Type 2 Diabetes Mellitus: Etiology, Pathophysiology and Complications

This report provides a detailed overview of Type 2 Diabetes Mellitus (DM), a significant cause of morbidity and mortality worldwide. It begins by highlighting the increasing prevalence of Type 2 DM globally, emphasizing the rising diabetic burden, particularly in developing nations. The report then explores the etiology, including genetic mutations and metabolic abnormalities such as insulin resistance, impaired insulin secretion, and inappropriate glucose production by the liver. It also discusses various risk factors like obesity, age, ethnicity, and lifestyle. The pathophysiology section delves into the complex metabolic defects, including the role of pancreatic β-cell function, insulin secretion, and the impact of hormones like GLP-1 and GIP. The report further outlines the clinical manifestations, including polyuria, polydipsia, and polyphagia, and the complications such as retinopathy, neuropathy, and nephropathy. Diagnostic criteria based on glycemia levels, including fasting glucose, two-hour glucose, and A1c values, are also discussed. The report concludes with a discussion on lifestyle modifications as a crucial part of DM prevention and management, emphasizing the importance of early identification and intervention.

Diabetes Mellitus- Type 2
DIABETES MELLITUS - TYPE 2
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Diabetes Mellitus- Type 2
Diabetes Mellitus (DM) - Type 2
Despite health-care advancements, Type-2 DM is still one among the cause for
premature-morbidity as well as mortality rates. According to International- Federation of
Diabetes (2014), Diabetes was found to have affected 371 millions (prevalence-rate: 8.3%)
worldwide in 2012 with 90% of type-2 DM to 422 millions in 2014 (WHO, 2017). The
percentage was estimated to rise to 552 million populations with a prevalence rate of 9.9% by
2030 which is mainly due to the increasing diabetic burden specifically in developing nations
(Hill, 2013). In-regard to US, the number of diabetic cases have raised from 23.6 million in 2007
to approximately 25.8 million in 2011. The objective of this post is to discuss the etiological with
risk factors, pathophysiology, clinical manifestations, diabetic-complications and diagnostic tests
for Type-2 DM.
Though the exact cause is unknown, polygenic-gene mutations of MODY-1, 2 and 3 may
increase DM risk. The 3 metabolic abnormalities that related with type-2 DM are: 1) insulin
resistance- unresponsiveness of bodily tissues to insulin action; 2) decreased ability of pancreas
to secrete insulin (fatigue of β-cells) and 3) inappropriate production of glucose by liver. Other
risk-factors include uncontrolled growth of population, central obesity, advanced age,
westernization/urbanization, ethnicity, familial history, unhealthy food intake, sedentary life-
style, polycystic-ovarian syndrome and gestational diabetes (Pratley, 2013).
Type-2 DM is highly complex as well as progressive disease that is characterized with
varied metabolic abnormalities affecting multiple organ-systems (Fig: 1, Appendix-1). The major
defects that contributes to the type-2 DM development involves decreased secretion of insulin as
well as resistance of body-tissues as adipose-tissues, muscles with liver for insulin. The impaired
insulin secretion occurs because of the gradual reduction of the pancreatic β-cellular function
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Diabetes Mellitus- Type 2
along with decreased β-cellular mass. Only 20% of β-cells were found to function at the time of
diagnosis (Pratley, 2013). The progression of hyperglycemia may also impair the functioning of
β-cells and secretion of insulin. Moreover, increased production of liver-glucose (reduced insulin
action) with excess glucagon-production and altered incretin-effect plays a role in DM
pathophysiology. The hormones such as GLP-1 (glucagon-like peptide-1) that inhibits β-cellular
apoptosis and GIP (glucose dependent insulin-tropic-polypeptide) controls incretin- effect, a
process in which the secretion of insulin increases in-response to oral glucose than that of
intravenous glucose. The incretin-effect will be altered in type-2 DM patients, specifically due to
the altered effect of GLP-1 with GIP (Pratley, 2013).
The classic features of type-2 DM include polyuria and polydipsia that occurs due to
osmotic effect of glucose and polyphagia that occurs due to cellular malnourishment. Other
features include increased fatigue because of glucose deprivation, blurred vision, frequent
infections, delayed wound healing, weight loss and acanthosis nigricans (sign indicating insulin-
resistance). These features appear gradually and the manifestations may not occur till
complication occurs. Varied complications as retinopathy, angiopathy, neuropathy, nephropathy
and frequent infections may arise if Type-2 DM is uncontrolled. DM increases risk for cardio-
vascular diseases because of diabetic-angiopathy that accounts for 65% of DM-based deaths.
