Life style Disorders:Diabetes

Presented By Lee-Ann Kara 551033

What is diabetes?

Diabetes is a chronic disease that arises when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces.

So what is insulin?Insulin is a hormone synthesized in significant quantities in beta cells in the pancreas. Insulin enables cells to take in glucose from the blood and use it for energy.

Figure 1: pancreatic islets contain beta cells which produces insulin.

Why is diabetes a serious concern?Global overview:

•At present 2014, it is estimated 285 million people.•The diabetic population is expected to explode to 438 million by 2030.•Currently the age group most affected is 40 – 59 years.• By 2030 it is expected that the age group 60-79 years are most likely to be affected the most.

•The worlds largest diabetic population is in India. (estimated at 50.8 million)• 70% of diabetic cases exist in poorer countries (with low incomes).

Add pic of old lady

Global Diabetes Epidemic (From 2000 to 2030 - in millions)Lifestyle disorders such as obesity are fuelling the incidence of diabetes on a global

scale.

Two main types of diabetes?

Type 1Type 2

Pix of diabtese graphs

Figure 2: diagram showing the difference of type 1 and type 2 diabetes

Causes of type 1 diabetes:

Genetic susceptibility

Autoimmune destruction of beta cells

Environmental factors

Viruses and Infections

Infant feeding practices

Causes of type 2 diabetes:

Genetic susceptibility

Obesity and Physical inactivity

Insulin resistance

Abnormal glucose production by the liver

Beta cell dysfunction

Major symptoms of Diabetes

•Excessive thirst and increased urination.

•Fatigue

•Weightloss

•Blurred vision

•Slow healing sores

•Tingling hands and feet

•Red swollen tender gums

TAKE YOUR BODY’S HINTS

SERIOUSLY!

Major symptoms of Diabetes

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Complications

•Eye complications •Foot complications •Skin complications•Heart problems•Hypertension •Mental health •Hearing loss •Gum disease•Neuropathy•Nephropathy•PAD (peripheral arterial disease)•Stroke•Erectile dysfunction•Healing of wounds

If diabetes is not

adequately controlled

the patient has a

significantly higher risk

of developing

complications!

Controlling Diabetes: Treatment

•Diabetes type 1 lasts a lifetime, there is no known cure.

•Type 2 usually lasts a lifetime, however, some people have managed to get rid of

their symptoms without medication, through a combination of exercise, diet and

body weight control.

•Type 1 diabetes is usually treated with

regular insulin injections, as well as a

special diet and exercise.

•Type 2 diabetes is usually treated with

tablets, exercise and a special diet, but

sometimes insulin injections are also

required.

Molecular action of insulin drugs

Figure 3:Insulin action in the cell. Insulin exerts multiple effects in the cell. Insulin action is mediated by the binding of insulin to its receptor, and thesubsequent phosphorylation of the receptor and other substrates by the receptor tyrosine kinase.

Prevention

•Control your weight

•Exercise regularly

•Eat a balanced diet

•Avoid sugary foods

•Try and avoid smoking

•Alcohol may help now and again

Summary•Diabetes is a complex group of diseases with a variety of causes. Scientists believe genes

and environmental factors interact to cause diabetes in most cases.

•People with diabetes have high blood glucose, also called high blood sugar or

hyperglycemia. Diabetes develops when the body doesn’t make enough insulin or is not able

to use insulin effectively, or both.

•Insulin is a hormone made by beta cells in the pancreas. Insulin helps cells throughout the

body absorb and use glucose for energy. If the body does not produce enough insulin or

cannot use insulin effectively, glucose builds up in the blood instead of being absorbed by

cells in the body, and the body is starved of energy.

•The two main types of diabetes are type 1 diabetes and type 2 diabetes..

•Type 1 diabetes is caused by a lack of insulin due to the destruction of insulin-producing

beta cells. In type 1 diabetes—an autoimmune disease—the body’s immune system attacks

and destroys the beta cells.

•Type 2 diabetes develops when the body can no longer produce enough insulin to

compensate for the impaired ability to use insulin.

Scientists discover new causes of diabetes

Flanagan,S.E., De Franco,E.,Allen,H.L.,Zerah,M.,Abdul-Rasoul,M.M.,Edge,J.A.,Stewart,H.,Alamiri,E., Hussain,K.,Wallis,S.,de Vries,L.,Rubio Cabezas,O.,Houghton,J.A.L.,Edghill,E.L.,Patch,A.M., Ellard,S., and Hattersley,A.T.(2014). Analysis of Transcription Factors Key for Mouse Pancreatic Development Establishes NKX2-2and MNX1 Mutations as Causes of Neonatal Diabetes in Man. Cell Metabolism 19, 146–154.

