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1985 lines
44 KiB
Markdown
# glucose homeostasis 2024.pdf
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**OCR Transcript**
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- Pages: 45
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- OCR Engine: pymupdf
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- Quality Score: 1.00
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---
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## Page 1
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2024-12-06
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1
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Prof Suzanne L Dickson
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Glucose Homeostasis
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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1
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Topics
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ØGlucose homeostasis – the physiological challenge
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ØGlucostatic hormones that decrease blood glucose.
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• Insulin
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• Incretins
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ØGlucostatic hormones that increase blood glucose
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• Glucagon
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• Adrenaline
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• Cortisol
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• Growth hormone
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ØOther hormones
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ØThe clinical context: diabetes mellitus
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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2
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---
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## Page 2
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2024-12-06
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2
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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GLUCOSE
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(mmol/l)
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time
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Clock time
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Normal range is
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4 to 6.5 mmol/L
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Learn values!!
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Blood glucose concentration is under tight homeostatic
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control
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3
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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HIGH BLOOD GLUCOSE IS BAD
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- CHRONIC. Persistent high glucose levels leads to many complications as seen in
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patients with diabetes mellitus (eg fatigue, thirst, retinopathy, kidney failure,
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diabetic foot etc - see later slides).
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- ACUTE high levels can be life threatening due to diuresis (fluid loss).
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LOW BLOOD GLUCOSE IS BAD
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–An insufficient glucose supply to the brain will cause coma and death.
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Why is it important to control blood glucose?
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4
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---
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## Page 3
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2024-12-06
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3
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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GLUCOSE
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(mmol/l)
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Meals
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time
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Clock time
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INSULIN
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µU/ml
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time
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Clock time
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The most important
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hormone that reduces
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blood glucose after
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meals is INSULIN.
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Blood insulin levels are
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determined by both
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the amount of food we
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eat and its
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composition.
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Meals
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The physiological challenge: to maintain <6.5 mmol/l no
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matter what and how much we eat.
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Glucose homeostasis – the problem of meals
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INSULIN REDUCES BLOOD GLUCOSE BY MOVING IT INTO CELLS, WHERE IT CAN BE USED AND/OR STORED.
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5
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Oral glucose tolerance test: a diagnostic tool for diabetes
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§ Overnight fast
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§ Oral glucose drink
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§ Measure glucose
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² Fasting level
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² How large an increase?
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² How rapid recovery?
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§ More sensitive than fasting
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glucose to identify (pre-)diabetes.
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How well does the body tolerate an acute glucose challenge?
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Minutes from oral glucose load
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Glucose concentration
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(millimoles/litre)
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DIABETES
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HEALTHY
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In healthy individuals blood glucose concentrations are tightly
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regulated. Fasting normal range: 4-6 mmol/l
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oral
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glucose
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0
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50
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100
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150
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0
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2
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4
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6
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8
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10
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12
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14
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16
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6
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---
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## Page 4
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2024-12-06
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4
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Diabetes mellitus
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This girl would have died within
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days without insulin treatment.
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- Blood glucose levels high
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- No/very low blood insulin
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levels
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- Blood glucose high
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- High insulin levels (but
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insufficient for need)
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- Insulin resistance - tissues
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cannot take up glucose.
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- Commonly associated with
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obesity
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TYPE 1
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TYPE 2
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7
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Insulin need and insulin production become uncoupled
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in disease
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Healthy
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(Normo-
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glycemia)
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Type I
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diabetes
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(Hyper-
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glycemia)
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Insulin
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Resistance
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(Normo-
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glycemia)
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Type II
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diabetes
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(Hyper-
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glycemia)
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Insulin need
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Insulin production
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8
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---
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## Page 5
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2024-12-06
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5
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Glucose homeostasis – the problem of fasting
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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ØNormally the brain only uses glucose as its energy source.
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ØAfter several days fasting, the brain can use ketones (eg acetyl acetate
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or ß-hydroxybutyrate) as an alternative fuel. BUT, at best, ketones only
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provide 50% of the brain's energy, the rest must come from glucose.
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5
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4
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Plasma Glucose (mM)
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Brain
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Glucose
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(mM)
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3
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2
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1
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0
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5
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10
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15
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The physiological challenge is to ensure plasma glucose remains high enough
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to supply enough glucose to the brain when fasting and between meals.
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Death occurs
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when plasma
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glucose levels
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fall below 1 mM
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9
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Glucose homeostasis – the problem of fasting
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How can we maintain >4 mmol/l if we don’t eat?
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Ø GET GLUCOSE FROM GLYCOGEN STORES
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IN LIVER (Glycogenolysis).
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Ø MAKE MORE GLUCOSE. Liver synthesizes
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glucose from non-carbohydrate carbon
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substrates (eg lactate, glycerol) and
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amino acids. (Gluconeogenesis).
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Ø DON’T LET ORGANS USE GLUCOSE (&
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KEEP FOR BRAIN INSTEAD). Less glucose
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uptake by muscle & fat (insulin
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resistance i.e. unable to respond to
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insulin).
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Go to the bank
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Make more money
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Stop spending
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I don’t
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have any
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money
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11
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---
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## Page 6
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2024-12-06
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6
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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The main glucose-regulating hormones
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Ø INSULIN
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Ø “INCRETINS” (eg. GLP-1)
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Ø GLUCAGON
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Ø ADRENALINE
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Ø GROWTH HORMONE
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Ø GLUCOCORTICOIDS
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In addition, the following hormones have beneficial (good) effects on blood
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glucose:
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Ø LEPTIN deficiency during fasting decreases blood glucose – as leptin helps
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glucose entry to muscle cells.
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Ø IGF-1 has insulin-like effects to reduce blood glucose.
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Ø GHRELIN (released in fasting) increases blood glucose, probably by inducing
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insulin resistance (could be growth hormone-dependent)
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MAIN
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HORMONES
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Decrease
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blood glucose
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after meals
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Increase
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blood glucose
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between meals
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12
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Topics
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ØGlucose homeostasis – the physiological challenge
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ØGlucostatic hormones that decrease blood glucose.
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• Insulin
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• Incretins
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ØGlucostatic hormones that increase blood glucose
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• Glucagon
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• Adrenaline
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• Cortisol
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• Growth hormone
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ØOther hormones
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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13
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---
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## Page 7
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2024-12-06
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7
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Insulin’s functions
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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ØPrimary target tissues: liver, adipose tissue, and skeletal muscle.
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ØInsulin’s major function: to facilitate cellular glucose uptake in
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many tissues (esp muscle and fat but not brain).
