Download Hormonal regulation of glycaemia

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)
Synthesis and secretion of insulin and glucagon:
 the islets of Langerhans (β- and α-cells)
 preprohormone (modification - in ER, GC, SV)
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:
Signal transduction:
 the tyrosine kinase activity
1. the ß-subunits autophosphorylate each other when insulin binds
(activating the receptor)
 a dimer (α and ß subunits)
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)
Regulators of insulin and glucagon
release:
Glucose
Insulin
+
Glucagon
-
Insulin
Amino acids
+
-
+
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 longterm
• 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
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
The glucose sensor in the
pancreas
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
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 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 ↓
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
Types of diabetes:
Type I (insulin-dependent)
Type II (non-insulindependent)
Incidence
10-20%
80-90%
Age
childhood, the teens
Middle-aged, older
Cause
An autoimmune disease
Complete absence of insulin
Unknown
Symptoms
Hyperglycemia,
hypertriglyceridemia, ketoacidosis
Hyperglycemia,
hypertriglyceridemia
Habitus
Thinness
Obesity
Ketoacidosis
Yes
No
Insulin
Very low or absent
Normal (increased)
Therapy
Insulin
Diet, drugs, insulin
Relative insulin deficiency
The oral glucose tolerance test (oGTT):
The blood glucose level returns to the basal level by 2 hours
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
Diagnosis
Diabetes mellitus
Time
Venous blood Plasm
Capillary blood
(glucose
mmol/l)
(glukose
mmol/l)
(glukose
mmol/l)
fasting
≥6,7
≥7,8
≥6,7
2h (after the
≥10
≥11,1
≥11,1
fasting
<6,7
<7,8
<6,7
2h (after the
6,7-10
7,8-11,1
7,8-11,1
glucose load)
Impaired glucose
tolerance
glucose load)
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 !
Lens metabolism:
Diabetic cataract :
↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol
accumulation → ↑osmolarity, structural changes of proteins
Questions:
1. Insulin (synthesis, receptor)
2. DM - major metabolic changes
3. Diabetes complications
4. oGTT