Session 11 Flashcards
What role does calcium play in the body?
Calcium plays a critical role in many cellular processes, including hormone secretion, muscle contraction, nerve conduction, exocytosis, and the activation and inactivation of many enzymes. Ca2+ also serves as an intracellular second messenger by carrying information from the cell membrane into the interior of the cell.
What role does phosphate play in the body?
Phosphate is no less important. Because it is part of the adenosine triphosphate molecule, phosphate plays a critical role in cellular energy metabolism. It also plays crucial roles in the activation and deactivation of enzymes. However, unlike calcium, the plasma phosphate concentration is not very strictly regulated, and its levels fluctuate throughout the day, particularly after meals.
Why is calcium homeostasis and phosphate homeostasis linked?
Calcium homeostasis and phosphate homeostasis are intimately linked to each other for two reasons. First, calcium and phosphate are the principal components of hydroxyapatite crystals [Ca10(PO4)6(OH)2)], which constitute by far the major portion of the mineral phase of bone. Second, they are regulated by the same hormones, primarily parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (calcitriol) and, to a lesser extent, the hormone calcitonin. These hormones act on three organ systems-the bone, the kidneys, and the gastrointestinal (GI) tract-to control the levels of these two ions in plasma. However, the actions of these hormones on calcium and phosphate are typically opposed in that a particular hormone may elevate the level of one ion while lowering that of the other.
What is the calcium distribution in a 70kg man? (helpful to use a diagram)
Most calcium is located within bone, approximately 1 kg. The total amount of calcium in the extracellular pool is only a fraction of this amount, about 1 g or 1000 mg. The typical daily dietary intake of calcium is approximately 800 to 1200 mg. Dairy products are the major dietary source of calcium. Although the intestines absorb approximately one half the dietary calcium (~500 mg/day), they also secrete calcium for removal from the body (~325 mg/day), and, therefore, the net intestinal uptake of calcium is only approximately 175 mg/day. The second major organ governing calcium homeostasis is bone, where calcium deposition of about 280 mg/day is matched by an equal amount of calcium reabsorption in the steady state. The third organ system involved, the kidneys, filter about 10 times the total extracellular pool of calcium per day (about 10,000 mg/day). More than 98% of this Ca2+ is reabsorbed and therefore the net renal excretion of Ca2+ is less than 2% of the filtered load. In a person in Ca2+ balance, urinary excretion (~175 mg/day) is the same as net absorption by the GI tract.
In the plasma, what physiochemical forms does calcium exist as?
1) As a free ionized species
2) Bound to (more accurately, associated with) anionic sites on serum proteins (especially albumin)
3) Complexed with low-molecular-weight organic anions (e.g., citrate and oxalate)
The total concentration of all three forms in the plasma is normally 2.2 to 2.7 mmol/L. In healthy individuals, approximately 45% of calcium is free, 45% is bound to protein, and 10% is bound to small organic anions. The ionized form is the most important with regard to regulating the secretion of PTH and is involved in most of the biological actions of calcium.
How could a calcium test be misleading as to the amount of active calcium?
It is the free ionized calcium in plasma that is physiologically active. However common laboratory tests measure total calcium which includes that which is bound to albumin and other proteins. The levels are then corrected depending on the level of albumin to determine if free calcium is in the correct range or not.
What happens if plasma calcium levels alter?
The consequence of plasma calcium levels straying outside these daily limits is significant. Hypocalcaemia (calcium too low) results in hyperexcitability in the nervous system, including the neuromuscular junction, leading to paraesthesia, then tetany, paralysis and even convulsions. Whereas, chronic hypercalcaemia (calcium too high) may result in the formation of kidney stones (renal calculi), constipation, dehydration, kidney damage, tiredness and depression.
How do hormones regulate serum calcium levels?
Given the consequence of dysregulation of serum calcium, it is clearly important that levels are maintained within set limits. Two key hormones are involved in this regulation, Parathyroid hormone (PTH) and the active form of Vitamin D (calcitriol). They both raise serum calcium concentrations, but act by different mechanisms and over quite different time scales. The short term regulation of serum calcium is under the control of PTH, whereas calcitriol is responsible for longer term regulation.