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ØInsulin’s mechanism for glucose homeostasis:
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§ Increases glucose transport into insulin-sensitive cells
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§ Enhances cellular utilization and storage of glucose
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§ Enhances utilization of amino acids
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§ Promotes fat synthesis
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14
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Insulin’s functions
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Insulin is released in response to feeding
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Inhibits
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lipolysis
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+
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glucose
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glucose
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fatty
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acids
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amino
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acids
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+
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¯ Glycogenolysis
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¯ Gluconeogenesis
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+
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+
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-
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Insulin transports nutrients to organs where they can be used or stored.
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It also suppresses breakdown of stores.
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15
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---
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## Page 8
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2024-12-06
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8
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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How does glucose get into cells? Glucose transporters
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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• Glucose enters cells by facilitated diffusion, involving glucose transporters
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• >14 kinds of glucose transporters in man (GLUT1-GLUT14). GLUT1-4 are best characterized.
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Tissue
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Function
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GLUT1
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Fetal tissues, blood-brain
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barrier, brain, red blood
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cells, colon
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Basal glucose uptake by most cells (not neurones).
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Glucose uptake into brain
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GLUT2
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b Cells of islets
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(pancreas), liver, kidneys,
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etc
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Glucose-sensing in pancreas.
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Bi-directional glucose flux in liver (uptake glucose for glycolysis,
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and release of glucose during gluconeogenesis).
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Transport of glucose, galactose and fructose out of intestinal cells
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GLUT3
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Brain, placenta, kidneys
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Basal glucose uptake including nerve cells
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GLUT4
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Brown & white fat,
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skeletal muscle
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Insulin- (and exercise)-stimulated glucose uptake.
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Note: SGLT2 (sodium glucose cotransporter 2) is involved in glucose reabsorption in the kidney.
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IMPORTANT: SGLT2 inhibitors à glucose loss in urine (i.e. new diabetes medication).
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16
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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GLUT4 – important for insulin’s effects
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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ØGlucose uptake (fat & muscle) - determined by number of GLUT4 transporters on cell
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surface.
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ØInsulin action moves GLUT4-containing intracellular vessicles to the cell surface. Exercise
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also does this (an insulin-independent effect).
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Insulin
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receptor
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Phosphoinositide
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3-kinase (PI3K)
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Glucose transport
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FUSION
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INTERNALISATION
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GLUT4
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AKT2
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GLUT 4 is the
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only insulin-
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sensitive
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glucose
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transporter
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17
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---
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## Page 9
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2024-12-06
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9
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Insulin causes the fusion of GLUT4 containing vessicles
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with the membrane
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Important:
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If GLUT4
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vesicles do not
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move to the
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surface, this
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can cause type
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2 diabetes.
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Eg AKT2
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mutation
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Adipocyte transfected with a fusion construct of GLUT4 and enhanced green fluorescent protein
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see Saltiel & Kahn (2001) Nature p. 799
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18
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Insulin receptor signalling – some key molecules: IRS-1,
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PI3-kinase and AKT2
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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• Plasma membrane receptor
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• Locations: mostly fat, liver & muscle
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• Belongs to the tyrosine kinase (TK) receptor family
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• Heterotetramer complex
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• a subunits – binds ligands and b subunits
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• b subunits – anchor receptor in membrane and contain
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TK activity.
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• A key intracellular signal is insulin receptor substrate 1
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(IRS-1).
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NOTE: It is absolutely NOT a
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G protein coupled receptor
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19
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---
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## Page 10
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2024-12-06
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10
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Insulin receptor signalling – some key molecules: IRS-1,
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PI3-kinase and AKT2
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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AKT2 mutation
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à One identified
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cause of type 2
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diabetes
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Important points
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Ø Insulin receptor activation à IRS1 phosphorylation (amongst others)
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Ø Phorphorylated IRS-1 binds to proteins that bear a SH2 homology domain, eg PI3K.
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Ø PI3K recruits Akt2 which is required for GLUT4 to translocate to cell membrane.
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DNA synthesis
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Activation of nuclear kinases
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Phosphorylation of transcription factors
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Lipid metabolism
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Amino acid uptake
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Ion transport
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Glycogen
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Synthesis
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p60
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Ras complex
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Phosphorylation cascade
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pp90 S6 kinase
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GLUT4
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Containing vessicles
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pp70 S6 kinase
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Alternative substrates
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Other signal
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GRB2
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nck
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syp
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sos RAS GAP
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p62
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Shc
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GRB2
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?
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AKT2
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?
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?
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?
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?
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?
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?
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PI3K
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Alternative substrates
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Other signals
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IRS-1
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20
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
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Where is insulin produced?
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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In the Islets of Langerhans in the pancreas
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– in the beta cells
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Endocrine portion
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of pancreas
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(Islets of Langerhans)
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Islet of Langerhans. Beta cells (green)
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produce insulin and alpha cells (red)
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produce glucagon. The nuclei of the
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cells is shown in blue. Image of Ge
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Li/Waterland lab/Environmental
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Epigenetics,2019.
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21
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---
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|
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## Page 11
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2024-12-06
|
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11
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
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Islets of Langerhans - anatomy
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| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
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Alpha cells (20%)
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à glucagon (only site produced)
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à ghrelin – (but not major site of
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production)
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Beta cells (~70%)
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à insulin (only site produced)
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à amylin (about 1/100 as much as
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insulin)
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Delta cells (<10%)
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à somatostatin (paracrine role?)
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PP cells (<5%)
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à pancreatic polypeptide
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Epsilon cells (<1%)
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à ghrelin (very little)
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Most abundant cell
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type is the beta cell.
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These are centrally
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located.
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22
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
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Insulin biosynthesis
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
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ØComprises 2 chains (A and B chains) linked by 2 disulphide bonds.
|
||
Gly-Ile-Val-Glu-Gin-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gin-Leu-Glu-Asn-Tyr-Cys-Asn
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Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Thr
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A Chain
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B Chain
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S
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S
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S
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S
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||
S
|
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S
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Human insulin
|
||
Ø Preproinsulin (110 aa), proinsulin (86 aa) & insulin (51 aa).
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||
Ø Insulin, Proinsulin and C-peptide are co-secreted into blood.
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||
Ø Insulin degredation 40-80% as it passes through liver.
