1. Hormonal regulation of glycaemia
Alice Skoumalová

2. Glycolysis

3. Gluconeogenesis

4. Pentose Phosphate Pathway

5. Formation and degradation of glycogen

6. Overview of the major pathways of glucose metabolism

7. Glucose homeostasis:
maintenance of blood glucose levels near 80 to 100 mg/dL (4,4-5,6 mmol/l)
insulin and glucagon (regulate fuel mobilization and storage)
Hypoglycemia prevention:
release of glucose from the large glycogen stores in the liver (glycogenolysis)
synthesis of glucose from lactate, glycerol, and amino acids in liver (gluconeogenesis)
release of fatty acids from adipose tissue (lipolysis)
Hyperglycemia prevention:
conversion of glucose to glycogen (glycogen synthesis)
conversion of glucose to triacylglycerols in liver and adipose tissue (lipogenesis)

8. Changes in blood glucose levels after a meal
Fasting: ~ 5 mmol/l
After a meal: ~ 8 mmol/l (returning to the fasting range by 2 hours)
Hyperglycemia:
the osmotic effect of glucose, dehydratation, hyperosmolar coma
Hypoglycemia:
a lack of energy (brain), hemolysis of erythrocytes

9. Pathways regulated by the release of:
glucagon (in response to a lowering of blood glucose levels)
insulin (in response to an elevation of blood glucose levels)

10. Synthesis and secretion of insulin and glucagon:
the islets of Langerhans (β- and α-cells)
preprohormone (modification - in ER, GC, SV)

11. Cleavage of proinsulin to insulin:
Proinsulin is converted to insulin by proteolytic cleavage, which removes the C-peptide

12. Major sites of insulin action on fuel metabolism:
The storage of nutriens
glucose transport into muscle and adipose tissue
glucose storage as glycogen (liver, muscle)
conversion of glucose to TG (liver) and their storage (adipose tissue)
protein synthesis (liver, muscle)
inhibition of fuel mobilization

13. Insulin receptor signaling:
the tyrosine kinase activity
a dimer (α and ß subunits)
Signal transduction: - the ß-subunits autophosphorylate each other when insulin binds (activating the receptor)
- the activated receptor binds and phosphorylates IRS (insulin receptor substrate)
- multiple binding sites for different proteins

14. Major sites of glucagone action on fuel metabolism:
Mobilization of energy stores
release of glucose from liver glycogen
stimulating gluconeogenesis from lactate, glycerol, and amino acids (liver)
mobilizing fatty acids (adipose tissue)

15. + - Regulators of insulin and glucagon release: Glucose Insulin
Amino acids +
Glucagon -

16. Insulin Glucagon Epinephrine Cortisol Hormone Function
Major metabolic pathways affected
Insulin
Promotes fuel storage after a meal
Promote growth
Stimulates glucose storage as glycogen (muscle,liver)
Stimulates FA synthesis and storage after a high-carbohydrate meal
Stimulates amino acids uptake and protein synthesis
Glucagon
Mobilizes fuels
Maintains blood glucose levels during fasting
Activates gluconeogenesis and glycogenolysis (liver) during fasting
Activates FA release from adipose tissue
Epinephrine
Mobilizes fuels during acute stress
Stimulates glucose production from glycogen (muscle, liver)
Stimulates FA release from adipose tissue
Cortisol
Provides for changing requirements over the long-term
Stimulates amino acid mobilization from muscle protein
Stimulates gluconeogenesis

17. Production of blood glucose
Glycogenolysis
2 hours after a meal
the primary source of blood glucose during the first few hours of fasting
Gluconeogenesis
after consumption of the liver glycogen
lactate (muscle, erythrocytes), amino acids (muscle), glycerol (adipose tissue)

18. Liver glycogen
Glycogen serves as a carbohydrate reserve, from which glucose can be released
The human body can store up to 450 g of glycogen (a third in the liver)
Liver glycogen serves in the maintenance of the blood glucose level, it declines to zero in periods of starvation that last more than one day
Glykogen ve svalech, pouze pro energii, svaly nemají glukosa-6-fosfatasu

19. Liver gluconeogenesis
Gluconeogenesis occurs predominantly in the liver (90%)
Precursors:
1. Amino acids derived from the muscles (prolonged fasting results in a massive degradation of muscle protein)
2. Lactate formed in erythrocytes and in muscles
3. Glycerol produced from the degradation of fats
Cortisol, glucagon, epinephrine: promote gluconeogenesis
Insulin: inhibits gluconeogenesis

20. Blood glucose levels at various stages of fasting:
Stage of fasting
Glucose (mg/dL)
Glucose (mM/L)
Normal level
80-100
4,4-5,6
Fasting (12 h) 80
4,4
Starvation (3 d) 70
3,9
Starvation (5-6 wk) 65
3,6

21. Regulation of glycogenolysis in the liver by glucagon:
cAMP → protein kinase A:
1. inactivates glycogen synthase
2. activates glycogen phosphorylase

