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Diabetes
What is it?
Prevalence of Diabetes
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15.7 million people (5.9% of pop)
10.3 diagnosed
5.4 undiagnosed
New cases per year: 798,000
Data from CDC
Types of Diabetes
• Type 1
– Aka insulin dependent or juvenile onset
– 5-10% of all diabetes cases
– Risk factors unclear, but include
• Autoimmune
• Genetic
• Environmental factors
Types of Diabetes
• Type 2 diabetes
– Aka non-insulin dependent (a misnomer) or adult
onset
– 90-95% of all cases
– Risk factors include
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Age
Obesity
Family history
Prior history of gestational diabetes
Impaired glucose tolerance
Physical inactivity
Race/ethnicity
– African American, Hispanic/Latino Americans, American
Indians, Asian Americans/Pacific Islanders
Types of Diabetes
• Gestational diabetes
– 2-5% of pregnancies
– Linked with
• Race/ethnicity
• Obesity
• Family history
– Perhaps 40% of women with GD develop Type 2
• “Other specific types”—1-2% of diabetes
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Other diseases
Drugs
Surgery
Malnutrition
Infections
Complications of Diabetes
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2-4 x increase in heart disease
2-4 x increase in strokes
60-65% have high blood pressure
Leading cause of blindness in adults 2074 yrs.
– 12-24,000 new case/year
• Primary cause of kidney disease
Complications of Diabetes
• 60-70% of diabetics have nervous
system damage
– Impaired sensation/pain in hands/feet
– Slowed digestion
– Carpal tunnel syndrome
• >50% of lower limb amputations are
diabetics
Complications of Diabetes
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Periodontal disease
Complications of pregnancy
Coma
General increase in disease
susceptibility
Cost
• $98 billion (1997)
• $44 billion in direct medical costs
• $54 billion in indirect cost
Treatment
• Type 1
– Diet
– Exercise
– Glucose testing/insulin injection
• Type 2
– Diet
– Exercise
– Glucose testing
– Oral medication
– Insulin injection
Causes
• Type 1
– Loss of pancreatic beta cells
– Little or no insulin
• Type 2
– May have very high insulin levels
– Failure to respond to insulin
• Insulin receptors
• Glucose transporters
– Failure to secret sufficient insulin
Our Questions:
• How does the pancreas sense glucose
levels and secret insulin?
– Metabolic coupling
– Hormonal signals
• How can this secretion be increased as
needed?
• What are some other disorders
associated with insulin secretion?
Mark J. Dunne, Karen E. Cosgrove, Ruth
M. Shepherd and Carina Ämmälä
(1999)
“Potassium Channels, Sulphonylureas
Receptors and Control of Insulin
Release”
Trends in Endocrinology and Metabolism
10(4):146-152.
The K+ Channel
• Pore formed by 4 copies of Kir6.2
– Part of large family
– Related to voltage gated K+ channels
SUR receptor
– High affinity for
sulfonylureas
– 4 copies of SUR1
– Superfamily of ATPbinding cassette
(ABC) proteins
Sulfonylureas
• Oral antidiabetic drugs
• Increase insulin secretion
Tolbutamide
O
N
H
O
N
H
S
O
Glyburide
Cl
H
N
OO
O H
N
S
O
H
N
O
Other effects of sulfonylureas
• Inhibit Na/K ATPase
• Inhibit and activate chloride channels
• Potentiate Ca-dependent exocytosis
Normal ligand of SUR1?
• -endosulfine
• 13 kD peptide
• Expressed in
– Muscle
– Brain
– Endocrine cells
• Endogenous regulator of KATP channel?
Other diseases associated with
insulin secretion
• Persistant hyperinsulinaemic
hypoglycaemia of Infancy (PHHI)
• Hyperinsulinaemic hypoglycaemia (HH)
PPHI
• Very rare (1:45,000)
• Very low blood sugar in neonate
• Risk of severe brain damage and
mental retardation
• Treat by
– Decrease carbohydrate intake
– Use drugs that inhibit insulin secretion
• Diazoxide
• Somatostatin
– Pancreatectomy (95%) removal
• At risk for diabetes later in life
Genetics of PPHI
• Not entirely clear
• To date
– >25 reported SUR1 defects
– 3 KIR6.2 defects
– Autosomal recessive
• Abnormalities in
– Trafficking
– Assembly
– Regulation
Experimental Evidence
• Cultured -cells from PPHI children
– Spontaneously electrically active
– No functional KATP channels
– Resting membrane is close to threshold for
Ca channels
• Easily open
• Trigger insulin secretion
Experimental Evidence, con’t
• Transgenic mice with ‘dominant
negative’ form of Kir6.2
– No K channel activity
– Developed hyperinsulinaemic
hypoglycemia
• Impaired KATP channel function
• Depolarized resting membrane potentials
• Elevated cytosolic [Ca]
– High frequency of apoptotic -cells
HH
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Milder than PPHI
Episodic
Later in life (even adulthood)
Always responsive to diazoxide
Autosomally dominant inheritance
Not linked to SUR1 or KIR6.2
Two forms of HH
HH-GK
– Defect in glucokinase
– Rate-limiting step in pancreas
– If mutation causes decrease in glucose
sensitivity of GK
• Maturity-onset diabetes of the young (MODY)
• Autosomal dominant
– GK-HH mutations increase glucose
sensitivity
Two forms of HH
• GDH-HH
– Hyperinsulinaemia with hyperammonaemia
– Defects in glutamate dehydrogenase
– Sporadic genetics or familial dominant
– Defects in allosteric inhibition by GTP
• Constantly “on” enzyme
• In liver, leads to increase ammonia
production
• In -cells, dietary leucine stimulates
GDH
– Increase flux of -kg into Kreb’s
– Increases ATP production
– Closes KATP channels
• Response to diazoxide