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Folded
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Pro-insulin
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C peptide
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insulin
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C-peptide
|
||
23
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||
---
|
||
|
||
## Page 12
|
||
|
||
2024-12-06
|
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12
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
C-peptide is a useful diagnostic tool for beta cell function
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØOne molecule of C-peptide is produced for every molecule of insulin.
|
||
ØC peptide does not have a clear biological role.
|
||
ØBlood assays for C-peptide enable us to estimate the ability of the
|
||
pancreas to synthesize insulin.
|
||
DIAGNOSTIC TOOL: Sometimes you want to know about the ability
|
||
of a patient’s pancreas to produce insulin. If a patient is receiving
|
||
insulin injections, how do you know if what you measure is the
|
||
insulin injected or insulin produced by the pancreas? C-peptide
|
||
informs on endogenous production but is unaffected by injected
|
||
insulin.
|
||
24
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Food substrates:
|
||
Glucose is the main controller of insulin secretion.
|
||
Amino acids and fatty acids also increase release.
|
||
Hormones:
|
||
Incretins (eg glucagon-like peptide 1, GLP-1) from enteroendocrine cells in
|
||
the gut increase release.
|
||
Adrenaline (from adrenal glands) decreases release.
|
||
Somatostatin – acts locally in the pancreas (paracrine) to suppress insulin
|
||
release.
|
||
Parasympathetic nervous system:
|
||
The sight, smell and taste of food can increase pancreatic insulin release,
|
||
engaging the vagus nerve.
|
||
B-Cell
|
||
INSULIN
|
||
25
|
||
|
||
|
||
---
|
||
|
||
## Page 13
|
||
|
||
2024-12-06
|
||
13
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
B-Cell
|
||
INSULIN
|
||
glucose
|
||
+
|
||
1. By blood glucose
|
||
Ø The more glucose is present in the blood, the more will be taken up by
|
||
the beta cell (involves GLUT2).
|
||
Ø More glucose inside the beta cell causes more insulin to be released.
|
||
Important Q: How does the pancreas know to adjust insulin production
|
||
according to blood glucose levels (ie according to need)?
|
||
26
|
||
Control of
|
||
insulin secretion
|
||
by glucose.
|
||
Drink glucose
|
||
solution
|
||
Drink glucose
|
||
solution
|
||
Glucose clamp
|
||
Plasma glucose (mmol/l)
|
||
Plasma insulin (mmol/l)
|
||
Glucose conc
|
||
Insulin – rate
|
||
of release
|
||
Insulin release rate (arbitary units)
|
||
Insulin release rate (arbitary units)
|
||
Insulin – rate
|
||
of release
|
||
Time (min)
|
||
Time (min)
|
||
Time (min)
|
||
Glucose conc (mM)
|
||
INSULIN
|
||
GLUCAGON
|
||
27
|
||
|
||
|
||
---
|
||
|
||
## Page 14
|
||
|
||
2024-12-06
|
||
14
|
||
Release of stored
|
||
insulin
|
||
Release of newly
|
||
synthesized insulin
|
||
Note: This is insulin
|
||
release RATE
|
||
Important Q: How does the pancreas know to adjust
|
||
insulin production according to blood glucose levels (ie
|
||
according to need)?
|
||
Clamp blood glucose at a high level
|
||
Control of insulin secretion by glucose
|
||
28
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Regulation of insulin secretion from the beta cells by
|
||
glucose (involves GLUT2)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Glut 2 – large quantity of low affinity
|
||
glucose transporters.
|
||
Blood glucose concentration controls the
|
||
rate of glucose transport into the beta cell.
|
||
Glucokinase (glucoseàglucose-6-P). Rate
|
||
limiting step for for glucose uptake.
|
||
glucose oxidation (glycolysis)
|
||
à ATP/ADP
|
||
à K+ channel closes
|
||
à K+ à depolarization
|
||
à opening of VSCC
|
||
à Ca2+ entry
|
||
à insulin release
|
||
GLUT 2
|
||
glucose
|
||
Glucose-6-P
|
||
glucokinase
|
||
Metabolism
|
||
ATP/ADP
|
||
¯K+
|
||
ATP-senstive
|
||
potassium
|
||
channels
|
||
close
|
||
depol
|
||
Voltage -sensitive
|
||
Ca channels open
|
||
Ca2+
|
||
insulin
|
||
K+
|
||
Note: Sulfonylurea close ATP-sensitive K
|
||
channels à Treatment for type 2 diabetes
|
||
Beta cell
|
||
29
|
||
|
||
|
||
---
|
||
|
||
## Page 15
|
||
|
||
2024-12-06
|
||
15
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Beta cells respond to an increase in extracellular
|
||
glucose by depolarizing
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Nature 1968
|
||
Glucose 6.5 mmol/l
|
||
Voltage (mV)
|
||
Glucose 10.0 mmol/l
|
||
The membrane potential (V) of a single beta cell within an intact pancreas islet
|
||
recorded in the presence of 6.5 and 10.0 mM glucose as indicated by the staircase.
|
||
0
|
||
-20
|
||
-40
|
||
-60
|
||
50 s
|
||
30
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Amino
|
||
acids
|
||
+
|
||
B-Cell
|
||
INSULIN
|
||
glucose
|
||
+
|
||
2. By amino acids
|
||
Unlike glucose, amino acids do not enter
|
||
the beta cell by facilitated diffusion.
|
||
Amino acids have dedicated transporters.
|
||
31
|
||
|
||
|
||
---
|
||
|
||
## Page 16
|
||
|
||
2024-12-06
|
||
16
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Regulation of insulin secretion by amino acids
|
||
Amino acid entry
|
||
à ionic changes
|
||
à depolarization
|
||
à Ca2+ uptake
|
||
à exocytosis.
|
||
Involves transporters
|
||
(i)
|
||
symporter for Ala, Gly
|
||
& Na+.
|
||
(ii)
|
||
arginine transport
|
||
protein
|
||
depol
|
||
Voltage -sensitive
|
||
Ca channels open
|
||
Ca2+
|
||
insulin
|
||
Beta cell
|
||
Alanine
|
||
Glycine
|
||
Na+
|
||
Arginine+
|
||
Na+ entry depolarizes cell.
|
||
Arginine+ also depolarizes cell.
|
||
32
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Amino
|
||
acids
|
||
+
|
||
B-Cell
|
||
INSULIN
|
||
glucose
|
||
+
|
||
3. By the parasympathetic system
|
||
+
|
||
Parasympathetic
|
||
system
|
||
33
|
||
|
||
|
||
---
|
||
|
||
## Page 17
|
||
|
||
2024-12-06
|
||
17
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion by the parasympathetic system
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØSight/taste/smell à
|
||
ØActivation of vagal reflexes à
|
||
ØInsulin secretion before food
|
||
enters gut.
|
||
ØEarly insulin release helps
|
||
prepare for the incoming
|
||
glucose – prevents massive
|
||
increase in glucose after meals.
|
||
ØIt can be detected (see graph).
|
||
In the absence of absorbed
|
||
glucose early insulin release
|
||
may even cause a small dip in
|
||
blood glucose.
|
||
Subjects have fasted before
|
||
experiment.