22. Regulation of gluconeogenesis:
inactivation of the glycolytic enzymes and activation of the enzymes of gluconeogenesis
1. Pyruvate → PEP
Pyruvate kinase - inactivation by cAMP (glucagon)
Phosphoenolpyruvate carboxykinase - induced by glucagon, epinephrine, and cortisol
2. Fructose 1,6-P → Fructose 6-P
Phosphofructokinase - activated by fructose 2,6-P)
Fructose 1,6-bisphosphatase - inhibited by fructose 2,6-P)
3. Glucose 6-P → Glucose
Glucokinase - high Km for glucose, induced by insulin
Glucose 6-phosphatase - induced during fasting

23. Sources of blood glucose in fed, fasting, and starved states:

24. Blood-placentar barier GLUT 2 Liver Kidney Pancreatic β-cells
Transporter
Tissue distribution
Comments
GLUT 1
Erythrocytes
Blood-brain barier
Blood-placentar barier
Present in high concentrations
GLUT 2
Liver
Kidney
Pancreatic β-cells
Intestinal mucosa cells
A high Km for glucose
The glucose sensor in the pancreas
GLUT 3
Brain
Major transporter in the brain
GLUT 4
Adipose tissue
Sceletal muscle
Heart muscle
Insulin-sensitive transporter! The number increases on the cell surface.
GLUT 5
Intestinal epithelium
A fructose transporter

25. Stimulation by insulin of glucose transport into muscle and adipose cells:
Binding of insulin to its cell membrane receptor causes vesicles containing glucose transport proteins to move from inside the cell to the cell membrane

26. Diabetes mellitus
chronic disease characterized by derangements in carbohydrate, fat and protein metabolism
caused by either complete absence of insulin or relative insulin deficiency
2 types:
Type 1 (insulin-dependent):
no insulin
defective ß-cells function (an autoimmune disease)
Type 2 (non-insulin-dependent):
„the insulin resistance“ (unknown cause, often obesity)
= impaired function of insulin receptors (TNF, resistin)
- the lower number of receptors
- signal cascade abnormalities

27. Pathways affected by insulin
1. Carbohydrate metabolism
stimulation of glucose utilization:
glycogen synthase ↑
glycolysis ↑
inhibition of gluconeogenesis
the transport of glucose into tissues (muscle, adipose tissue)
2. Lipid metabolism
stimulation of the glucose conversion into FA:
acetyl CoA carboxylase ↑
NADPH (PPP ↑)
storage of fat:
lipoprotein lipase ↑
inhibition of the degradation of fat:
hormone sensitive lipase ↓

28. Effects of insulin deficiency
1. Glucose uptake and utilization↓
2. Proteolysis↑
3. Gluconeogenesis↑
3. Degradation of fat↑
Hypeglycemia (≥9mmol/l)
Glucosuria
Hyperlipidemia
Metabolic acidosis
Ketonuria

29. Types of diabetes: Type I (insulin-dependent)
Type II (non-insulin-dependent)
Incidence
10-20%
80-90%
Age
childhood, the teens
Middle-aged, older
Cause
An autoimmune disease
Complete absence of insulin
Unknown
Relative insulin deficiency
Symptoms
Hyperglycemia, hypertriglyceridemia, ketoacidosis
Hyperglycemia, hypertriglyceridemia
Habitus
Thinness
Obesity
Ketoacidosis
Yes No
Insulin
Very low or absent
Normal (increased)
Therapy
Diet, drugs, insulin

30. The oral glucose tolerance test (oGTT):
The blood glucose level returns to the basal level by 2 hours

31. The oral glucose tolerance test (oGTT):
diagnosis of diabetes; administration of glucose (75g) in an aqueous solution
glucose level determination before and at 30, 60 and 120 minutes after the glucose load
Diagnosis
Time
Venous blood
(glucose mmol/l)
Plasm
(glukose mmol/l)
Capillary blood
(glukose mmol/l)
Diabetes mellitus
fasting
2h (after the glucose load)
≥6,7
≥10
≥7,8
≥11,1
Impaired glucose tolerance
<6,7
6,7-10
<7,8
7,8-11,1

32. The diabetes complications:
1. Acute
A. Hyperglycemic coma:
the elderly, DM 2 (not recognized diabetes, failure to take insulin, an infection, coincidental medical problem), hyperglycemia ( 50mM), dehydratation
B. Hypoglycemic coma:
insulin overdose, sweating, tremulousness, palpitations, confusion
C. Ketoacidosis:
acute insulin deficiency, DM 1, the smell of acetone on the breath, Kussmaul respiration, dehydratation
2. Chronic
A. Microvascular (diabetic retinopathy, nefropathy, neuropathy)
nonenzymatic glycation of proteins in vascular tissue
B. Makrovascular (atherosclerosis)
nonenzymatic glycation of proteins in vascular tissue and lipoproteins
C. Diabetic cataract:
increased osmolarity of the lens (increased acitivity of the polyol pathway → ↑sorbitol)
nonenzymatic glycation of proteins of lens

33. Hyperglycemia - protein glycation:
hemoglobin
vascular tissue proteins → contribute to the diabetic complications (cataracta, atherosclerosis, retinopathy, nephropathy)
Glycated proteins:
- impaired structure and fucntion
The importance of the maintance of low glucose levels in diabetic patients !

34. Lens metabolism: Diabetic cataract :
↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins