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 1
Type 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

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 the
subsequent 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
Cohort
Exclusion 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 in
the 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