|
||
Blood glucose (mM/l)
|
||
0
|
||
5
|
||
10 15 20
|
||
-5
|
||
min
|
||
4
|
||
8
|
||
Insulin already being
|
||
released before
|
||
glucose absorbed
|
||
34
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Amino
|
||
acids
|
||
+
|
||
B-Cell
|
||
INSULIN
|
||
glucose
|
||
+
|
||
4. By incretins
|
||
+
|
||
Parasympathetic
|
||
system
|
||
incretins
|
||
+
|
||
35
|
||
|
||
|
||
---
|
||
|
||
## Page 18
|
||
|
||
2024-12-06
|
||
18
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Incretins
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØPeptide hormones secreted into blood by
|
||
enteroendocrine cells in the G-I tract
|
||
ØExamples:
|
||
•
|
||
GLP-1: Glucagon-like peptide 1
|
||
•
|
||
GIP: gastric inhibitory peptide (or glucose-
|
||
dependent insulinotropic polypeptide)
|
||
L cells
|
||
(GLP-1)
|
||
K cells
|
||
(GIP)
|
||
ØMAIN ROLES: insulin secretion, both in
|
||
preparation for food being absorbed after eating.
|
||
ØAdditional roles:
|
||
•
|
||
slow rate of nutrient absorption by reducing gastric
|
||
emptying.
|
||
•
|
||
directly reduce food intake (CNS).
|
||
•
|
||
GLP-1 (BUT NOT GIP) inhibit glucagon release.
|
||
Food ingestion
|
||
•GLP-1: Decreases glucagon secretion when
|
||
glucose high but not when low. Helps avoid
|
||
hyperglycemia.
|
||
•GIP: Stimulating glucagon release when glucose
|
||
levels are low but not when high. Helps avoid
|
||
36
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
The presence of food in the gut triggers insulin secretion
|
||
via incretin release
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØEnteroendocrine cells respond
|
||
to the presence of food in the
|
||
gut (starting even before
|
||
absorption) by releasing
|
||
incretins.
|
||
ØIncretins stimulate insulin
|
||
secretion after eating but also
|
||
before food is absorbed.
|
||
ØThus, they help prepare for the
|
||
incoming glucose load.
|
||
Subjects have fasted before
|
||
experiment.
|
||
Blood glucose (mM/l)
|
||
0
|
||
5
|
||
10 15 20
|
||
-5
|
||
min
|
||
4
|
||
8
|
||
Insulin already being
|
||
released before
|
||
glucose absorbed
|
||
37
|
||
|
||
|
||
---
|
||
|
||
## Page 19
|
||
|
||
2024-12-06
|
||
19
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucagon-like peptide 1 (GLP-1)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØSynthesized by entero-endocrine
|
||
L cells and in the brainstem.
|
||
ØReleased when food present in
|
||
gut.
|
||
ØDecreases blood glucose (incretin
|
||
effect)
|
||
ØVery short half-life in blood
|
||
(approx. 2 minutes)
|
||
ØStimulates insulin secretion (&
|
||
inhibit glucagon release).
|
||
38
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Why are incretins important?
|
||
In normal physiology …
|
||
•
|
||
Thanks to incretins, a little insulin is released into the blood even before
|
||
glucose in the food is absorbed. Without incretin-induced insulin release, the
|
||
body would not be prepared for the incoming glucose and it could suddenly
|
||
become very high, which can be dangerous.
|
||
•
|
||
In the presence of incretins, much more insulin is released in response to a
|
||
meal. This is called the “incretin effect”.
|
||
In T2DM patients …
|
||
Drugs based on the incretin system have been developed
|
||
•
|
||
Long acting GLP-1 analogues (eg exenatide, semaglutide (Ozempic®)
|
||
•
|
||
Enzyme inhibitors - that inhibit the enzyme that breaks down GLP-1, thereby
|
||
increasing circulating GLP-1 levels.
|
||
39
|
||
|
||
|
||
---
|
||
|
||
## Page 20
|
||
|
||
2024-12-06
|
||
20
|
||
Insulin
|
||
Glucose
|
||
Glucose
|
||
The Incretin Effect
|
||
Glucose
|
||
i.v.
|
||
Insulin
|
||
Oral
|
||
Oral
|
||
i.v.
|
||
GLP-1, GIP
|
||
+
|
||
hh Insulin
|
||
Incretin Effect
|
||
Nauck et al 1986 Diabetologia. 1986 Jan;29(1):46-52.
|
||
Oral glucose makes
|
||
contact with GI tract and
|
||
triggers incretin
|
||
secretion
|
||
à more insulin secreted
|
||
after an oral glucose
|
||
load than after i.v.
|
||
infusion.
|
||
This difference =
|
||
incretin effect
|
||
1. Experimentally match i.v. glucose
|
||
to that caused by a glucose infusion
|
||
2. Measure blood insulin
|
||
40
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
GLP-1 system à new drugs for diabetes (and obesity)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
à GLP-1 long acting agonists (eg
|
||
Exenatide)
|
||
à DPP-4 inhibitors (DPP-4 =
|
||
enzyme inactives both GLP-1 &
|
||
GIP). Mechanism: Prevents GLP-
|
||
1 breakdown & prolongs GLP-1
|
||
half-life.
|
||
41
|
||
|
||
|
||
---
|
||
|
||
## Page 21
|
||
|
||
2024-12-06
|
||
21
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Data from Zander M, et al. Lancet 2002; 359:824-830
|
||
Mean Change (%) in Weight From Baseline
|
||
Mean (SE)
|
||
r Weight (%)
|
||
-3.5
|
||
-3.0
|
||
-2.5
|
||
-2.0
|
||
-1.5
|
||
-1.0
|
||
-0.5
|
||
0.0
|
||
0.5
|
||
1.0
|
||
Saline
|
||
GLP-1
|
||
0
|
||
2
|
||
3
|
||
4
|
||
5
|
||
6
|
||
Time (wk)
|
||
Effect of 6-Week Continuous GLP-1 infusion on Mean Body Weight
|
||
Incretin-based drugs are new treatments for type 2
|
||
diabetes (and cause weight loss)
|
||
42
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Topics
|
||
ØGlucose homeostasis – the physiological challenge
|
||
ØGlucostatic hormones that decrease blood glucose.
