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WHY REGULATE PLASMA GLUCOSE?
Set Point: 80-100 mg/100 ml plasma
• Glucose is virtually the only fuel the brain can use tomake ATP (also ketones)
• If plasma glucose falls too low, brain activity declines
• If plasma glucose rises too high, there are both acuteand longterm complications – diabetes mellitus
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Absorptive state
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Post absorptive state
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HOW IS ALL THIS REGULATED?
HORMONES!
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Hormones that decrease glucose Hormones that increase glucose
Insulin Glucagon
Epinephrine
Growth hormone
Cortisol
How come so many backup systems to prevent low plasma glucose?
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Pancreas – insulin staining in brown
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EFFECTS OF INSULIN
• Increased numbers of glucose transporters on cell surface
• Activation of enzymes involved in synthesis of glycogen, glycerol,fatty acids, activation of lipoprotein lipase
• Inhibition of enzymes involved in gluconeogenesis, glycogenolysis,conversion of triacylglycerides to fatty acids and glycerol,synthesis of ketones
Net effect = decreased plasma glucose
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Green = insulin promotesRed = insulin inhibits
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What causes insulin to be released?
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Hormones that decrease glucose Hormones that increase glucose
Insulin Glucagon
Epinephrine
Growth hormone
Cortisol
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Effects of glucagon that lead to increased plasma glucose
Liver: • Activation of enzymes that cause gluconeogenesis• Activation of enzymes that promote ketone synthesis• Inhibition of enzymes that cause synthesis of glycogen
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Post absorptive state
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What causes glucagon to be released from the pancreas?
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Factors increasing glucagon release from the pancreas
• Decreased plasma glucose
• Increased plasma amino acids*
• Epinephrine and sympathetic stimulation
• Cortisol and growth hormone
* Important in preventing meal induced hypoglycemia in carnivores
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Factors increasing glucagon release from the pancreas
• Decreased plasma glucose
• Increased plasma amino acids*
• Epinephrine and sympathetic stimulation
• Cortisol and growth hormone
* Important in preventing meal induced hypoglycemia in carnivores
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Hormones that decrease glucose Hormones that increase glucose
Insulin Glucagon
Epinephrine
Growth hormone
Cortisol
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Hormones that decrease glucose Hormones that increase glucose
Insulin Glucagon
Epinephrine
Growth hormone
Cortisol
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Diabetes Mellitus• Juvenile/insulin dependent/ Type 1
– often follows viral illness (with a latency period)– autoimmune attack on islets– decreased insulin production– Prevalence: 0.2-0.3% of the US population
• adult-onset/non-insulin dependent/ Type 2)– associated with obesity and older age– insulin levels can be normal or elevated, especially early– peripheral insulin resistance– Prevalence: 6-10% of the US population (and rising)
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The insulin receptor
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Acute Complications
• Hyperglycemia– Increased serum glucose leading to loss of water and glucose
in the urine– Hyperosmolarity– Hypotension– Hyperkalemia (increased serum potassium)– Ketosis
• Hypoglycemia– Resulting from overdose of insulin causing excessive uptake
of glucose by cells, manifestations include activation of the sympathetic nervous system
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Insulin deficiency
glucose uptakegluconeogenesis
plasma glucose
lipolysis
ketone synthesis
plasma ketones
plasma H+
Brain dysfunction, coma, death
plasma osmolarity
Loss of Na+ andH2O in urine
Blood volume
Blood pressure
Brain blood flow
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K+
Na+
K+
Na+
insulinadrenalinaldosterone
K+
K+
acidosisincreased osmolaritycell injury
Hyperkalemia in diabetes mellitus
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Consequences of high plasma glucose
• Increased glycosylation of proteins– hemoglobin (useful as an index of average
blood glucose levels over last 3 months)– collagen in basement membrane
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Consequences of high plasma glucose
• Distrubances in polyol pathways in cells that do not require insulin for glucose uptake (nerves, lens of the eye, kidney, blood vessels)
Glucose
aldose reductase
sorbitol Increased osmolarity swelling
Impaired ion pumps injury
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Chronic Complications
• Atherosclerosis• Microvascular disease
– nephropathy– retinopathy
• Peripheral Neuropathy• Infections
– Leading cause of amputations
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Diabetic Retinopathy• major cause of blindness
– 10% of type I after 30 yrs– Leading cause of new blindness in the US
• Nonproliferative lesions– BM thickening, edema, hemorrhage
• Proliferative lesions– new blood vessels, fibrous tissue– proliferate over retina over time– secondary to ischemia, microvascular disease– most severe seen in type I
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dambrosio-eye-care-boston.com
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CAUSES OF END STAGE RENAL DISEASE PERCENT OF CASES
Diabetes 34.2Hypertension 29.2Glomerulonephritis 14.2Interstitial nephritis 3.4Cystic kidney disease 3.4Other or unknown 15.4
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Diabetic Nephropathy
• approx. 1/3 of type I DM will get renal failure
• Mechanism: basement membrane damage
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Peripheral Neuropathy• Mechanisms:
– changes in nerve components (myelin, schwann cells, etc.)
– microvascular disease• Consequences
– pain, abnormal sensation in extremities– touch, pain sensation eventually lost--
allows tissue damage– autonomic nerve dysfunction
• GI tract motility• GU tract dysfunction
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CAUSES OF INFECTIONS
• Decreased neutrophil function - due to high glucose
• More frequent skin eruptions - peripheral neuropathies
• Ischemia - vascular disease
• Increased plasma glucose - good growth medium for microorganisms
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TREATMENT
• Juvenile/insulin dependent/Type I– Insulin injections/pumps/transdermal
• adult-onset/non-insulin dependent/Type II)– Diet and exercise– Sulfonylureas (increase insulin release)– Thiazolidinediones (PPARg agonists) – glucophage (metformin) (increases insulin sensitivity)– Insulin (in severe cases when insulin has been depleted)