The Endocrine Pancreas

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Regulation of Carbohydrate Metabolism

Nutritional Requirements Living tissue is maintained by constant

expenditure of energy (ATP). Indirectly from glucose, fatty acids, ketones,

amino acids, and other organic molecules. Energy of food is commonly measured in

kilocalories. One kilocalorie is = 1000 calories.

One calorie = amount of heat required to raise the temperature of 1 cm3 of H20 from 14.5o to 15.5o C.

The amount of energy released as heat when food is combusted in vitro = amount of energy released within cells through aerobic respiration.

Metabolic Rate and Caloric Requirements

Metabolic rate is the total rate of body metabolism. Metabolic rate measured by the amount of

oxygen consumed by the body/min. BMR:

Oxygen consumption of an awake relaxed person 12–14 hours after eating and at a comfortable temperature.

BMR determined by: Age. Gender.

Body surface area. Thyroid secretion.

Anabolic Requirements

Anabolism: Food supplies raw materials for synthesis

reactions. Synthesize:

DNA and RNA. Proteins. Triglycerides. Glycogen.

Must occur constantly to replace molecules that are hydrolyzed.

Aerobic Requirements (continued)

Catabolism: Hydrolysis (break down monomers

down to CO2 and H2O.): Hydrolysis reactions and cellular

respiration. Gluconeogenesis. Glycogenolysis. Lipolysis.

How do we use food components in catabolic and anabolic pathways?

Involves specific chemical reactions:- Each reaction is catalyzed by a specific enzyme.- Other compounds, besides those being directly metabolized, are required as intermediates or catalysts in metabolic reactions

- adenosine triphosphate (ATP)- nicotinamide adenine dinucleotide

(NAD+)- flavin adenine dinucleotide (FAD+)- Coenzyme A

ATP ATP is the energy currency of the cell The structure of ATP is similar to that of nucleic

acids The energy in ATP is “carried” in the

phosphate groups- to convert ADP into ATP requires energy- the energy is stored as potential energy

in the phosphate group bond- removal of the third phosphate releases

that energy

NADH, FADH2

NAD+ can accept a hydrogen ion and become reduced to NADH:

NAD+ + 2[H+] + 2e- NADH + H+

The added hydrogen ion (and electrons) can be carried to and used in other reactions in the body.

FAD+ is similarly reduced to FADH2. NADH and FADH carry hydrogen ions and

electrons to the enzymes in the electron transport chain of the mitochondria, allowing ATP production there.

Coenzyme A

The enzyme coenzyme A converts acetyl groups (2-carbon structures) into acetyl CoA, which can then be used in metabolic reactions

During the course of acetyl CoA production, energy is released and is used to convert NAD+ to NADH

Cellular Respiration Generating ATP from food requires

glycolysis, the Krebs Cycle, and the electron transport chain.

Overall reaction:C6H12O6 + 6 O2----> 6 CO2 + 6 H2O + 38 ATP + heat

The Main point: the break down of glucose releases LOTS of energy:

- about 40% in usable form (ATP)- about 60% as heat

Glycolysis Glycolysis is the breakdown of glucose

into pyruvic acid Two main steps are involved, occurring

in the cytoplasm of cells (no organelles involved).

The two main steps of glycolysis:

glucose glucose 6-phosphate fructose 1,6- diphosphate

Step one:

ATP ATP

Step two:fructose 1,6-diphosphate

2 ATP 2 ATP2 NADH2 pyruvic acid

What happens to pyruvic acid?

In aerobic respiration (oxygen present):- pyruvic acid moves from

cytoplasm to mitochondria- pyruvic acid (3 carbons) is

converted to acetyl group (2 carbons), producing CO2 in the process

- acetyl group is converted to acetyl CoA by coenzyme A

- acetyl CoA is used in the Krebs cycle.

Krebs Cycle

Acetyl CoA combines with oxaloacetic acid, forming citric acid

A series of reactions then occurs resulting in:

- one ATP produced- three NADH and one FADH2

produced (go to electron transport chain)- two CO2 molecules produced

Electron-transport Chain

The main point: NADH and FADH2 carry H+ ions to the electron-transport chain, resulting in production of ATP

To do this, the H+ ions are moved along the transport chain, eventually accumulating in the outer mitochondrial compartment

The H+ ions move back into the inner mitochondrial compartment via hydrogen channels, which are coupled to ATP production.