|
||
• Insulin
|
||
• Incretins
|
||
ØGlucostatic hormones that increase blood glucose
|
||
• Glucagon
|
||
• Adrenaline
|
||
• Cortisol
|
||
• Growth hormone
|
||
ØOther hormones
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
43
|
||
|
||
|
||
---
|
||
|
||
## Page 22
|
||
|
||
2024-12-06
|
||
22
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Blood glucose mmol/l
|
||
Result
|
||
>8
|
||
Exceeds renal threshold for uptake of glucose from
|
||
pre-urine, diuresis (loss of glucose, water*, Na+ and
|
||
K+ in urine)
|
||
5.5
|
||
Insulin secretion increases
|
||
4.6
|
||
Insulin secretion decreases
|
||
3.8
|
||
Increased secretion of glucagon, adrenaline and
|
||
growth hormone
|
||
3.2
|
||
Cortisol secretion
|
||
2.8
|
||
Confusion
|
||
1.7
|
||
Weak, sweat, nauseous
|
||
1.1
|
||
Muscle cramps
|
||
0.6
|
||
Brain damage, death
|
||
*Acute fluid loss can
|
||
become a medical
|
||
emergency
|
||
Consequences of hyper- & hypoglycemia (i.e. too high
|
||
and too low glucose)
|
||
•
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
44
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucagon, adrenaline, growth hormone promote glycogenolysis & gluconeogenesis.
|
||
Glucocorticoids break down muscle (à amino acids for gluconeogenesis).
|
||
Glucose
|
||
Production
|
||
(liver)
|
||
Blood Glucose
|
||
Glucose
|
||
Consumption
|
||
(Muscle and adipose tissue)
|
||
insulin
|
||
_
|
||
+
|
||
+ (muscle breakdown)
|
||
_
|
||
glucocorticoids
|
||
glucagon
|
||
Adrenaline &
|
||
noradrenaline
|
||
Growth hormone
|
||
+
|
||
+
|
||
_
|
||
Key glucostatic hormones- divergent roles
|
||
•
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
45
|
||
|
||
|
||
---
|
||
|
||
## Page 23
|
||
|
||
2024-12-06
|
||
23
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Synergistic effects of anti-insulin hormones to increase
|
||
blood glucose
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Cortisol has
|
||
a “permissive role”
|
||
Permissive:
|
||
allows a
|
||
biological or
|
||
biochemical
|
||
process to
|
||
occur
|
||
46
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucagon
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØWhere produced? Peptide hormone, produced by alpha
|
||
cells in the Islets of Langerhans of the pancreas
|
||
47
|
||
|
||
|
||
---
|
||
|
||
## Page 24
|
||
|
||
2024-12-06
|
||
24
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucagon
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØWhere produced? Peptide hormone, produced by alpha
|
||
cells in the Islets of Langerhans of the pancreas
|
||
ØWhat stimulates & inhibits release?
|
||
CCK=cholecystokinin
|
||
48
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucagon
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØWhere produced? Peptide hormone, produced by alpha
|
||
cells in the Islets of Langerhans of the pancreas
|
||
ØWhat stimulates & inhibits release?
|
||
ØPrimary actions: increase blood glucose by increasing
|
||
glycogen breakdown and gluconeogenesis in the liver
|
||
glucose
|
||
+
|
||
Glycogenolysis
|
||
¯ Glycogen synthesis
|
||
Gluconeogenesis
|
||
+
|
||
amino
|
||
acids
|
||
Important during initial stages of fasting
|
||
49
|
||
|
||
|
||
---
|
||
|
||
## Page 25
|
||
|
||
2024-12-06
|
||
25
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucagon
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØWhere produced? Peptide hormone, produced by alpha
|
||
cells in the Islets of Langerhans of the pancreas
|
||
ØWhat stimulates & inhibits release?
|
||
ØPrimary actions: increase blood glucose by increasing
|
||
glycogen breakdown and gluconeogenesis in the liver.
|
||
ØThe glucagon receptor is a G protein-coupled receptor.
|
||
ØA life-saving safe injectable treatment for hypoglycemia.
|
||
50
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
ØThink of glucagon as the main hormone acting in the opposite way to
|
||
insulin. It is important inbetween meals, helping to keep glucose levels up,
|
||
by enhacing glycogen breakdown and gluconeogenesis.
|
||
ØIf you eat a diet low in carbs (eg LCHF – low carb high fat diet), you need to
|
||
mobilize glucose from stores and generate new glucose. The substrates for
|
||
gluconeogenesis are free fatty acids (from fat breakdown) and amino acids
|
||
(from protein breakdown).
|
||
Glucagon
|
||
51
|
||
|
||
|
||
---
|
||
|
||
## Page 26
|
||
|
||
2024-12-06
|
||
26
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
52
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Effect of high carbohydrate and high protein meal on
|
||
hormone secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Protein meal
|
||
(ie high amino acids)
|
||
mg%
|
||
pg/ml
|
||
Plasma Concentration
|
||
µU/ml
|
||
GLUCOSE
|
||
INSULIN
|
||
GLUCAGON
|
||
mg%
|
||
pg/ml
|
||
µU/ml
|
||
meal
|
||
GLUCOSE
|
||
INSULIN
|
||
GLUCAGON
|
||
aaminonitrogen
|
||
minutes
|
||
meal
|
||
Carbohydrate meal
|
||
(ie high glucose)
|
||
Both meals stimulate
|
||
insulin release.
|
||
Amino acids also
|
||
stimulate glucagon
|
||
release, which saves
|
||
B-glucose levels
|
||
from falling if carbs
|
||
are low
|
||
53
|
||
|
||
|
||
---
|
||
|
||
## Page 27
|
||
|
||
2024-12-06
|
||
27
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Control of insulin secretion
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Amino
|
||
acids
|
||
+
|
||
B-Cell
|
||
INSULIN
|
||
glucose
|
||
+
|
||
2. By amino acids
|
||
Although amino acids increase insulin
|
||
secretion (which lowers blood glucose by
|
||
increasing glucose uptake to fat and
|
||
muscle), they also stimulate glucagon
|
||
release (which promotes glycogenolysis
|
||
and gluconeogenesis i.e. release and
|
||
production of new glucose).
|
||
blood
|
||
glucose
|
||
-
|
||
+
|
||
A-Cell
|
||
GLUCAGON
|
||
+
|
||
glycogenolysis
|
||
gluconeogenesis
|
||
(via increased glucose
|
||
uptake in muscle & fat)
|
||
54
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Pro-glucagon
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Thus, although proglucagon can be found in many tissues, glucagon is only
|
||
released from the alpha cells.
