BC21DCarbohydrate Metabolism

Rachael Irving

Biochemistry

Metabolism/Energy

• Body needs energy for life– Metabolism : brain, muscle -

• Energy available from CHO, protein, fats• Some lost as heat• Excess stored for use• Large excess stored as fat - obesity• Metabolic rate (RMR, BMR)– rate at which

calories used• Inadequate supply – failure of several systems

death

Carbohydrates-- Glucose

• Digestion converts all carbohydrates to monosaccharides which are transported to the liver and converted to glucose.

• The liver is important in the storage and distribution of fuels including glucose within the body.

• Glucose in the body undergoes one of three metabolic fates : it is catabolised to produce ATP This occurs in all peripheral tissues, particularly in brain, muscle and kidney.

Carbohydrate Metabolism

• The breakdown is accompanied by the formation of energy-rich bonds, primarily the pyrophosphate bond of the coenzyme Adenosine triphosphate (ATP), which serves as a coupling agent between different metabolic processes.

• The breakdown sugars, particularly glucose is one of the principal sources of energy for living organisms.

• The sum of the biochemical and physiological processes involved in the breakdown, synthesis and transport of sugar across cell membranes is called carbohydrate metabolism

Carbohydrate as electron donor

• Series of steps in which energy is stored as ATP

• Heat production • Glucose → 38

ATP,6 CO2 + 12H2

Fate of Glucose

• Glucose is stored as glycogen.• This storage occurs in liver and muscle. • It is converted to fatty acids. Once

converted to fatty acids, these are stored in adipose tissue as triglycerides.

• Glucose will be oxidised by all tissues to synthesise ATP. The first pathway which begins the complete oxidation of glucose is called glycolysis.

Biosynthesis of insulin

• Insulin is synthesized in significant quantities in the β cells in the pancreas.

• The insulin mRNA is translated as a single chain precursor called pre-proinsulun .

• Removal of its signal peptide during insertion into the endoplasmic reticulum generates pro-insulin.

• Within the endoplasmic reticulum, pro-insulin is exposed to specific endopeptidases (enzymes) and the mature form of insulin is generated.

Insulin secretion

• Glucose triggers β cell membrane electrical activity.

• The glucose transporter in the β cell is GLUT-2.

• The triggering of the β cell electrical activity by glucose metabolism is understood to be obligate step in insulin secretion mechanism.

Release of insulin• The actual release of insulin occurs by exocytosis.• The granule membrane fuses with the cell membrane.• The membranes are disrupted at the point of fusion. • The insulin crystal is discharged to the extracellular

space, leaving the granule membrane inserted into the cellular plasma membrane.

• The granule membrane and the proteins it contains are thus inserted into and become part of the cellular plasma

membrane.• The process of exocytosis is the rate limiting step for

physiologic insulin secretion.

Effect of Glucose infusion (carbohydrate) on insulin secretion

• Immediately after glucose infusion begins, plasma insulin level increases dramatically.

• This initial increase is due to secretion of preformed insulin, which is soon depleted.

• The secondary rise in insulin reflects the considerable amount of newly synthesized insulin that is released immediately.

Insulin and regulation of glucose transport

• Insulin rapidly stimulates the transport of glucose across muscle and fat membranes.

• Only fat and muscle cells exhibit this extraordinary responsiveness to insulin with respect to glucose uptake, and only these cell types express a particular glucose transporter protein isoform, GLUT-4

• In the absence of insulin, almost all of the GLUT-4 transporters are sequestered into intracellular, tubulovesicular endosomal membrane structures, rendering them useless for transporting glucose.

Insulin and regulation of Glucose transport

• Binding of insulin to receptors on fat/muscle cells leads to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters,giving the cells the ability to take up glucose.

• When blood level of insulin decreases and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.

• Some tissues do not require insulin for efficient uptake of glucose: important examples are brain and liver.

• These cells do not use GLUT-4 for importing glucose, but rather another transporter that is insulin independent.

Insulin and regulation of Glycogen synthesis

• Insulin stimulates the liver to store glucose in the form of glycogen.

• A large fraction of the glucose absorbed into the liver is immediately taken up by hepatocytes, which convert glucose into the storage polymer- glycogen.

