HORMONAL CONTROL OF INTERMEDIARY METABOLISM AND CONTROL IN DIABETES

26
BABCOCK UNIVERSITY COLLEGE OF HEALTH AND MEDICAL SCIENCES BENJAMIN S. CARSON (SNR) SCHOOL OF MEDICINE DEPARTMENT OF BIOCHEMISTRY 2014/2015 ORAL SEMINAR PRESENTATION (BCHM 433) HORMONAL CONTROL OF INTERMEDIARY METABOLISM OF GLUCOSE AND CONTROL IN DIABETES. BY OLUTOLA, MICHAEL OLAJIDE BIOCHEMISTRY, 400 LEVEL (11/2913) 9 th ,October 2014. SUPERVISED BY MR OMENKA.

Transcript of HORMONAL CONTROL OF INTERMEDIARY METABOLISM AND CONTROL IN DIABETES

BABCOCK UNIVERSITYCOLLEGE OF HEALTH AND MEDICAL SCIENCES

BENJAMIN S. CARSON (SNR) SCHOOL OF MEDICINEDEPARTMENT OF BIOCHEMISTRY

2014/2015 ORAL SEMINAR PRESENTATION (BCHM 433)

HORMONAL CONTROL OF INTERMEDIARY METABOLISM OF GLUCOSE AND CONTROL IN

DIABETES.BY

OLUTOLA, MICHAEL OLAJIDEBIOCHEMISTRY, 400 LEVEL (11/2913)

9th,October 2014.SUPERVISED BY MR OMENKA.

IntroductionWhat is intermediary metabolism?

It refers to the intracellular process by which nutritive material is converted into cellular components-can also be called intermediate metabolism

(Merriam-webster dictionary, 2014).

The sum of all metabolic reactions between uptake of nutrient and formation of its excretory products (Great soviet encyclopedia,1979).

Intermediary metabolism of glucose begins with the uptake by glucose transporters located on the surface of the cell membrane (Bell et al.,1990).

Glucose Transporters (Glut)

Glucose transporters are integral membrane

proteins that facilitate the transport of glucose

across a plasma membrane (oka et al.,1990)

Each glucose transporter isoform plays a

specific role in glucose metabolism determined

by its pattern of tissue expression, substrate

specificity, and regulated expression in

different physiological conditions (Thorens, 1996).

(Burant et al., 1991)

table 1: Table showing glucose transporters, location and function.

UTILIZATION OF GLUCOSE INTRACELLULARLY

Glucose is utilized based on the current requirement of the cell

and state of the body system.

Once its actively transported into the cell, its is immediately

phosphorylated to Glucose 6-phosphate by the enzyme

hexokinase or its isozyme depending on the tissue.

Glucose 6-phosphate can be further metabolized in the

glycolytic pathway to pyruvate which in turn can be converted

to lactate or alanine or oxidized to acetyl-CoA.

Alternatively, glucose 6-phosphate can be converted to

glucose 1-phosphate for glycogen synthesis or metabolized in

the pentose phosphate pathway to generate the ribose 5-

phosphate needed for nucleotide/nucleic acid synthesis and

the NADPH. (Nelson and Cox, 2008).

Insulin, Glucose metabolism and Diabetes.

Insulin is a small protein (5.7 kD) with two polypeptide chains, A and B containing 51 amino acids, joined by two disulfide bonds.

It is synthesized in the pancreas as an inactive single-chain precursor; preproinsulin with an amino-terminal “signal sequence” that directs its passage into secretory vesicles. Proteolytic removal of the signal sequence and formation of three disulfide bonds produces proinsulin, which is later cleaved (Nelson and Cox, 2008).

After cleavage of the C peptide, mature insulin is formed in the β-granules and is stored in the form of zinc-containing hexamers until secretion (Koolman and Roehm, 2005).

Figure 1: Insulin (Koolman and Roehm,2005).