|
||
55
|
||
|
||
|
||
---
|
||
|
||
## Page 28
|
||
|
||
2024-12-06
|
||
28
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Fear- fright – flight. Need energy (glucose) fast
|
||
A role for adrenaline
|
||
56
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Adrenaline’s effects on glucose homeostasis
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Glycogenolysis, lipolysis
|
||
Important during acute stress (minutes) eg exercise
|
||
free
|
||
fatty
|
||
acids
|
||
á glucose
|
||
+
|
||
á Glycogenolysis
|
||
á Glycogenolysis
|
||
Lactic
|
||
acid
|
||
á Gluconeogenesis
|
||
57
|
||
|
||
|
||
---
|
||
|
||
## Page 29
|
||
|
||
2024-12-06
|
||
29
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
During acute stress adrenaline increases blood glucose
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Central
|
||
Nervous
|
||
System
|
||
Splanchnic
|
||
nerves
|
||
(+)
|
||
Liver
|
||
(+)
|
||
(+)
|
||
(-)
|
||
Hypoglycaemia
|
||
Glucose
|
||
Glucagon
|
||
adrenaline
|
||
a islets
|
||
Adrenal
|
||
medulla
|
||
Adrenaline
|
||
- in liver, it causes glycogenolysis (& gluconeogenesis to a lesser extent)
|
||
- It also stimulates glucagon release from the pancreas.
|
||
Stress from eg fear-flight-flight, hypoglycemia and cold exposure
|
||
58
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucocorticoids (from adrenal cortex)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
Important during long term/repeated stress and starvation
|
||
+
|
||
Ketone
|
||
bodies
|
||
á Glycogen synthesis
|
||
+
|
||
Subcutaneous
|
||
fat “slow”
|
||
Visceral fat
|
||
“fast”
|
||
free
|
||
fatty
|
||
acids
|
||
amino
|
||
acids
|
||
glucose
|
||
+
|
||
á Gluconeogenesis
|
||
+
|
||
Insulin
|
||
resistance
|
||
Protein catabolism, glycogenesis, gluconeogenesis,
|
||
ketogenesis, decreased glucose utilization
|
||
59
|
||
|
||
|
||
---
|
||
|
||
## Page 30
|
||
|
||
2024-12-06
|
||
30
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Cortisol deficiency (eg Addison’s disease)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
ØBlood glucose normal as long as food intake is maintained.
|
||
ØFasting/starvation is life-threatening due to risk of
|
||
hypoglycaemia
|
||
ØGlycogen stores in liver and muscle become depleted.
|
||
ØBecomes difficult to use other sources of stored energy eg
|
||
protein & triglycerides.
|
||
JF Kennedy – probably the most famous person to
|
||
suffer from this disease
|
||
60
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Cortisol excess – Cushings disease
|
||
ØGlucose tolerance* reduced by 80% - they have high
|
||
blood glucose levels.
|
||
Ø20% patients have type 2 diabetes.
|
||
ØGlucocorticoids are required for glucagon to exert its
|
||
gluconeogenic effect during fasting (permissive role).
|
||
*Impaired glucose tolerance (IGT) is a pre-diabetic state
|
||
of hyperglycemia that is associated with insulin resistance
|
||
and increased risk of cardiovascular pathology.
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
61
|
||
|
||
|
||
---
|
||
|
||
## Page 31
|
||
|
||
2024-12-06
|
||
31
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Growth hormone (GH)
|
||
ØProduced by the somatotrophs of the anterior pituitary.
|
||
ØRelease controlled by the hypothalamus, by negative
|
||
feedback (via GH and IGF-1) and by ghrelin.
|
||
ØPlasma membrane receptor. Dimerization.
|
||
ØActions: growth (anabolic) and metabolism (lipolytic,
|
||
diabetogenic). Metabolic actions important when fasting or
|
||
when blood glucose levels fall.
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
62
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Growth hormone (GH) is diabetogenic, lipolytic (and anabolic)
|
||
Important when using fat rather than carbohydrate as an energy source (eg fasting).
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
free
|
||
fatty
|
||
acids
|
||
glucose
|
||
Gluconeogenesis
|
||
amino
|
||
acids
|
||
(Not during
|
||
fasting)
|
||
63
|
||
|
||
|
||
---
|
||
|
||
## Page 32
|
||
|
||
2024-12-06
|
||
32
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Metabolic profile of the GH-deficient patient
|
||
Ø central adiposity (apple-shaped)
|
||
ØInsulin resistance (maybe secondary to
|
||
the central adiposity).
|
||
ØLiver: ¯ glycogen stores, ¯
|
||
gluconeogenesis
|
||
ØLipid profile: triglycerides, LDL-
|
||
cholesterol, ¯ HDL-cholesterol,
|
||
apolipoprotein b (promotes CV disease
|
||
and arterosclerosis).
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
64
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Metabolic profile of a patient with acromegaly
|
||
ØInsulin resistance,
|
||
ØGH blocks insulin’s actions (inhibits
|
||
phosphorylation of the insulin receptor
|
||
and IRS-1)
|
||
ØMobilization of free fatty acids leading to
|
||
further worsening of insulin resistance.
|
||
ØAbnormalities overcome by either
|
||
lowering of GH secretion or by blocking
|
||
GH action.
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
65
|
||
|
||
|
||
---
|
||
|
||
## Page 33
|
||
|
||
2024-12-06
|
||
33
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Acetyl CoA
|
||
b-oxidation
|
||
(liver)
|
||
Gluconeogenesis
|
||
Glycogenolysis
|
||
Amino
|
||
acids
|
||
glycerol
|
||
Glucose
|
||
ketones
|
||
Cortisol
|
||
GH
|
||
Adrenaline
|
||
Glucagon
|
||
Cortisol
|
||
Glycogen
|
||
synthesis
|
||
Glucagon, GH,
|
||
cortisol
|
||
Cortisol
|
||
Summary of anti-insulin hormone action (eg in fasting)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
FFA
|
||
66
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Topics
|
||
ØGlucose homeostasis – the physiological challenge
|
||
ØGlucostatic hormones that decrease blood glucose.
|
||
• Insulin
|
||
• Incretins
|
||
ØGlucostatic hormones that increase blood glucose
|
||
• Glucagon
|
||
• Adrenaline
|
||
• Cortisol
|
||
• Growth hormone
|
||
ØOther hormones
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
67
|
||
|
||
|
||
---
|
||
|
||
## Page 34
|
||
|
||
2024-12-06
|
||
34
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Leptin – beneficial effects to lower blood glucose
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
68
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Ghrelin – improves (raises) blood glucose when fasting
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
69
|
||
|
||
|
||
---
|
||
|
||
## Page 35
|
||
|
||
2024-12-06
|
||
35
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
DIABETES MELLITUS: Topics
|
||
Contect from Anders Rosengren
|
||
Type 1, Type 1.5, Type 2 & gestational diabetes
|
||
Symptoms and Diagnosis
|
||
Insulin resistance and carbohydrate metabolism in
|
||
diabetes.
