Ahmed Mashkour ahmed'mashkourutoronto'ca

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Biochemistry of Diabetes Mellitus
Ahmed Mashkour (ahmed.mashkour_at_utoronto.ca) Sachin
Ibrahim (doublecross_007_at_hotmail.com) Samer
Charab ( samer_charab_at_hotmail.com ) Omair Lakhani
(omair.lakhani_at_utoronto.ca) January 28th, 2009
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Biochemistry of Diabetes Mellitus

• Diabetes Mellitus is a disease characterized by
  disordered metabolism of glucose in body due
  abnormal levels of insulin

• Type 1 diabetes or childhood-onset diabetes or
  juvenile diabetes or insulin-dependent diabetes
  (IDDM)
• Loss of the insulin-producing beta cells from
  islets of Langerhans in the pancreas, leading to
  a deficiency of insulin.
• Type 2 diabetes or adult-onset diabetes or
  obesity-related diabetes or non-insulin-dependent
  diabetes (NIDDM)
• ? Relatively reduced insulin secretion and
  Insulin resistance (reduced insulin sensitivity)

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Biochemistry of Diabetes Mellitus

• Diabetes Mellitus negatively affects health in
  the following ways

• ? Blurred vision or retinal damage (could lead to
  blindness)
• Diabetic ketoacidosis low insulin levels leads
  the body to make another fuel source ketone
  bodies which could decrease blood pH (lt7.35) and
  this denatures proteins / enzymes fatal
  condition
• Chronic renal failure cardiovascular problems
• Poor wound healingcould lead to gangrene and
  amputations
• Since there is too much glucose in blood, the
  reabsorption of glucose in the kidneys is
  incomplete. The excessive glucose in urine
  increases the osmotic pressure of the urine and
  inhibit water reabsorption in proximal renal
  tubules in kidneys dehydration

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Biochemistry of Diabetes Mellitus
Before we look at the pathophysiology of
Diabbetes Mellitus, lets look at what normally
happens in the body.. HOW IS INSULIN MADE?
WHY IS INSULIN NEEDED?
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Biochemistry of Diabetes Mellitus
How is insulin made?
Insulin is released from the Beta cells in the
pancreas as shown below
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Biochemistry of Diabetes Mellitus

• Why is insulin needed?
• Insulin bind at receptor ? binding promotes
  autophosphorylation of beta subunits. This
  autophosphorylation enables docking protein IRS-1
  to bind to the receptor complex ? IRS protein
  interact with signalling molecules such as p85,
  and Grb2-Sos and SHP-2 ?activate MAP kinase ?
  causes GLUT 4 glucose transporters to be placed
  in cell membrane to absorb glucose.
• Stimulation of the formation of glycogen from
  glucose
• Inhibition of glycogenolysis
• Inhibition of protein catabolism

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Biochemistry of Diabetes Mellitus

• Pathophysiology of Diabetes Mellitus Type 1
• Recall that Type 1 Diabetes is characterized by
  loss of the insulin-producing beta cells from
  islets of Langerhans in the pancreas, leading to
  a deficiency of insulin.
• How are the Beta cells destroyed?
• Due to the IDDM1 gene on chromosome 6, the beta
  cells in pancreas display improper antigens ?
  Leads the immune system to produce antibodies
  which will attack the beta cells.
• OR
• 2. Environmental factors viruses such as
  Coxsackie B4 alters the surface proteins on the
  beta cells ? the immune systems mounts an attack
  thinking that the beta cells are viral
  particles/proteins.

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Biochemistry of Diabetes Mellitus

• Pathophysiology of Diabetes Mellitus Type 2
• Recall that Type 2 Diabetes is characterized by
  relatively reduced insulin secretion and Insulin
  resistance (reduced insulin sensitivity)
• Part 1 What causes reduced insulin secretion?
• Uncoupling protein-2 decreases mitochondrial
  membrane potential ? decrease in ATP production ?
  this causes the voltage gated calcium channels to
  be closed low intracellular Calcium preventing
  the exocytosis of insulin from beta cells.

