Diabetes Brief Introduction

Sunday 12 January 2014

All About Diabetes Mellitus Type 1


Overview of Diabetes Type 1

Throughout the world, an estimated of 347 million people are affected by a chronic ailment known as diabetes or, also known as, diabetes mellitus.  Diabetes Mellitus is defined as a group of metabolic diseases whereby an individual has high blood glucose (blood sugar), due to low insulin production or because the body's cells do not respond properly to insulin, or both. There are different types of diabetes, however, in our blog we will focus on Type 1 Diabetes Mellitus (T1DB). Many complications may arise in the body such as hyperglycemia. Such complications may affect an individual daily life. To educate the public on T1DB, we decided to do a blog write up to share information on diabetes so that the general mass will be more equipped in knowledge on T1DB.

What is T1DB? 


T1DB is a medical condition where the body is unable to produce insulin, hence, leads to a very high level of blood sugar level and associated complications. This condition usually develops in childhood or adolescence period, and affects millions of people globally.



What causes T1DB?


T1DB is the result of autoimmunity of the own body’s immune cells. This results in the body’s immune system attacking the beta cells (cells that create insulin) of the pancreas. Therefore, people with type 1 diabetes cannot make enough insulin to control their blood sugar.


What triggers diabetes mellitus type 1?


1) Genetics
The inheritance of diseased autosomal dominant disease, where the mutated genes are passed down from the parents to their offsprings for generation. This results in the mutation in the human leukocytes antigen (HLA) on the leukocytes, thus decrease in the histocompatibility of leukocytes with the pancreatic beta cells and the secreted insulin as this mutation recognise the self-antigens as foreign. 


2) Viral infection 
One with viral infections such as coxsackievirus B, adenovirus, rubella, and mumps may develop type 1 diabetes because of molecular mimicry to the host pancreatic beta cells. The specific antibodies secreted by plasma cells against these viruses instead also binds to its own similar antigenic structure of the pancreatic cells, resulting in immune response by the T cells.


3) Environmental factors


 Imbalance lifestyle and diet may trigger the autoimmune destruction of beta cells in people with a genetic susceptibility to diabetes but its exact role is unknown.


Symptoms:



  • Increased thirst and frequent urination
  • Extreme hunger
  • Weight loss
  • Fatigue (due to cardiovascular disease)
  • Blurred vision





More severe consequences of diabetes type 1

  • Increase risk of getting stroke and heart disease of diabetic patients 
  • Foot ulcer and feet infection due to reduce in blood flow and neuropathy in the feet
  • Blindness due to long-term accumulated damage to the small blood vessels in the retina
  • Kidney Failure
  • Death


Biochemistry behind the disease:


Insulin action on glycogen regulation


 General function of insulin:
Insulin is a hormone that increase the permeability of the muscle and liver cells to increase the uptake of glucose and also activates glycogen synthase to convert glucose to glycogen for storage. This is to ensure excess carbohydrate is stored in the muscles and liver as glycogen after a meal. 
Please take note that insulin action is far more complex than just the control of enzyme phosphorylation. But we will just explain the control of enzyme phosphorylation by insulin.


 Regulation of cAMP by insulin: 
Insulin regulates cAMP level through the stimulation of cyclic nucleotide phosphodiesterases. These esterases degrades the phosphodiester bond in the cAMP molecule. Thus, reducing the cAMP level and protein kinase A then will not be activated. 




Activation of Protein Kinase B by insulin:
Activation of protein kinase B plays the main role in insulin's stimulation of glucose uptake. This is one of the role that protein kinase B does.

Another pathway stimulated by insulin: Protein phosphatase 1 activity

Insulin also stimulates protein phosphatase-1 activity. In the diagram below, it shows how protein phosphatase 1 affect the activation and deactivation of glycogen synthase, phosphorylase kinase and glycogen phosphorylase.





In conclusion, if a type 1 diabetic patient could not produce insulin, the various actions of insulin as shown and listed above will not be carried out in their bodies. 

Ketoacidosis 


Shortage of insulin in the blood will lead to diabetic ketoacidosis (DKA). Deficiency of insulin leads to increased levels of fatty acids caused by abnormal lipolysis in adipose tissues. Insulin functions are impaired in peripheral tissues due to the suppression by free fatty acids. Hence, gene expressed in response to insulin for respective tissues decreases. Major metabolic derangement such as glucose, lipid and protein metabolism is resulted. These major metabolisms account for the various diabetic symptoms.
Glucose metabolism is impaired due to insulin deficiency. Reduction of glucose uptake by peripheral tissues results in reduced rate of glucose metabolism. Thus the rate of glucose phosphorylation in hepatocytes reduced which in turn increase rate of delivery to blood. The elevation of hepatic glucose production and decrease in peripheral tissues metabolism results in high plasma glucose levels. Glucosuria is ensued when the ability of glucose absorption of the kidney is surpassed as glucose is an osmotic diuretic. The loss of water causes polyuria and activates thirst mechanism, polydipsia. Polyphagia follows due to negative caloric balance and tissue catabolism.

Protein metabolism is affected as insulin can no longer increase the rate of protein synthesis and the rate of protein degrading. The elevation of gluconeogenesis results in hyperglycemia.

Lipid metabolism is affected when insulin is absent. Absence of insulin causes the adipose tissues to release free fatty acids which will be converted into ketone bodies, acetoacetate and β-hydroxybutyrate. The increased availability of ketone bodies and free fatty acids will result in hyperglycemia.  Excess production of ketone bodies will also lead to ketoacidosis.




Prevention:


Restoration of the protective MHC class II expression through genetic engineering of hematopoietic stem cells for individuals that possess the susceptible allele.

Current treatments:


1) Insulin therapy

How is insulin being administered?:



Different types of insulin:


The problem of insulin therapy is it is not permanent treatment, where the patient has to constantly take note of his blood glucose level and inject the appropriate dosage of insulin several times daily. This is costly for long-term treatment, maintaining glucose control is also difficult and it is only a temporary cure.


2) Pancreas transplant

Requires donors to provide suitable pancreas to the patients. With functioning pancreas, there's isn't a need for insulin injections. However, due to immune rejection, the pancreas may be destroyed by the patient's immune system, thus the donated pancreas could only last for months or for a few years. Moreover, limited donors is also another problem.

3) Stem cells therapy (research ongoing)

 It involves the reprogramming of non-beta stem cells into beta cells. They will mature into insulin producing cells (unlimited source of functioning pancreatic beta cells) to produce insulin. This treatment has been carried out and researched on diabetic mice
However, the differentiation and growth of the stem cells are inconsistent from patients to patients. Moreover, if the stem cells in the pancreas remains undifferentiated, it will form teratomas (cancerous tumour) in the pancreas. Thus, if one uses human embryonic stem cells transplantation, it has to be first coaxed into precursors of the pancreatic tissue. 

4) Gene therapy (research ongoing)

Gene therapy experiments were carried out on diabetic rats. The diabetes rats were injected with viral or non-viral vector carrying the recombinant plasmid that contains the human insulin gene. The target cells of this gene therapy is the gastrointestinal K cells because it has favourable glucose response and could secrete hormones to convert proinsulin (inactive form) into insulin (active form). This therapy can be accompanied by stem cells therapy as most beta cells that are induced from non-beta cells couldn't process proinsulin into insulin.

References:

 1) World Health Organisation (2013) Diabetes, viewed on 13 Jan 2014, <http://www.who.int/mediacentre/factsheets/fs312/en/>

2) C.Nordqvist (2013) What is Diabetes? What causes diabetes?, viewed on 13 Jan 2014 <http://www.medicalnewstoday.com/info/diabetes/>

3) A.Mandal, What is type 1 diabetes?, viewed on 13 Jan 2014, <http://www.news-medical.net/health/What-is-Type-1-Diabetes.aspx>

4) R.Kivi and E.Boskey, Type 1 diabetes, viewed on 13 Jan 2014, <http://www.healthline.com/health/type-1-diabetes>

5) Conger. K (2011), New method allows human embryonic stem cells to avoid immune system rejection, study finds, 3rd March, viewed on 28 Dec 2013, <http://med.stanford.edu/ism/2011/march/wu.html>

 6) Welsh. N (2000), Prospects for gene therapy of diabetes mellitus, Gene therapy, vol7, no 3, p181-182
7) C.Tian, J.Bagley, N.Cretin, N.Seth,K.W.Wucherpfennig,J.Iacomini (2004), Prevention of type 1 diabetes using gene therapy, The Journal of Clinical Investigation, vol 114, no. 7, p969-978

 8) Symptomfind (2012), Diabetes Cause and Risk Factors, viewed on 13 Jan 2014, 
Stem cell-based treatments for Type 1 diabetes mellitus: bone marrow, embryonic, hepatic, pancreatic and induced pluripotent stem cells, Diabetic Medicine, vol 29, no.1, p14-23

10) Glogster, Diabetes Type 1, viewed on 15 Jan 2014, <http://www.glogster.com/glog/6n8a3269hptuttt5c26fua0>

11) Li.N, Yan.C.X, Zhe.D, and Hui.Q.T (2008), Gene therapy for type 1 diabetes mellitus in rats by gastrointestinal administration of chitosan nanoparticles containing human insulin gene, World J Gastroenterol, Vol 14, No. 26, Pg 4209–4215

 12) Alldredge J. (2010), The Biochemistry of Diabetes Mellitus and its Associated Complications, viewed on 1 Jan 2014, <http://science.csustan.edu/stone/chem4400/SJBR/JustinAlldredge.pdf >
13) The Global Diabetes Community (2014), Type 1 Diabetes Symptoms, diabetes.co.uk, viewed on 1 Jan 2014, < http://www.diabetes.co.uk/type1-diabetes-symptoms.html>

 14) King, M W. (2013), Diabetes Mellitus, The Medical Biochemistry Page, viewed 1 Jan 2014, <http://themedicalbiochemistrypage.org/diabetes.php>

15) MedBio, How Insulin Works, viewed on 3 Feb 2014, 
<http://www.medbio.info/horn/time%203-4/insulin's%20mechanism%20of%20action.htm> 
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