Diabetes Mellitus Type 2 (Adult Onset Diabetes Mellitus)

Blue circle for diabetes[1]

Diabetes mellitus is a metabolic disorder associated with permanently increased serum levels of glucose. In diabetes mellitus type 2, this condition mainly results from peripheral insulin resistance.

This disorder is the consequence of the following process: metabolic.

Presentation

Complications as mentioned in the previous section don't usually occur until years after onset of hyperglycemia. In fact, the majority of DM2 patients may note merely unspecific symptoms or none at all. Thus, clinical presentation is of minor importance for DM2 diagnosis during the early stage of the disease. Due to the high prevalence of DM2, regular check-ups should be conducted and should comprise an evaluation of blood glucose levels, lipid profiles and blood pressure. The main finding that prompts workup of DM2 is hyperglycemia as detected during routine screens. Evaluation of the latter parameters aims at assessing cardiovascular risk factors and identifying possible comorbidities.

Nevertheless, there are some symptoms and signs that may indicate DM2:

Workup

Detection of hyperglycemia during routine screens is often the first hint at DM2. But although the measurement of blood glucose levels is a very sensitive approach to DM2 diagnosis, it is also very unspecific. Hyperglycemia may be induced by a variety of physiological and pathological conditions, the most common one being the recent ingestion of food. Thus, blood samples should be drawn from patients after overnight fasting. They should be collected in sodium fluoride tubes. Fasting glucose concentrations above 125 mg/dl are required for the diagnosis of DM.

Some patients who show unaltered fasting glucose levels, may nevertheless present impaired glucose tolerance. This condition may be considered a pre-diabetic pathology that should ensue therapy similar to manifest DM2. The World Health Organization (WHO) defines impaired glucose tolerance as "a state of higher than normal blood (or plasma) glucose concentration 2 hours after 75 gram oral glucose load" that does not meet criteria for DM, i.e., that surpasses 140 mg/dl, but not 200 mg/dl [10]. In case this value is > 200 mg/dl, the patient suffers from DM.

The aforementioned tests represent the current condition of the patient; in contrast, hemoglobin A1c (HbA1c) tests may be conducted to evaluate how well blood glucose levels were controlled during the last trimester. This test is often applied in DM2 diagnostics, but is of even greater importance during follow-ups: It shows if the patient responds well to therapy and/or if they comply with the therapeutic regimen.

Further diagnostic measures, e.g., ophthalmologic examination or urine analysis, are carried out to evaluate whether a DM2 patient is developing diabetic retinopathy, diabetic nephropathy or other complications.

Treatment

Treatment aims at normalizing blood glucose levels and consists in lifestyle adaptations and medical therapy. With regards to the latter, several oral antidiabetic drugs are available. Metformin, a bioguanide, is most frequently prescribed as first-line treatment of DM2. Metformin counteracts peripheral insulin resistance and diminishes hepatic gluconeogenesis. Combination of metformin with other compounds may be required. Sulfonylureas and meglitinides, for instance, may supplement metformin therapy by stimulating pancreatic insulin release. Insulin administration is another option to this end. Decision aids have been developed to facilitate the selection of the most appropriate drug to combine with metformin [11].

Regular follow-ups are required to evaluate response to therapy. As has been indicated in the previous section, HbA1c tests are very helpful to this end.

Prognosis

DM2 may be associated with significant morbidity and - at least indirectly - mortality. Persistent hyperglycemia causes diabetic microangiopathy, which interferes with microcirculation and the respective pathophysiological development is assumed to account for severe complications like:

In sum, the average reduction of life expectancy has been estimated to be about eight years [2]. An adequate control of blood glucose levels is the key to risk minimization and can only be achieved if patients understand the importance of compliance. Further improvement of prognosis can be attained by intensive treatment of accompanying cardiovascular risk factors [9].

Etiology

DM2 is a multifactorial disease; and while several risk factors have been identified to date, there are still considerable knowledge gaps regarding the etiology and pathogenesis of this disorder. According to current knowledge, both genetic predisposition [3] and lifestyle decisions contribute to hyperglycemia, preferentially in patients aged 50 years an older. Additionally, DM2 and other civilization diseases are frequently mutually dependent.

In detail, the following factors favor the development of DM2:

Cut-off values can hardly be defined. The more severe a certain pathology, the higher the increase of risk of DM2. With regards to overweight and obesity, for instance, people with a body mass index (BMI) > 25 have been shown to have a 3-fold augmented risk of developing DM2. In contrast, those individuals whose BMI > 30 present a 10-fold increased risk [4].