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Biochemistry of Diabetes Mellitus

• Pathophysiology of Diabetes Mellitus Type 2
• Recall that Type 2 Diabetes is characterized by
  relatively reduced insulin secretion and Insulin
  resistance (reduced insulin sensitivity)
• Part 2 What causes insulin resistance (reduced
  insulin sensitivity)?
• In obese people, adipocytokines are released
  which causes resistance
• Interleukin -6 is released which causes insulin
  resistance
• RBP4, a member of the lipocalin family, impairs
  insulin action
• Non-esterified fatty acids (NEFA) which causes
  reduced glucose uptake, promote hepatic glucose
  output, and decreases insulin secretion by beta
  cells

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Biochemistry of Diabetes Mellitus
Treatment for Type 1
1. An insulin pump is used (note that oral
insulin can not be used since the insulin protein
will be denatured in gastric acid/GI
bacteria) 2. Pancreas transplant risky and
requires immunosuppressant drugs 3. Transplants
of exogenous beta cells using Encapsulation
method which is putting the beta cells in a
semi-permeable membrane that protects the cells
from immune system. 4. glucosidase inhibitors
(acarbose and miglitol) which decreases the
absorption of glucose to manage blood sugar levels
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Biochemistry of Diabetes Mellitus
Treatment for Type 2
1. exercise to lower the adipocyte reserve and
lower the amount of adipocytokines that are made
to decrease resistance. 2. Adopting a diet low
in starch / carbohydrates 3. Glibenclamide
(sulfonylureas) The drug works by inhibiting
ATP-sensitive potassium channels in pancreatic
beta cells which stimulates insulin release
(diagram of mechanism shown on previous
slide) 4. metformin a drug that decreases
hepatic glucose production by inhibiting
gluconeogenesis and glycogenolysis. It also
stimulates glycogen synthesis by acting on
glycogen synthase.
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Biochemistry of Diabetes Mellitus
Summary Diabetes Mellitus Diabetes Mellitus is a
disease characterized by disordered metabolism of
glucose in body due abnormal levels of insulin in
body Type 1 diabetes Loss of the
insulin-producing beta cells from islets of
Langerhans in the pancreas, leading to a
deficiency of insulin. ? This can be caused by
IDDM1 gene which causes the beta cells to present
improper antigens on surface, causing the immune
system to mount an attack ? This can be also
causes by viruses such as Coxsackie B4. Type 2
diabetes Relatively reduced insulin secretion
and Insulin resistance (reduced insulin
sensitivity) ? Reduced insulin secretion can be
caused by Uncoupling protein-2 which decreases
mitochondrial membrane potential which leads to a
decrease in ATP production that ultimately has an
effect of not letting calcium enter the cell.
Without calcium, insulin can not be released by
beta cells using exocytosis. ? Insulin resistance
can be caused by a number of adipocytokines
released in obese people, including IL-6, RBP4,
and Non-esterified fatty acids (NEFA). Diabetes
is associated with a lot of complications
including Retinal damage, renal failure,
cardiovascular problems, impaired wound healing
and dehydration.
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Biochemistry of Diabetes Mellitus
Summary Type 1 treatment 1. An insulin pump
since oral insulin can not be used since the
insulin protein will be denatured in gastric
acid/GI bacteria 2. Pancreas transplant risky
and requires immunosuppressant drugs 3.
Transplants of exogenous beta cells using
Encapsulation method which is putting the beta
cells in a semi-permeable membrane that protect
the cells from immune system. 4. glucosidase
inhibitors (acarbose and miglitol) which
decreases the absorption of glucose to mange
blood sugar levels Type 2 treatment 1. exercise
to lower the adipocyte reserve and lower the
amount of adipocytokines that are made to
decrease resistance. 2. Adopting a diet low in
starch / carbohydrates 3. Glibenclamide
(sulfonylureas) The drug works by inhibiting
ATP-sensitive potassium channels in pancreatic
beta cells which stimulates insulin release. 4.
metformin a drug that decreases hepatic glucose
production by inhibiting gluconeogenesis and
glycogenolysis. It also stimulates glycogen
synthesis by acting on glycogen synthase.
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Biochemistry of Diabetes Mellitus
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es/DMOverview.pdf 4. http//emedicine.medscape.com
/article/117739-overview 5. http//content.karger.
com/ProdukteDB/Katalogteile/isbn3_8055/_86/_40/fdi
ab19_02.pdf 6. http//diabetes.diabetesjournals.or
g/cgi/reprint/49/12/2063.pdf 7.
http//www.medilexicon.com/medicaldictionary.php?t
44649 8. http//www.mayoclinic.com/health/type-1-
diabetes/DS00329/DSECTIONtreatments-and-drugs 9.
http//www.diabetes.co.uk/news/2006/Aug/New-encaps
ulation-technology-for-diabetes.html