Vitamin D is the collective term for a group of prohormones, the two major forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D obtained from sun exposure, food, and supplements, is biologically inert and must undergo two hydroxylation reactions to be activated in the body. Calcitriol (1,25dihydroxycholecalciferol) is the active form of vitamin D found in the body, involved in calcium regulation. The term vitamin D also refers to these metabolites and other analogues of these substances.
Parathyroid hormone related peptide (PTHrP) is a peptide produced by tumours which may lead to hypercalcaemia. The measurement of PTHrP can be of assistance in determining the cause of an otherwise unexplained hypercalcaemia. PTHrP is a peptide secreted by some cancer cells leading to humeral hypercalcaemia of malignancy (HHM). PTHrP is produced commonly in patients with breast or prostate cancer and occasionally in patients with myeloma. PTHrP shares many actions with PTH leading to increased calcium release from bone, reduced renal calcium excretion and reduced renal phosphate reabsorption. However PTHrP does not increase renal C-1 hydroxylase activity and therefore does not increase calcitriol concentration, unlike parathyroid hormone.
There is a third hormone, calcitonin, which in animal models lowers serum calcium levels. However, in humans this peptide hormone which is secreted from the thyroid gland appears to lack pathology associated with either hypo or hyper secretion, suggesting that it has little function. If the thyroid gland is removed or destroyed the lack of secretion of calcitonin has no apparent effect on calcium homeostasis. However, there is some suggestion that during pregnancy this hormone may serve to preserve the maternal skeleton.
What forms of fuel are normally available in the blood?
Glucose
- It’s the preferred fuel source
- Little (~12g) free glucose available
- More glucose available in the form of glycogen (~300g)
Fatty Acids
- Can be used as fuel by most cells, except red blood cells, brain and CNS.
- Stored as triacylglycerol (fat) in adipose tissue
- 10-15kg fat in 70kg man (roughly 2 months fuel supply)
What forms of fuel are available in the body under special conditions?
Amino Acids
- Some muscle protein (~6kg) can be broken down to provide amino acids for fuel.
- Converted to glucose or ketone bodies
- ~2 week supply of energy
Ketone Bodies
- Mainly from fatty acids
- Used when glucose is critically short
- Brain can metabolise instead of glucose
Lactate
- Product of anaerobic metabolism in muscle.
- Liver can convert back to glucose (Cori cycle) or can be utilised as fuel source for TCA cycle in other tissues (e.g heart)
What influence do hormones have on blood glucose concentration?
Hormonal control is a major factor in determining the availability of fuel molecules in the blood and alterations in hormone concentrations may have dramatic effects on blood fuel concentrations. The hormone insulin lowers fuel concentrations in the blood while glucagon, adrenaline, growth hormone and cortisol increase their concentrations. Since the effects of glucagon, adrenaline, growth
hormone and cortisol oppose those of insulin they are collectively known as the anti-insulin hormones.
Where is glucose in the body and how much is there?
Glucose can be used by all cells and is the preferred fuel. However, there is very little free glucose in the body. About 12g is present in solution in the body fluids and this would support the metabolism of the CNS for ~2hr. More glucose (∼300g) is stored as glycogen, principally in liver and muscle. Only the glucose stored in the liver (∼100 g) can be made available to tissues such as the CNS.
How are fatty acids used as fuel?
Many cells, but, not red blood cells or those in the central nervous system can also use fatty acids as fuels. These are derived from triacylglycerol stored in adipose tissue. In a typical 70kg individual there is 10-15kg of fat, enough to supply the body’s fuel needs for about two months. This makes up about 80% of the total fuel reserve in the body and is substantially greater in the obese. Fatty acids can be converted to ketone bodies in the liver to be used as fuel by tissues including the CNS when glucose is critically short during a period of starvation
How can protein be sued as a fuel source?
Some of the protein in muscle (∼6kg) can be broken down (proteolysis) to amino acids that can also be used to provide fuel in times of shortage, either by conversion to glucose and ketone bodies or by direct oxidation. This fuel reserve corresponds to about two weeks supply of fuel at normal rates of metabolism.
How is fuel used by the CNS?