It has been reported that neuropsychiatric disorders are more prevalent among DM2 patients than among the general population. Thus, depression, schizophrenia and similar diseases are sometimes named as risk factors for DM2. In the light of recent findings though, neuropsychiatric disorders are rather assumed to be consequences of DM2 than causes [5].

Epidemiology

As has been indicated in the previous section, the individual risk of developing DM2 increases with age. Available epidemiological data confirm that DM2 is most commonly diagnosed in patients aged 40 to 60 years, but they also show that the average age of onset is decreasing. Such developments are presumably due to lifestyle changes and an increased prevalence of other risk factors, e.g., of poor diets, overweight/obesity and lack of exercise. Data representing the current situation in the United States shall be mentioned exemplarily [2]:

  • Lifetime risks of developing DM2 range from 33% in women to 39% in men.
  • Prevalence peaks in people aged > 60 years, and in this age group, a total of 67% is assumed to suffer from manifest DM2 or pre-diabetic conditions.
  • About 69% of US-American adults are overweight or obese.
  • With respect to the elderly, 73% of all women and 77% of all men have BMI > 25.
  • Increasing tendencies are noted for all these values.

The latter statement also applies for countries that are not considered part of the Western world. Here, adoption of unhealthy diets contributes to rising incidence and prevalence of DM2. To date, the overall values are much lower, though [6].

Sex distribution
Age distribution

Pathophysiology

Both peripheral insulin resistance, i.e., a diminished response to insulin release, as well as a reduction of insulin synthesis in pancreatic β cells accounts for the onset of persistent hyperglycemia in DM2 patients.

To date, the pathogenesis of insulin resistance is not well understood. Similar to DM2 itself, this condition is presumably multifactorial. Insulin receptors are tyrosine kinase receptors and consist of α and β subunits. Upon binding of insulin, phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are activated and mediate distinct effects. In DM2 patients, PI3K-dependent signaling cascades are insufficiently stimulated [7], which results in a reduction of glucose and potassium uptake by myocytes, hepatocytes, adipocytes and other cell types. This initial stage of the disease is marked by hyperglycemia and normoinsulinemia.

In an attempt to overcome this condition, synthesis and release of insulin by pancreatic β cells is stimulated further. Because of the underlying insulin resistance, blood glucose levels cannot be normalized and hyperglycemia and hyperinsulinemia develops. This condition is rarely recognized before β cell exhaustion sets in. Insulin-producing cells are unable to keep up with the persistent demand for hormone release and finally, patients show deficient insulin production and hypoinsulinemia. Only the combination of insulin resistance and secretion deficit trigger the onset of DM2 [8].

Prevention

Several preventive measures can be deducted from the above given list of risk factors for DM2. In general, maintenance of a healthy, balanced diet, regular exercise and avoidance of overweight and obesity go a long way towards reducing the individual risk of developing this chronic disease. Such measures have both direct and indirect effects, i.e., they also contribute to diminish hypertension, dyslipidemia and atherosclerosis, and these pathologies are, in turn, risk factors for DM2.

Patients should be advised about the severity of DM2. Hyperglycemia is not painful and symptoms may not manifest in years, which is why large parts of the population underestimate the morbidity associated with that condition. Many people have heard about diabetic retinopathy, diabetic nephropathy and diabetic food ulcer, but may chose not to adhere to recommendations regarding prevention or therapy since they are currently feeling well.

In case of manifest DM2, compliance with the therapeutic regimen is of utmost importance to decrease the risk of severe complications of the disease. However, medical treatment should never be a substitute for lifestyle adaptation.

Summary

Diabetes mellitus (DM) is a very common metabolic disorder characterized by permanently increased blood glucose levels. Distinct types of DM have been described, according to the pathomechanisms that cause hyperglycemia.

Under physiological conditions, high serum concentrations of glucose trigger insulin release from pancreatic β cells. Subsequently, insulin binds to cell surface receptors expressed by a variety of distinct tissues and thus mediates the influx of glucose and potassium ions. This way, cells are supplied with the most important substrate for glycolysis and generation of ATP, and blood glucose levels are decreased.

Hyperglycemia may result from distinct disturbances of the chain of events described above. For instance, the overall amount of insulin released by β cells may be reduced because of an autoimmune reaction against those cells. This is the case in diabetes mellitus type 1 (DM1). On the other hand, its target cells may lose their susceptibility to insulin and despite satisfactory release of this hormone, blood glucose concentrations cannot be diminished to physiological values. This is characteristic for diabetes mellitus type 2 (DM2). Of note, there are several additional types of DM that may be related to hereditary dysfunction of β cells or peripheral resistance to insulin, pancreatic diseases [1], or the effects of other hormones or drugs. DM2 is by far the most prevalent type of DM.