Type-2 DM patients are found to have 2-6 times increased risk for stroke and 2-8 times for
cardiac-failure (Pratley, 2013).
Diabetic-retinopathy is the main cause for blindness in persons aged 20-74 years (IDF,
2014, Bourne, 2013). Diabetic-nephropathy that affects 40% of Type-2 DM patients is the
mainetiology of chronic-renal disease and diabetic-neuropathy that affects 50% of DM adults
increases the chance of developing foot-ulcers and limb-amputation (Tesfaye, 2012, Singh,
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Diabetes Mellitus- Type 2
2013). At-least 80% of limb-amputations are done for foot ulcer/ injury as well as the amputation
risk is 25 times higher in DM persons as compared to non-DM persons (Callaghan, 2012).
Hearing loss, skin infections and Alzheimer's disease may develop if DM remains uncontrolled.
WHO with IDF (2014) have framed the criteria for diagnosing DM with cutoff values
based on glycemia levels that are linked with micro-vascular complications as well as the
population-distribution of glucose (plasma). Glucose tolerance-test (oral) showing fasting
glucose (plasma) value of 126 mg/L and/or two-hour glucose (plasma) of 200 mg/dL is
diagnosed as DM. A1c-value is used in diagnostics with 6.5% as cutoff value. The random
glucose (plasma) of 200 mg/dL is a diagnostic criterion in individuals having severe hyper-
glycemia. If a person meets these criteria, it will be confirmed by repeating tests and diagnosed
as DM. After diagnosing, DM individuals will be classified as type-1 (auto-immune) or 2
(insulin-deficiency/resistance) along with 8 sub-categories (ADA, 2017).
As, overeating as well as reduced physical activity levels are the major causes of the
overweight and obesity epidemic that contributes to DM, they have to be controlled by dietary
modifications by consuming less caloric food, avoiding sugars, staying active and performing
regular exercises (150 minutes of activity/ week). Life-style modifications play a greater role in
DM prevention that involves avoiding alcoholic beverages, quitting smoking and increasing
physical activities which help to slow-down the diabetic progression by delaying the
pathophysiological process of DM (Pratley, 2013). Life-style changes are safe and effective in
reducing risk of DM to 40%. Effective strategies has to be used to control diabetic burden by
early identification with intervention soon after alterations in glucose level is detected. But, as
the early features of type-2 diabetes are asymptomatic, identifying pre-diabetes is highly
challenging.
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Reference
ADA-American Diabetes Association. (2017). Classification and Diagnosis of Diabetes: American
Diabetes Association. 40(1): S11-S24. Retrieved from https://doi.org/10.2337/dc17-S005
Bourne, R.R et al. (2013). Causes of vision loss worldwide, 1990-2010: a systematic analysis:
Lancet Global Health. 1:e339-e349
Callaghan, B.C et al. (2012). Diabetic neuropathy: clinical manifestations and current treatments:
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Hill, J. (2013). Understanding the Social Factors That Contribute to Diabetes: A Means to
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IDA. (2014). International Diabetes Federation: Diabetes prevalence. Retrieved from
http://www.idf.org/home/index.cfm
Pratley, R.E. (2013). The Early Treatment of Type 2 Diabetes: The American Journal of
Medicine. 126: S2-S9. Retrieved from http://www.amjmed.com/article/S0002-
9343(13)00485-3/pdf
Singh, R., Kishore, L & Kaur, N. (2014). Diabetic peripheral neuropathy: current perspective and
future directions: Pharmacol Res. 80:21–35. doi. 10.1016/j.phrs.2013.12.005
Tesfaye, S & Selvarajah, D. (2012). Advances in the epidemiology, pathogenesis and
management of diabetic peripheral neuropathy: Diabetes Metab Res Rev. 28(1):8–14. doi.
10.1002/dmrr.2239
World Health Organization (WHO). (2017). Diabetes fact sheet. Retrieved from
http://www.who.int/mediacentre/factsheets/fs312/en/
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Appendix- 1
Fig: 1 shows pathophysiological sequence of type-2 DM
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