• Binding of insulin to its receptors leads to activation of hexokinase, which phosphorylates glucose, and traps glucose within the cell.

• In the absence of insulin, glycogen synthesis in the liver ceases and the enzymes responsible for breakdown of glycogen become active.

Too much energy from food predispose to DM

Obesity and Insulin Resistance

• Obesity is associated with insulin resistance. • Insulin delivers glucose to the cells. • Obesity causes cells to become less sensitive to the

insulin released by the pancreas.• Fat cells are more resistant to insulin than muscle

cells. • More fat cells than muscle cells, means that insulin

becomes less effective, glucose remains in circulation instead of being absorbed

High Glucose level and Definition of Diabetes Mellitus

• Diabetes Mellitus is characterized by hyperglycaemia and disturbances of carbohydrate, fat and protein metabolism.

• The disturbances are associated with absolute or relative deficiencies in insulin action and secretion.

• Based on the facts above, therefore, although diabetes is an endocrine disease in origin, its major manifestation are those of a metabolic disease.

Obesity, Insulin resistance and diabetes

• The incidence of diabetes correlates with the rise in obesity.

• More than 85% of people with diabetes are overweight or obese

• A prevalent theory is that being overweight causes cellular changes that make the cells resistant to insulin, a condition referred to as insulin resistance.

• Insulin Resistance leads to overworking of the pancreas and eventual failure

Description of Diabetes Mellitus

• Diabetes causes a chronic disorder in metabolism.

• It is characterized by hyperglycaemia in the postprandial and/or fasting state.

• The chronic hyperglycaemia is associated with long term damage, dysfunction and failure of various organs especially the eyes, kidneys, nerves, heart and blood vessels.

Description of Diabetes Mellitus

• Symptoms of chronic hyperglycaemia include polyuria, polydipsia, weight loss and blurred vision.

• Impairment of growth and susceptibility to certain infections are also associated with diabetes.

• Long term complication of diabetes include retinopathy with loss of vision and nephropathy leading to renal failure.

At what blood glucose Level can we define diabetes?

• Casual plasma glucose concentration 200 mg/dl (11.1 mmol/l). Symptoms of diabetes.

• FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 hours.

• After a 2-hour post-load glucose, blood glucose level of 200 mg/dl (11.1 mmol/l) during an Oral Glucose Tolerance Test (OGTT)

Types of diabetes(4 major types)

Type 1 :

• Formerly called IDDM or Juvenile diabetes.

• Characterized by β cells destruction caused by an autoimmune process, usually leading to absolute insulin deficiency.

• Over 95 percent of persons with type1 diabetes mellitus develop the disease before the age of 25 years

Types continue

Type 11• Formerly called NIDDM or adult-onset diabetes• Characterized by insulin resistance and an insulin

secretory defect of the β cells.• The most common type .• Highly associated with a family history of

diabetes, older age, obesity and lack of exercise.• It is more common in women, blacks, Hispanics

and Native Americans.

Types continues

Gestational • Identifies women who develop diabetes mellitus during

gestation(pregnancy).• Most women classified with gestational diabetes mellitus

have normal glucose homeostasis during the first half of pregnancy but develop a relative insulin deficiency during the last half of the pregnancy, leading to hyperglycemia and a diagnosis of diabetes in pregnancy.

• Majority of cases diagnosed between 24-28 weeks of pregnancy.

• The hyperglycemia resolves in most women after delivery but places them at increased risk of developing type 2 diabetes mellitus later in life.

Types continue

Other Specific Types• Other types of diabetes mellitus of various known

etiologies are grouped together to form the classification “Other Specific Types.“

• This group includes persons with genetic defects of the β cells (MODY).

• Defects in insulin action.• Persons with diseases of the exocrine pancreas, such as

pancreatitis or cystic fibrosis.• Persons with dysfunction associated with other

endocrinopathies (example: acromegaly)• Persons with pancreatic dysfunction caused by drugs,

chemicals or infections (HIV, other viral infections)

Prevalence Rate of Diabetes

• Type 1 : 1-2% of the Jamaican population

• Type 2 : 15-20% of the Jamaican population (increasing rapidly)

• Gestational : 3-5% of the Jamaican population

• Other Specific Types : 5% of the Jamaican population

Counter-regulatory hormones and carbohydrate metabolism

Cortisol• Cortisol preserves carbohydrate reserves by

promoting gluconeogenesis in the liver.• Promotes protein degradation in muscle and

lymphoid tissues.• Promotes triglyceride breakdown in adipose

tissue to provide substrates for gluconeogenesis. • Cortisol decreases triglyceride synthesis in

adipose tissue and glucose metabolism in muscle.