Insulin is the only hormone that reduces blood glucose

levels, and it does this by activating the glucose transport

mechanisms and glucose-utilizing metabolic pathways in

different tissues of the body. Insulin also downregulates

glucose forming pathways. The effects of insulin are given

below:

1. Stimulates the uptake of glucose by muscle and

adipose tissue;

2. Stimulates glycolysis;

3. Stimulates glycogenesis;

4. Stimulates protein synthesis

5. Inhibits gluconeogenesis;

6. Inhibits lipolysis;

(Kahn, 2007).

Functions of insulin.

Figure 2: Mobilization of Glut 4 by insulin (Nelson and Cox,2008)

Functions of insulin cont. Insulin stimulates glycolysis by translocating

Glucokinase through the action of Glucokinase

regulatory protein (GKRP) to and fro the nucleus in

hepatocytes based on glucose concentration

(Schaftingen, 1994; Veiga da Cunha et al., 2004).

In subject to diabetes it is either:

Insulin production is absent because of autoimmune

pancreatic β-cell destruction. OR

Insulin secretion is inadequate because the body has

developed resistance to insulin.

(Preeti, 2014).

Figure 3: Insulin signal transduction (Koolman and Roehm,2005).

Amylin, Glucose metabolism and Diabetes.

Amylin also called Islet Amloid polypeptide (IAPP), is a 37 – residue peptide hormone weighing 7404 Dalton.

It is co-secreted with insulin from the pancreatic (beta) cells in the ratio of approximately 1:100.

Proislet Amyloid Polypeptide (pro IAPP, Proamylin, Proislet protein) is produced in the pancreatic (beta) cells as 67- amino acid.

it undergoes a post-translational modifications including protease cleavage to produce amylin (Sanke et al., 1988).

Amylin, Glucose metabolism and Diabetes cont.

Amylin exerts it actions primarily through the central nervous system.

Animal studies have identified specific calcitonin-like receptor sites for amylin in regions of the brain, predominantly in the Area Postrema (Ratner et al., 2004).

The Area Postrema is a part of the dorsal vagal complex of the brain stem.

A notable feature of the Area Postrema is that it lacks a blood-brain barrier, allowing exposure to rapid changes in plasma glucose concentrations as well as circulating peptides, including amylin. (Wimalawansa et al., 1997).

Functions of Amylin. Amylin plays a role in glycemic regulation by slowing

gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

Amylin’s metabolic function is well-characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. (Pittner et al., 1994)

it functions as a synergistic partner of insulin, with which it is cosecreted from pancreatic (beta) cells in response to meals. The overall effect is to slow the rate of appearance (Ra) of glucose in the blood after eating.

this is accomplished via coordinate slowing down gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection], and a resulting reduction in food intake.

Functions of Amylin cont.

amylin works to regulate the rate of glucose appearances from both endogenous (liver-derived) and exogenous (meal-derived) sources, and insulin regulates the rate of glucose disappearance. (Buse et al., 2002).

In subject with diabetes:

Amylin is deficient in type 1 and impaired in type 2 (Kruger et al., 1999).

Glucagon, Epinephrine, Glucose metabolism and Diabetes.

The pancreatic hormone glucagon is a 29-amino acid peptide that is synthesized by the Alpha-cells at the periphery of the islets of Langerhans and released primarily in response to low blood glucose levels (hypoglycemia). (Miller et al., 2003)

Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (enteroglucagon) (Bowen,1999).

Epinephrine (also known as adrenaline, or β,3,4-trihydroxy-N-methylphenethylamine) is a hormone and a neurotransmitter.

Epinephrine is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the amino acid tyrosine into a series of intermediates and, ultimately, adrenaline.

Tyrosine is first oxidized to L-DOPA, which is subsequently decarboxylated to give dopamine. Oxidation gives norepinephrine and the methylation of the primary amine of norepinephrine gives epinephrine. This reaction is catalyzed by the enzyme phenylethanolamine N-methyltransferase (PNMT)

This enzyme utilizes S-adenosylmethionine (SAMe) as the methyl donor.

(Koolman and Roehm, 2008).

Glucagon, Epinephrine, Glucose metabolism and Diabetes.