The central nervous system. The main problem in the control of fuel reserves is to ensure that the CNS receives an adequate supply of glucose, in the face of apparently dangerously small glucose stores. Glucose has to be available at all times as metabolism in the CNS (~140g/24hr) and other glucose-dependent tissues (~40g/24hr) proceeds at a relatively constant rate throughout the day. Since the rate of glucose uptake by the CNS is related to the blood glucose concentration, the problem reduces to maintaining the blood glucose concentration within a particular range. In a healthy individual, blood glucose concentration is maintained in the range 4.0 - 6.0 mmol/L. The blood glucose concentration is controlled via the endocrine system by regulating the rates of entry of glucose into the blood and removal from it.
What is hypoglycaemia and what can it lead to?
Hypoglycaemia. A reduction in blood glucose to 3.0 mmol/L or lower, is known as hypoglycaemia. The acute effects of hypoglycaemia can include: trembling, weakness, tiredness, headache, sweating, sickness, tingling around the lips, palpitations, changes in mood (angry/bad temper), slurred speech, and a staggering walk. They can be confused with intoxication. Hypoglycaemia may rapidly lead to unconsciousness and death if untreated as the CNS is starved of glucose
What is hyperglycaemia and what can it lead to?
Hyperglycaemia. Elevation of the fasting blood glucose above 7.0 mmol/L is known as hyperglycaemia. The chronic effects of hyperglycaemia are generally insidious and reduce both the quality and duration of life. Many systems of the body including the nervous, cardiovascular and renal systems may be affected. Glucose appears in the urine, because all that is filtered by the kidney cannot be recovered (the renal threshold for glucose is exceeded). More water is lost in the urine as a result of the osmotic effect of the glucose (‘polyuria’) and so increased thirst follows (polydipsia). Hyperglycaemia is also associated with abnormal metabolism of glucose to products that may be harmful to cells. There is increased non-enzymatic glycosylation of plasma proteins such as lipoproteins that leads to disturbances in their function
What are the effects of fasting?
Effects of feeding: The absorption of glucose, amino acids and lipids from the gut raises their blood concentration. These increases stimulate the endocrine pancreas to release insulin. Insulin has the following actions:
• Increases glucose uptake and utilisation by muscle and adipose tissue.
• Promotes storage of glucose as glycogen in liver and muscle.
• Promotes amino acid uptake and protein synthesis in liver and muscle.
• Promotes lipogenesis and storage of fatty acids as triacylglycerols in adipose tissue.
What are the effects of fasting?
Effects of fasting: As the blood glucose concentration falls insulin secretion is depressed. This reduces the uptake of glucose by adipose tissue and muscle. The falling blood glucose concentration also stimulates glucagon secretion i.e. insulin/anti-insulin ratio decreases. This stimulates:
• Glycogenolysis in the liver to maintain blood glucose for the brain and other glucose dependent tissues.
• Lipolysis in adipose tissue to provide fatty acids for use by tissues.
• Gluconeogenesis to maintain supplies of glucose for the brain.
Should fasting proceed beyond 10hr the changes associated with starvation begin.
What is the body’s initial response to starvation?
The initial response to starvation is merely a prolonged version of the normal fasting (inter-meal) response. At first blood glucose falls, but is maintained at an adequate level (3.5 mmol/L) by the actions of glucagon, which stimulates the breakdown of hepatic glycogen. As these stores last only a few hours, the continuing reduction of blood glucose stimulates the pituitary to release ACTH, and consequently blood cortisol is elevated. This hormone, amongst other effects, acts to maintain blood glucose by stimulating gluconeogenesis, and at the same time making gluconeogenic substrates available (mainly alanine and glycerol) by stimulating the breakdown of protein and fat. In addition to cortisol, glucagon also stimulates gluconeogenesis and the actions of both hormones involve increasing the amounts and activities of key enzymes of the gluconeogenic pathway in liver cells as well as increasing the availability of gluconeogenic substrates.
How does rate of lipolysis change during starvation?
Lipolysis occurs at a high rate, because of the fall in plasma insulin and rise in lipolytic hormones such as glucagon, cortisol and growth hormone. Free fatty acids in blood rise to about 2 mmol/L, from a normal value in the fed individual of ~0.3 mmol/L. The continuing action of cortisol stimulates fat breakdown, and as the reduction in insulin, reinforced by the anti- insulin effects of cortisol, prevents most cells from using glucose, the fatty acids so produced are preferentially metabolised. Glycerol then provides an important substrate for gluconeogenesis, reducing the need for breakdown of proteins.
