggers oxidative stress — production of free radicals — which cause even more cell damage and even more inflammation.

However, the good news is that you can interrupt this vicious cycle by eating anti-inflammatory and antioxidant- rich foods to reduce the inflammation and oxidation.


CONCLUSIONS—

Our study showed that in people with diabetes diagnosis after the age of 30 years, the impact of type 1 and type 2 diabetes on the risk of CVD and total mortality was similar. Furthermore, the harmful effect of hyperglycemia on mortality was more profound in type 1 diabetic participants than in type 2 diabetic participants.

Our study is in agreement with the Early Treatment Diabetic Retinopathy Study, which showed that 5-year all-cause mortality rates were quite similar regardless of the type of diabetes and sex. All-cause mortality rate per 1,000 person-years was 15.3 in type 1 diabetic men, 10.3 in type 1 diabetic women, 15.6 in type 2 diabetic men, and 16.1 in type 2 diabetic women in the age-group of 50–59 years (13). In contrast, the World Health Organization Multinational Study of Vascular Disease in Diabetes Study demonstrated that type 2 diabetic women had lower relative CVD mortality compared with that in type 1 diabetic subjects and type 2 diabetic men (14).

We observed a higher hazard ratio of GHb for CVD in type 1 than in type 2 diabetic participants. Because the risk of CVD did not differ between the types of diabetes, this implies that nonglycemic related risk factors have to play a significant role in the risk of CVD in type 2 diabetes. Indirect evidence for this notion comes from the adjustment for major CVD risk factors, because it substantially reduced the hazard ratio for CVD in type 2 diabetic women but increased it in type 1 diabetic women. Similar results have been observed in previous studies (15,16), particularly in women with type 2 diabetes. This underlies the importance of multiple risk intervention in type 2 diabetic subjects (17) and possibly even more importantly in type 2 diabetic women.

A marked increase in the relative risk of CVD in women has been observed not only in type 2 diabetes (15) but also in type 1 diabetic subjects, with higher diabetes-related relative risk for all-cause, CVD, or CHD mortality in women than in men (18–23). Also in our study diabetes-related relative risk was, to a greater extent, increased in women (10- to 13-fold) than in men (3- to 4-fold).

A recent comparative analysis on CVD and coronary artery disease risk in type 1 diabetes, based on findings from the Pittsburgh Epidemiology of Diabetes Complications Study, suggested that glycemia may have a stronger effect on coronary artery disease in patients without albuminuria than in those with albuminuria (24). Our results were different because glycemia had a prominent effect on CVD mortality in type 1 diabetic subjects with proteinuria.

Poorly controlled and long-lasting glycemia in type 1 diabetes leads to the development of nephropathy. Even milder abnormalities of renal function are known to lead to dyslipidemia, raised blood pressure, and thus contribute to the high risk of CVD in type 1 diabetes (21,25). Similar pathways of vascular complications are likely to be shared in type 1 and type 2 diabetes. On the basis of our observations and previous epidemiological studies, it is not surprising that the treatment of hyperglycemia has been shown to reduce long-term complications in type 1 diabetic patients (26). A recent meta-analyses of randomized trials demonstrated comparable benefits of improving glycemic control to reduce the incidence of macrovascular events in both type 1 and type 2 diabetes (27). Intensive therapy of diabetes decreases the risk of complications, including CVD, as demonstrated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study in subjects with type 1 diabetes (8).

This study has limitations. The glucometabolic status was not reevaluated in the nondiabetic study cohort during the study period. No repeated GHb measurements were performed. Therefore, the effect of hyperglycemia on the risk of CVD mortality may be underestimated. Because the age of onset of diabetes in our study participants was >30 years, our results cannot be generalized to early-onset type 1 diabetes. Furthermore, the number of type 1 diabetic participants was limited.

In summary, our findings indicate similarities in the risk of CVD related to type 1 and type 2 diabetes in people with diabetes diagnosis after the age of 30 years. Based on our results, hyperglycemia is the key risk factor for mortality in both main types of diabetes, with a greater hazard ratio per unit change of GHb in type 1 than in type 2 diabetes. Our findings imply that intensified therapy aimed at achieving near normoglycemia in both type 1 and type 2 diabetes is warranted.

Total and CVD mortality during 18 years of follow-up in type 1 (T1D) diabetic, type 2 diabetic (T2D), and nondiabetic (Non-D) men (M) and women (W). The Cox model plot for total and CVD mortality, adjusted for age, area of residence, current smoking, use of alcohol, systolic blood pressure, BMI, total and HDL cholesterol, Cockroft-Gault estimate of creatinine clearance, and urinary protein (log).

CHD, CVD, noncardiovascular, and total mortality according to the status of diabetes and glycemia. Deaths per 1,000 person-years (y-axis) by GHb (x-axis) plotted by group-specific medians of tertile ranges. Black lines, type 1 diabetic participants gray lines, type 2 diabetic participants solid lines, men and women long dashes, men short dashes, women.

Cox model hazard ratio (95% CI) of total, CVD, CHD, and non-CVD mortality according to the presence and type of diabetes

Increment of the risk of CVD mortality (%) (Cox model) per increase of one unit (%) of GHb