hormonal regulation of glycaemia
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Hormonal regulation of glycaemia
Alice Skoumalová
The oral glucose tolerance test (oGTT):
Used if:
elevated fasting levels of glucose - 5,3-6,7 mmol/l (for diagnosis of diabetes, screening of patients with impaired glucose tolerance)
screening of gestational diabetes
Procedure:
administration of 75g glucose in an aqueous solution
after overnight fasting (10h)
„common“ diet and physical activity during previous three days
be seated and do not smoke during the test
determination of the glucose levels in the capillary blood before the glucose load and after 60 and 120 minutes
Factors affecting oGTT: previous diet, infection, stress
Revision:
1. Glucose homeostasis (hypoglycemia and hyperglycemia prevention)
2. Insulin (which metabolic pathways are activated/inhibited)
3. Glucagon (which metabolic pathways are activated/inhibited)
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:
1. release of glucose from the large glycogen stores in the liver (glycogenolysis)
2. synthesis of glucose from lactate, glycerol, and amino acids in liver (gluconeogenesis)
3. release of fatty acids from adipose tissue (lipolysis)
Hyperglycemia prevention:
1. conversion of glucose to glycogen (glycogen synthesis)
2. conversion of glucose to triacylglycerols in liver and adipose tissue (lipogenesis)
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)
the islets of Langerhans (β- and α-cells)
preprohormone (modification - in ER, GC, SV)
Synthesis and secretion of insulin and glucagon:
Cleavage of proinsulin to insulin:
Proinsulin is converted to insulin by proteolytic cleavage, which removes the C-peptide
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
Insulin receptor signaling:
the tyrosine kinase activity
a dimer (α and ß subunits)
Signal transduction:
1. the ß-subunits autophosphorylate each other when insulin binds (activating the receptor)
2. the activated receptor binds and phosphorylates IRS (insulin receptor substrate)
3. multiple binding sites for different proteins
Major sites of glucagone action on fuel metabolism:
Mobilization of energy stores
1. release of glucose from liver glycogen
2. stimulating gluconeogenesis from lactate, glycerol, and amino acids (liver)
3. mobilizing fatty acids (adipose tissue)
Glucose Insulin Amino acids
Insulin + +
Glucagon - - +
Regulators of insulin and glucagon release:
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• Stimulates FA release from adipose tissue
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
Binding of insulin to its cell membrane receptor causes vesicles containing glucose transport proteins to move from inside the cell to the cell membrane
Stimulation by insulin of glucose transport into muscle and adipose cells:
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
Pathways affected by insulin
1. Carbohydrate metabolismstimulation of glucose utilization:
glycogen synthase ↑glycolysis ↑
inhibition of gluconeogenesisthe transport of glucose into tissues (muscle, adipose tissue)
2. Lipid metabolismstimulation 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 ↓
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
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 Insulin Diet, drugs, insulin
Types of diabetes:
The oral glucose tolerance test (oGTT):
The blood glucose level returns to the basal level by 2 hours
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
≥6,7
≥11,1
Impaired glucose tolerance
fasting
2h (after the glucose load)
<6,7
6,7-10
<7,8
7,8-11,1
<6,7
7,8-11,1
The oral glucose tolerance test (oGTT):
diagnosis of diabetes; administration of glucose (75g) in an aqueous solution
glucose level determination before the glucose load and at 30, 60 and 120 minutes after
The chronic diabetes complications:
A. Microvascular (diabetic retinopathy, nefropathy, neuropathy)
nonenzymatic glycation of proteins in vascular tissue
B. Macrovascular (atherosclerosis)
nonenzymatic glycation of proteins in vascular tissue and lipoproteins
C. Diabetic cataract:
increased osmolarity of the lens (increased activity of the polyol pathway → ↑sorbitol)
nonenzymatic glycation of proteins of lens
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 !
Diabetic cataract :
↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins
Lens metabolism:
Questions:
1. Insulin (synthesis, receptor)
2. DM - major metabolic changes
3. Diabetes complications
4. oGTT
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