This article provides further insights on how the insulin-producing beta cells are formed in the pancreas.

Aim:To perform a comprehensive search for recessive mutations in genes encoding transcription factors known to be critical for pancreatic development in mice in a large collection of PNDM patients born to consanguineous parents.

Tested mutations in homozygous regions encompassing known transcription factor genes independently of the clinical features to avoid the possible bias introduced when clinical features guide candidate gene testing.

Brief introduction:

•Transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes.

•To date, mutations in eight different pancreatic transcription factor genes(PDX1, PTF1A, GLIS3, PAX6, RFX6, NEUROD1, NEUROG3, GATA6) have been identified in patients with neonatal diabetes

•Neonatal diabetes is diagnosed when a child is less than six months old, and some of these patients have added complications such as muscle weakness and learning difficulties with or without epilepsy.

•Neonatal diabetes is caused by a change in a gene which affects insulin production. This means that levels of blood glucose (sugar) in the body rises dangerously high.

Experimental procedures

CohortExclusion of

Nontranscription factor mutations in

PDNM

Detecting mutations of pancreatic

transcription factor genes

Genome- wide SNP analysis to

localize etiological gene

by linkage

Sequencing of pancreatic

transcription factor genes

Patient phenotype assessment

Results

•88 % patients with known genetic etiology had homozygous mutations.•This confirms that neonatal diabetes in the offspring of consanguineous families is usually recessive.•Nonsense homozygous NKX2-2 mutations were identified in 3 patients from two families.•These mutations are pathogenic.•All 3 patients were found to have severe defects in insulin secretion and show normal exocrine function.•This has been show to be similar to mice that are homozygous for a targeted disruption of Nkx2-2 and die after birth due to severe hypergylcemia. They also have normal exocrine function however but lack beta cells.•Patients found with NKX2-2 mutations were found to have severe developemental delay, thus affecting motor and intellectual function. Other features are cortical blindness and hearing impairment.•This is consistant as the same neurological features have been seenin the Nkx2-2 knockout mouse, with Nkx2-2 being important for hindbrain development, ventral neuronal patterning and oligodendrocyte differentiation.

•Discovered that mutations in two specific genes which are important for development of the pancreas can cause the disease

Figure 4: Partial pedigrees of two families in which NKX2-2 mutations were identified. Below each pedigree is an electropherogram depicting the homozygous mutation identified in each patient. N/A, not available

Figure 5: Partial pedigrees of two families with MNX1 mutations. Below each pedigree is an electropherogram depicting the homozygous mutation identified in each patient.

Results

•Two patients were found to have homozygous missense mutations in MNX1.•p.F248L and p.F272L•Homeodomain

Figure 6: The highly conserved sequence of the homeobox domain within MNX1 is provided for various species. An arrow points to the residues found to be mutated inthe two probands with permanent neonatal diabetes.

•Both patients in this study showed severe intrauterine growth retardation and have been

diagnosed with diabetes in infancy. Showing no evidence of exocrine pancreatic dysfunction.

•A similar scenario was seen in Mnx1 null mice, where these mice are much smaller as

compared to normal size mice, have reduced number of beta cells but a normal exocrine

function.

•Patient 1 was found to have extrapancreatic developmental features which includes growth

retardation, difficulties swallowing, severe constipation, and neurological complications.

•This patient died at 10 months due to respiratory failure.

•Mnx1 null mice are difficult to study since they die at birth due to respiratory paralysis.

•Patient 2 didn’t show any extrapancreatic developmental features.

•Further studies are required to investigate the variability in phenotype between the two

patients.

Limitations

•The minimum prevalence of transcription factor mutations in our

cohort of patients with consanguineous PDNM was 7.5 % but the true

prevalence may be slightly higher since heterozygous or compound

heterozygous mutations would have been missed as a result of the

study design.

•Limited information on pancreatic development is provided since

patients with the two mutations have severe developmental delay

suggesting that in depth studies of pancreatic development and

neurological function isnt possible.

Conclusion

•Results confirm that the consequence of inactivation of pancreatic

transcription factor genes in humans is similar to the phenotype

observed in knockout mice.

•Mutations in NKX2-2 and MNX1 cause neonatal diabetes.

•Confirms a key role for NKX2-2 and MNX1 in human pancreatic

development.

•This study validates the use of knockout mice for understanding beta cell

development in humans.

Future prospects

•Parents will now have answers for their children with this rare

condition.

•This study will help scientists understand how the pancreas develops.

•Knowing the cause of diabetes will result in improved treatment.

•Will provide insight to people with future pregnancies.

•Knowing the which mutations of etiological genes are responsible for

diabetes, can potentially serve as a platform for future research and

create therapeutic drugs that can prevent these mutations from

occuring.

•However further research is needed

References