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
70
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Why is diabetes mellitus an important disease?
|
||
• Increases the most amongst all diseases!
|
||
Current worldwide: 463 million, 50% 20-60 years old
|
||
By 2035: 592 million worldwide
|
||
Current Sweden: 4.8% of the population
|
||
• A worldwide pandemic
|
||
The increase in type 2 diabetes mellitus (T2DM): ”diabetes-causing
|
||
lifestyle”
|
||
• Developing countries – those affected even younger
|
||
50% type 2 diabetes occurs in those aged 40-59
|
||
T2DM is even the most common form in adolescents.
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
71
|
||
|
||
|
||
---
|
||
|
||
## Page 36
|
||
|
||
2024-12-06
|
||
36
|
||
2014
|
||
2035
|
||
WORLD
|
||
387
|
||
million
|
||
WORLD
|
||
592
|
||
million
|
||
people living
|
||
with diabetes
|
||
Middle East and North Africa 85%
|
||
South East Asia 64%
|
||
South and Central America 55%
|
||
Western Pacific 46%
|
||
North America and Caribbean 30%
|
||
Europe 33%
|
||
Africa 93%
|
||
53%
|
||
Contect from Anders Rosengren
|
||
72
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Most
|
||
common.
|
||
90-95%
|
||
all
|
||
diabetes
|
||
73
|
||
|
||
|
||
---
|
||
|
||
## Page 37
|
||
|
||
2024-12-06
|
||
37
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Kalle 12 years old
|
||
• Previously healthy
|
||
• Recent weeks - tired
|
||
• Very thirsty
|
||
Polydipsi (↑ urine)
|
||
• Frequent urination
|
||
|
||
Polyuria – osmotic
|
||
diuresis
|
||
• Very tired (+ mucous membranes
|
||
• Acetone smell
|
||
• B-glucose: 22 mmol/l
|
||
• Urine teststick:
|
||
↑ glucose (fungal infections, genital
|
||
itching)
|
||
↑ ketones
|
||
• Stomach pain/vomiting (ketoacidosis,
|
||
hyperosmolar hyperglycaemic syndrome)
|
||
• Serum insulin: 0 ng/mL C-peptide: 0
|
||
nmol/L
|
||
• Previously normal vision but now sits
|
||
1 metre in front of TV
|
||
Myopathy – eye swells (osmotic effect
|
||
of glucose)
|
||
• Lost 3 kg in weight during 2 weeks
|
||
(insulin deficiency à ↑ lipolysis & ↓
|
||
lipogenesis)
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
74
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucose metabolism in diabetes
|
||
Glucose
|
||
Glycogenolys
|
||
Glukoneogenes
|
||
Heart
|
||
Red
|
||
blood
|
||
cells
|
||
Kidneys
|
||
Adipose tissue
|
||
Musculature
|
||
Brain
|
||
Liver
|
||
Glycerol
|
||
FFA
|
||
Insulin 0
|
||
Lactate
|
||
Alanin
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
75
|
||
|
||
|
||
---
|
||
|
||
## Page 38
|
||
|
||
2024-12-06
|
||
38
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Even type 1 diabetes mellitus (T1DM) is increasing
|
||
• 10% of all diabetes is type 1.
|
||
• T1DM increasingly common. Almost 30% ↑↑ over past 30 years. Number of
|
||
sick children with T2DM aged 0-14 has ↑↑ by 3% every year since 1980.
|
||
• There is a clear tendency for T1DM to affect younger children. It is not
|
||
uncommon for 1-2 year olds to become ill.
|
||
• Just over 1% of all children born in Sweden have T1DM (about 700 children
|
||
and adolescents develop the disease each year)
|
||
• Around 98,000 children are affected by T1DM each year in the world
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
76
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Type 1 diabetes mellitus (T1DM)
|
||
• Insulin-producing β-cells destroyed due to auto-antibodies.
|
||
• 90% T1DM have auto-antibodies: directed against substances in the beta cells: insulin,
|
||
GAD (glutamic acid decarboxylase) and IA-2 (tyrosine phosphatase).
|
||
• Theory: a certain type of gene + triggering factor is required (e.g. viruses, chemicals or
|
||
other environmental factors).
|
||
• 60% of the hereditary risk of T1DM is in the HLA (human leucocyte antigen) system (that
|
||
labels cells as belong to the body or to be rejected).
|
||
• Risk genes are common in the population (about 20%) but only 7% (of this 20%) get T1DM.
|
||
• Autoimmune disease? – Limited evidence for this. Inhibition of T-cell mediated autoimmunity
|
||
in newly infected patients has failed.
|
||
• Inflammatory disease affecting the entire pancreas, most important clinical symptoms come
|
||
from the loss of insulin producing cells.
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
77
|
||
|
||
|
||
---
|
||
|
||
## Page 39
|
||
|
||
2024-12-06
|
||
39
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Ove, 58 år
|
||
• Fatigue, dizziness, depression
|
||
• Mother with diabetes
|
||
• Weight 126 kg
|
||
• Waist circumference 103 cm
|
||
• BMI 33 kg/m2
|
||
• Blood pressure 185/100
|
||
• Heart, lungs, abdomen – no
|
||
problem.
|
||
• Wound infection knee
|
||
•
|
||
B-glucose: 12 mmol/l
|
||
•
|
||
Urine teststick glucose: ++
|
||
•
|
||
Ketones: negative
|
||
•
|
||
Serum insulin (ref. 68-245
|
||
ng/mL) 345 ng/mL
|
||
•
|
||
LDL-cholesterol ↑
|
||
•
|
||
HDL-cholesterol ↓
|
||
•
|
||
High triglycerides ↑
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
78
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucose metabolism with diabetes
|
||
Glucose
|
||
Glycogenolysis
|
||
Gluconeogenesis
|
||
Heart
|
||
Red
|
||
blood
|
||
cells.
|
||
Kidney
|
||
Musculature
|
||
Brain
|
||
Liver
|
||
Glycerol
|
||
FFA
|
||
Insulin
|
||
Lactate
|
||
Alanine
|
||
Contect from Anders Rosengren
|
||
Glucotoxicity
|
||
Lipotoxicity
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
79
|
||
|
||
|
||
---
|
||
|
||
## Page 40
|
||
|
||
2024-12-06
|
||
40
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Glucotoxicity (High blood glucose toxic)
|
||
à ↓ ability of β-cells to release enough insulin,
|
||
à ↓ ability of peripheral target cells' to respond to insulin.
|
||
àà a vicious cycle that accelerates hyperglycemia.
|
||
Lipotoxicity (High lipid levels toxic)
|
||
β-cell damaged. ↓ insulin release.
|
||
Peripheral target cells, e.g. vascular endothelium, muscle
|
||
and liver cells: impaired function and ↓ insulin sensitivity.
|
||
Can be counteracted by metabolic control mainly diet and
|
||
exercise but also lipid-lowering pharmacological treatment.