Catabolism of tissue glycogen is triggered by the actions of the hormones epinephrine and glucagon . In response to decreased blood glucose, glucagon is released from the cells in pancreatic islets of Langerhans.(Glucagon is active in liver and adipose tissue, but not in other tissues).

Similarly, signals from the central nervous system cause release of epinephrine from the adrenal glands into the bloodstream. Epinephrine acts on liver and muscles. When the hormone binds to its receptor on the outside surface of the cell membrane, a cascade is initiated that activates glycogen phosphorylase and inhibits glycogen synthase (Voet and Voet, 2004).

Although the role of glucagon in the regulation of blood glucose is well documented, its potential to cause target organ damage in type 2 diabetes remains poorly understood.(Miller et al.,2003)

In the kidney, glucagon induces glomerular hyperfiltration, a characteristic of early type 2 diabetic glomerular injury.(Tolins, 2004)

Glucagon and Epinephrine works in synergy.

Figure 4: Biosignaling cascade of Epinephrine in myocyte and Glucagon in hepatocyte (Nelson and Cox, 2008).

Tissue Specificity. The Liver is the major organ targeted by glucagon

which inhibits glucose utilizing pathways like (glycolysis, glycogenesis , hexose monophosphate shunt etc.) and promote glucose producing pathways such as (gluconeogenesis, glycogenolysis) to supply or replenish glucose into circulation. The kidney is also targeted by glucagon to replenish glucose into circulation.

These are the only tissues (liver and kidney) capable of replenishing blood glucose due to the possession of glucose 6-phosphatase, other tissues in the body system aren't capable of this due to absence of this enzyme.

(Garrett and Grisham,)

Cortisol, Glucose metabolism and Diabetes.

Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the zona fasciculata of the adrenal cortex (Scott, 2011).

It is released in response to stress and a low level of blood glucose.

Its primary functions are to increase blood sugar through gluconeogenesis, and aid the metabolism of fat, protein, and carbohydrate(Hoehn and Marieb, 2010).

Cortisol, Glucose metabolism and Diabetes cont.

Cortisol is a primary stress hormone secreted by the adrenal glands in response to inflammation from infection,injury,reactive substances like allergens or toxins, and certain digestive disturbances (Nelson and Cox, 2008).

High level of cortisol decreases metabolism of glucose and increases mobilization and metabolism of fats.

Decreased metabolism of glucose contributes to increased blood glucose levels, and increased blood fat levels contribute to insulin resistance.

Increased levels of blood glucose and blood fats are classic symptoms of diabetes. When blood cortisol levels are too high, insulin will not lower blood sugar (Cartwell, 2006).

Somogyi Effect and Dawn phenomenon

Somogyi Effect: nocturnal hypoglycemia (from fasting) leads to a surge of counterregulatory hormones (glucagon and epinephrine) that produce hyperglycemia at around 7AM.

Dawn Phenomenon: reduced tissue sensitivity to insulin between 5 and 8 AM.

Conclusion

Hormones are responsible for the control and modulation of enzymes through complex cascade biosignaling pathways that functions majorly via the generation or activation of second messengers located in a biological cell.

In general the imbalance between insulin and glucagon results into Diabetes mellitus.

References

Beaumont K, Kenney MA, Young AA, Rink TJ (1993). “High affinity amylin binding sites in the rat brain”. Molecular Pharmacology 44:493-497.

Matschinsky FM, Meglasson MD, Schimizu T, Prentki M, Garfinkel D, Achs M, Erecinska M, Najafi H, Parker J, Weik H (1988). “Glucose metabolism, glucose sensing and stimulus response coupling in insulin release by pancreatic beta-cells”. Pathogenesis of Non-Insulin-Dependent Diabetes Mellitus”. pp. 61-78.

Matschinsky, F., Liang, Y., Kesavan, P. (1993). “Glucokinase as pancreatic beta cell glucose sensor and diabetes gene”. Journal of Clinical Investigation 9:2092–2098.

Matthaei S, Stumvoll M, Kellerer M, Haring H-U. “Pathophysiology and pharmacological treatment of insulin resistance”. Endocrinology Reviews. 2000(21):585–618.