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