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
80
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Type 2 Diabetes Mellitus (T2DM)
|
||
• Insulin resistance and insulin deficiency
|
||
• Heterogenous illness with many different potential causes
|
||
– 80% patients are overweight/obese (BMI > 30 kg/m2)
|
||
– Insulin resistance increases with increasing obesity and
|
||
abdominal obesity
|
||
• Clear association between physical inactivity and
|
||
increased risk of T2DM.
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
81
|
||
|
||
|
||
---
|
||
|
||
## Page 41
|
||
|
||
2024-12-06
|
||
41
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Genes and environment work together
|
||
• T2DM highly hereditary. If a parent has T2DM, the children have a 40%
|
||
risk. They have a 70% risk of falling ill during their lifetime.
|
||
• Heredity in T2DM complicated - difficult to identify risk genes.
|
||
Polygenetic inheritance (GWAS> 120 loci strongly linked but explains
|
||
only 20% of the disease). "A genetic nightmare"!
|
||
• Genetics (several genes in collaboration) + lifestyle contribute to the risk
|
||
of developing the disease
|
||
Contect from Anders Rosengren
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
82
|
||
Insulin resistance + Insulin need è T2DM
|
||
Insulin need
|
||
B-Glucose
|
||
Insulin secretion
|
||
“Healthy”
|
||
Insulin
|
||
Resistance.
|
||
T2D “β cell loss”.
|
||
Not reversible
|
||
Reversible
|
||
~ 7 yr
|
||
0-15yr
|
||
83
|
||
|
||
|
||
---
|
||
|
||
## Page 42
|
||
|
||
2024-12-06
|
||
42
|
||
Type I DM
|
||
Type 2 DM
|
||
Lean or over weight
|
||
Overweight ~ 80%
|
||
Ketosis inclined
|
||
No ketosis
|
||
Symptoms for weeks before
|
||
diagnosis
|
||
Symptoms for months before
|
||
diagnosis
|
||
Age onset <40 år
|
||
Age onset typically >40 år
|
||
Heredity 10 %
|
||
Heredity common
|
||
HLA antigens precede disease in
|
||
90-95 % cases
|
||
HLA antigens precede disease in
|
||
60 % cases
|
||
(as in normal population)
|
||
Islet cell antibodies at onset
|
||
positive in about 70-80 % cases
|
||
Islet cell antibodies at onset -
|
||
negative
|
||
Clinical characteristics of type 1 and type 2 diabetes
|
||
84
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Gunilla 37 years old
|
||
• Presented as sweating and
|
||
frequent urination
|
||
• 28th week of gestation
|
||
• Heredity: Mother with DM
|
||
• B-glucose: 12 mmol / l
|
||
• Urine test stick glucose: +++
|
||
• Ketones: 0
|
||
• U-Nitrite: +
|
||
• Serum insulin (ref. 68- 245 ng
|
||
/ mL) 675 ng / mL
|
||
Referral to a diabetes
|
||
nurse and nutritionist
|
||
85
|
||
|
||
|
||
---
|
||
|
||
## Page 43
|
||
|
||
2024-12-06
|
||
43
|
||
0.8–4.3% of all pregnancies in Sweden
|
||
Women with GDM are a heterogeneous group (with varying degrees of
|
||
deviation in glucose tolerance) that developed T2DM
|
||
Insulin resistance is more pronounced than in a normal pregnancy, and
|
||
cannot be entirely explained by co-occurring obesity
|
||
The main cause is a defective insulin response that cannot keep up
|
||
with increasing insulin resistance during pregnancy
|
||
GDM usually runs asymptomatically, requiring screening
|
||
Gestational diabetes Mellitus GDM
|
||
Defined as pathological glucose tolerance detected during pregnancy. After
|
||
termination of pregnancy, the glucose metabolic disorder is usually normalized.
|
||
If not, "reclassification" to type 1 or type 2 diabetes occurs
|
||
86
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Fredrik 37 years old
|
||
• Presented with frequent
|
||
urination. Prostate?
|
||
• 70 kg BMI 23 kg/m2
|
||
• Blood pressure, heart, lungs,
|
||
abdomen – no problem.
|
||
• B-glucose: 13 mmol/l
|
||
• Blood fats u.a.
|
||
• Urine teststick glucose: +++
|
||
ketones: 0
|
||
• Serum insulin (ref. 68-245
|
||
ng/mL) 130 ng/mL
|
||
Metformin
|
||
Lifestyle advice
|
||
Referral to
|
||
diabetes nurse
|
||
and dietician
|
||
Type 2 diabetes?
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
87
|
||
|
||
|
||
---
|
||
|
||
## Page 44
|
||
|
||
2024-12-06
|
||
44
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
Fredrik 8 months later
|
||
Type 1 diabetes?
|
||
• Tired & frquent urinating
|
||
• Acetone smell
|
||
• 66 kg
|
||
• Blood pressure, heart, lungs,
|
||
abdomen – no problem.
|
||
• B-glucose: 17 mmol/l
|
||
• Urine teststick glucose: +++
|
||
•
|
||
Ketones: +++
|
||
• Serum insulin: 0 ng/mL
|
||
• C-peptid: 0 nmol/L
|
||
• Islet cell antibodies (GAD) positive
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
88
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
LADA (Latent Autoimmune Diabetes in Adults)
|
||
between type 1 & type 2 diabetes - type 1.5 diabetes
|
||
• An autoimmune disease with islet cell antibodies (cf. T1DM) but usually older
|
||
at the onset of illness. The disease course is slower and milder with preserved
|
||
insulin production for an extended period of time. Similar in time to the debut of
|
||
T2DM.
|
||
• require insulin treatment sooner or later. Important with proper diagnosis in the
|
||
beginning so that insulin needs are met a.s.a.p. and not delayed.
|
||
• About 10% of all people with diabetes after the age of 35 have LADA (ie
|
||
almost as common as T1DM)
|
||
• LADA was first described at the beginning of the1980s.
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
89
|
||
|
||
|
||
---
|
||
|
||
## Page 45
|
||
|
||
2024-12-06
|
||
45
|
||
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
|
||
• Diabetes is a worldwide pandemic and the problem is
|
||
increasing.
|
||
• Type 1 and Type 2 are the most common forms
|
||
• The impact of carbohydrate metabolism is insulin
|
||
deficience and insulin resistance
|
||
• Insufficient insulin secretion relative to insulin need à
|
||
Type 2 DM
|
||
Summary Diabetes
|
||
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
|
||
90
|
||
|
||
|
||
---
|
||
|