Diabetes Type 2 Characteristics

Diabetes Mellitus

• Diabetes type 2: usually later onset, insulin resistance, milder than type 1, associated with diet and lifestyle (e.g. obesity), increasing incidence (including in children)
• Hyperglycemia but usually no ketoacidosis, often responds to diet and oral hypoglycaemic agents

Metabolic Pattern in Uncontrolled Diabetes Mellitus

• Resembles starvation, but effects are more exaggerated
• In starvation, insulin is low, glucagon acts unopposed
• KB produced in starvation stimulate insulin release, limiting muscle protein breakdown, FA release from adipocytes, and uncontrolled KB production
• This mechanism does not operate in diabetes

Metabolism in Diabetes

• High glucagon, low insulin
• Glucose and KB production

Chronic Complications of Diabetes Mellitus

• Microangiopathy: changes in small blood vessel walls, thickening of basement membrane
• Retinopathy: blindness 25 times more common in diabetic patients
• Nephropathy: renal failure 17 times more common
• Neuropathy: postural hypotension, impotence, foot ulcers

Treatment

• Type 1: exogenous insulin by injection

Fuel Reserves in the Average Man

• Total fuel reserves: 167,850 Kcal (697.8 MJ)
• Glycogen: 300g (muscle), 80g (liver), energy value: 1460 Kcal (6.1 MJ), 330 Kcal (1.4 MJ)
• Glucose: 15g (body fluids), energy value: 60 Kcal (0.3 MJ)
• TAG: 15kg (adipose tissue), energy value: 140,000 Kcal (580 MJ)
• Protein: 6kg (muscle), energy value: 26,000 Kcal (110 MJ)

The Fasting (Post-Absorptive) State

• Blood glucose concentrations peak an hour after eating, return to normal by 2 hours
• Blood glucose is removed for oxidation or storage
• Concentration of insulin drops, glucagon rises

Metabolism in the Fasting State

• Early events: liver and adipose tissue
• Liver maintains blood glucose concentrations at about 4mM
• Adipose tissue provides greatest source of energy as TAGs
• Hormone-sensitive lipase activated by glucagon and adrenaline
• FA transported to liver bound to albumin

Glucose Production by the Liver

• Liver glycogen is the first supplier of blood glucose
• Gluconeogenesis follows from lactate, glycerol, and amino acids
• After 24 hours of fasting, all blood glucose comes from gluconeogenesis

Sources of Blood Glucose After Ingestion of 100g Glucose

• Not shown in the original text, but mentioned as a topic

Fatty Acids are NOT Gluconeogenic Precursors

• Reaction catalysed by Pyruvate dehydrogenase is IRREVERSIBLE
• PDH is activated by insulin and inhibited by glucagon
• Ensures that in fasting, gluconeogenic substrates are channelled into glucose production, not acetyl CoA formation

Fed State, Liver:

• Glycolytic enzymes are activated, pyruvate dehydrogenase is activated, and excess acetyl CoA is channelled into FA synthesis

Fasting State, Liver:

• FA can be used as fuel by liver, adipose tissue, and muscle; draining of gluconeogenic substrates into acetyl CoA is inhibited, and conversion to glucose is favoured

Ketone Body Formation

• FA oxidation in hepatocyte leads to high concentrations of Acetyl CoA
• It exceeds the capacity of the TCA cycle
• It is channelled into ketone body formation
• Acetoacetate and β-hydroxybutyrate are released into the bloodstream
• Most tissues oxidize a mixture of FA and KB
• Erythrocyte uses glucose
• Brain uses glucose and small amount of KB

Prolonged Fasting (Starvation)

• If the early pattern continued, body protein would be severely depleted
• Only about a third of body protein can be lost without severe or fatal consequences

Fuel Concentration in the Blood in Prolonged Fasting

• Not shown in the original text, but mentioned as a topic

Metabolism in Starvation

• As starvation continues, more KB are recovered from the kidney
• Muscle uses FA rather than KB
• FA concentrations plateau, KB rise
• Brain can use more KB and less glucose
• Need for gluconeogenesis is reduced, muscle protein breakdown decreases
• Urea production decreases

Ketone Bodies

• Act on pancreas to stimulate insulin release
• Limit muscle proteolysis and adipose tissue lipolysis
• Muscle tissue is conserved

Eventually

• Amount of adipose tissue is an important determinant of survival
• Death comes from fuel exhaustion, loss of function from loss of protein, and impairment of the immune system
• Death from starvation is often due to infection
• About 40 days (young and fit, may be longer)

Glucose Tolerance Curves of Normal and Diabetic Subjects

• Not shown in the original text, but mentioned as a topic

Diabetes Mellitus

• Affects 6% of population in UK
• 90% of all endocrine disorders
• Major cause of blindness, amputations, premature deaths
• 10% of total health care budget