Counter-regulatory hormones and carbohydrate metabolism

• Glucagon stimulates the liver and muscles to break down stored glycogen (glycogenolysis) and releases the glucose.

• Glucagon stimulates gluconeogenesis in the liver and kidneys.

• In contrast to insulin, glucagon mobilizes glucose from stores inside the body and increases the concentration of glucose in the bloodstream.

Counter-regulatory hormones and carbohydrate metabolism

Human Placental Lactogen (pregnancy hormone)

• Human placental lactogen contributes to insulin resistance by lipolysis of fat cells, resulting in increased levels of circulating free fatty acids (FFA).

• Free fatty acids block the uptake and use of glucose by peripheral tissues such as skeletal muscle.

• FFA also inhibit important enzymatic reactions such as that of hexokinase, hence increasing the level of glucose in the maternal circulation.

Insulin Resistance

• Insulin resistance is a state in which a given concentration of insulin produces a less than normal biologic response; causing reduced glucose disposal in response to insulin.

• The major role of insulin is to promote glucose metabolism.

• Insulin travels from the cell through the circulation to the target tissue. Events at any one of these loci can influence the ultimate action of the hormone.

Insulin resistance continues

• Insulin resistance may be due to four general categories or causes:

(i) An abnormal β cell secretory product. (ii) Circulating insulin antagonists. (iii) Target tissue defect in insulin action (iv) Defective adiponectin secretion

1. An abnormal β cell secretory product.

• Insulin resistance can be caused by secretion of a structurally and biologically defective insulin molecule as a result of mutation in the gene encoding insulin.

• Incomplete conversion of pro-insulin to insulin in the β cell can also lead to insulin resistance.

2. Circulating Insulin Antagonists

• Circulating antagonists can be grouped into hormonal and non-hormonal.

• Hormonal antagonists include normally all the counter-regulatory hormones such as cortisol, growth hormone, glucagon and catecholamines.

• Non-hormonal antagonists include anti-insulin antibodies and anti-insulin receptor antibodies .

3.Target Cell Defect

• The overall scheme of insulin action represents a multi-step sequence in which the binding of insulin to receptors is only the initial event.

• A defect in any of the effector systems downstream from the receptor binding can lead to impaired insulin action and resistance.

Defective Adiponectin Secretion

• Adiponectin encoded by the APMI gene is one of the adipocyte-expressed proteins.

• It functions in the homeostatic control of glucose, lipid, and energy metabolism.

• Its dysregulation has been suggested to be involved in disorders such as insulin resistance, obesity and type 2 diabetes

Elevated Fatty Acids and Insulin Resistance

• Free fatty acids block the uptake and use of glucose by peripheral tissues such as skeletal muscle.

• FFA also inhibit important enzymatic reactions such as that of hexokinase, hence increasing the level of glucose in the maternal circulation.

• Though insulin is being secreted to meet the rising glucose level, the uptake of glucose is not optimal because of the inhibition in the glycolytic pathway hence insulin resistance and eventually diabetes develops .

• Resolving fatty acids elevation will alleviate insulin resistance

Insulin Sensitivity

• The ability of pancreatic β cells to react correctly to glycaemic changes by promptly increasing or decreasing the insulin response is defined as insulin sensitivity.

• Insulin sensitivity is critical to glucose and metabolic homeostasis.

• For any amount of insulin secreted by the pancreas, the biological response of a given effector is dependent on its insulin sensitivity.

• Any decrease in insulin sensitivity is immediately translated into minute increases in blood glucose concentrations which can lead to diabetes

Summary

• Carbohydrate metabolism is central to all metabolic pathways

• Derangement in carbohydrate metabolism leads to derangements in fat and protein metabolism

• Diabetes Mellitus is the pathological condition most closely associated with disturbance of carbohydrate metabolism.