Adequate regulation of blood glucose levels may be a real challenge and both severe hyperglycemia and hypoglycemia may have detrimental consequences in the short term. Fortunately, only minor shares of DM2 patients present in a life-threatening hyperosmolar hyperglycemic state, with diabetic coma or hypoglycemic coma. However, large parts of the elder population have to face long-term sequelae of permanently increased concentrations of blood glucose: diabetic retinopathy, diabetic nephropathy and diabetic food ulcer are only examples for severe complications of DM2 [2]. These and other DM2-related pathologies account for the high morbidity associated with this disease.

Patient Information

Diabetes mellitus type 2 (DM2) is a metabolic disorder characterized by permanently increased blood glucose levels. This condition is mainly the result of peripheral insulin resistance and reduced insulin release by pancreatic β cells. The term peripheral insulin resistance refers to the inability of insulin to mediate glucose uptake into cells of muscles, liver and other tissues. Consequently, blood glucose concentrations remain high, and pancreatic β cells are continuously stimulated to release more insulin. Eventually, this causes β cell exhaustion and lack of insulin. Thus, DM2 patients typically show hyperglycemia and hypoinsulinemia.

DM2 is a prime example for what is commonly called a civilization disease. Thereby, it is put on the same footing as hypertension, atherosclerosis and hypercholesteremia. And in fact, these diseases share many risk factors - and while some of them are beyond the patient's control, others can be prevented by taking the corresponding lifestyle decisions. In detail, the following pathologies have been identified as risk factors of DM2:

  • Family history of DM2
  • Medical history of gestational DM (patient or their mother)
  • Older age
  • High-caloric diet
  • Lack of exercise
  • Overweight and obesity
  • Hypertension
  • Atherogenic dyslipidemia (hypercholesteremia, hypertriglyceridemia)

Adaptations of lifestyle and compliance with therapeutic regimens is of utmost importance to delay disease progression and to minimize the risk of severe, potentially life-threatening complications like myocardial infarction, diabetic foot ulcer, end-stage renal disease and blindness. Medical treatment should always be considered a supplement of lifestyle adjustments, not a substitute of the latter.

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References

  1. Balzano G, Dugnani E, Pasquale V, et al. Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients. Acta Diabetol. 2014; 51(5):801-811.
  2. Gray N, Picone G, Sloan F, Yashkin A. Relation between BMI and diabetes mellitus and its complications among US older adults. South Med J. 2015; 108(1):29-36.
  3. Fuchsberger C, Flannick J, Teslovich TM, et al. The genetic architecture of type 2 diabetes. Nature. 2016.
  4. Bonora E, Kiechl S, Willeit J, et al. Population-based incidence rates and risk factors for type 2 diabetes in white individuals: the Bruneck study. Diabetes. 2004; 53(7):1782-1789.
  5. Lunghi C, Moisan J, Gregoire JP, Guenette L. Incidence of Depression and Associated Factors in Patients With Type 2 Diabetes in Quebec, Canada: A Population-Based Cohort Study. Medicine (Baltimore). 2016; 95(21):e3514.
  6. Sabir A, Ohwovoriole A, Isezuo S, Fasanmade O, Abubakar S, Iwuala S. Type 2 diabetes mellitus and its risk factors among the rural Fulanis of Northern Nigeria. Ann Afr Med. 2013; 12(4):217-222.
  7. Muntoni S, Muntoni S. Insulin resistance: pathophysiology and rationale for treatment. Ann Nutr Metab. 2011; 58(1):25-36.
  8. Carrera Boada CA, Martinez-Moreno JM. Pathophysiology of diabetes mellitus type 2: beyond the duo "insulin resistance-secretion deficit". Nutr Hosp. 2013; 28 Suppl 2:78-87.
  9. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet. 2011; 378(9786):156-167.
  10. World Health Organization. About diabetes. Diabetes Programm. 2016; http://www.who.int/diabetes/action_online/basics/en/index2.html. Accessed 15th July, 2016.
  11. Shillington AC, Col N, Bailey RA, Jewell MA. Development of a patient decision aid for type 2 diabetes mellitus for patients not achieving glycemic control on metformin alone. Patient Prefer Adherence. 2015; 9:609-617.

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Media References

  1. Blue circle for diabetes, Public Domain

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