At the end of the transport chain, four hydrogen ions join with two oxygen molecules to form water:

4 H+ + O2 ----> 2 H2O In the absence of oxygen, the transport chain

stalls (no ATP production)

Net Result of Glycolysis, Citric Acid Cycle, and Electron Transport Chain:

Production of ATP (stored, potential energy for chemical reactions in the body; 40% of energy released).

Production of heat (maintains body temperature; 60% of energy released).

Also, production of CO2 and H2O.

Storage and Utilization of Glycogen Excess glucose can be stored as

glycogen.glucose glucose glucose glycogen

6-phosphate 1-phosphate Stored glycogen can be utilized, by glycogenolysis. Glycogenolysis:

-glycogen is broken down into glucose 6-phosphate- liver transforms glucose 6-phosphate to glucose, maintaining blood glucose levels

Lipid Metabolism Over 95% of stored energy in the body is in the

form of triacylglycerol During lipid catabolism (lipolysis), triacylglycerol is

broken down into free fatty acids and glycerol Free fatty acids are metabolized by beta-oxidation:

1) fatty acid (18 C) + coenzyme A2) fatty acid (18 C)-coA3) fatty acid (16 C) and acetyl-coA

Acetyl-CoA used in citric acid cycle This reaction also yields NADH => electron

transport chain Excess acetyl-CoA forms ketone bodies

Lipid Metabolism (cont.) The glycerol is converted into glyceraldehyde

3-phosphate, which is converted to pyruvic acid

Pyruvic acid is metabolized under aerobic conditions into acetyl-coA

While lipids are major storage form of energy, accessing lipids for metabolism takes time

- water insoluble- less efficient energy source- potential for keto-acidosis

Protein Metabolism

Amino acids are NOT stored for energy However, protein can be broken down,

and amino acids can be modified and utilized to create glucose or for metabolism

Modification of amino acids to produce substrate for energy involves oxidative deamination

Oxidative Deamination Oxidative deamination removes the

amino group from the amino acid, forming ammonia, NADH, and a keto acid:

NADH => electron transport chain ammonia => liver, converted to urea keto acid => acetyl-coA => citric acid

Proteins and Energy Utilization of proteins for quick energy is

not very efficient:- more difficult to break apart

(multiple proteases)- toxic byproduct (ammonia)- can get accumulation of keto

acids- proteins are important structural

and functional components of cells

Interconversion of Nutrients Lipogenesis: once glycogen stores are filled,

glucose and amino acids are converted to lipids Rate limiting enzyme: acetyl CoA carboxylase

amino acids acetyl fatty CoA acids

glucose

glucose 6-phosphate

glyceraldehyde 3-phosphate glycerol

triglyceridesacetyl CoA carboxylase

Interconversion of Nutrients (cont.)

Gluconeogenesis: amino acids and glycerol can be used to produce glucose (liver)

More glucose is produced via gluconeogenesis than glycogenolysis Rate-limiting enzyme: phosphoenolpyruvate carboxykinase

Glycerol glyceraldehyde glucose3- phosphate 6-phosphate

Amino pyruvic acid glucoseacids

oxaloacetate

phosphoenol pyruvatePEPCK

Importance of Blood Glucose Homeostasis Blood glucose levels must be

maintained as a nutrient source for nervous tissue (no glucose stores)

What mechanisms regulate blood nutrient levels in tissues and blood glucose levels?

The Endocrine Pancreas: Regulation of Nutrient Metabolism Located on the posterior abdominal wall,

retroperitoneal. Exocrine portion: secretes digestive enzymes

via pancreatic duct, to small intestine. Endocrine portion: pancreatic islets (of

Langerhans), involved in regulation of blood glucose levels.

Production of Pancreatic Hormones by Three Cell Types

Alpha cells produce glucagon. Beta cells produce insulin. Delta cells produce somatostatin.

Structure of Insulin Insulin is a polypeptide hormone,

composed of two chains (A and B) BOTH chains are derived from

proinsulin, a prohormone. The two chains are joined by disulfide

bonds.

Roles of Insulin Acts on tissues (especially liver, skeletal

muscle, adipose) to increase uptake of glucose and amino acids.

- without insulin, most tissues do not take in glucose and amino acids well (except brain).

Increases glycogen production (glucose storage) in the liver and muscle.

Stimulates lipid synthesis from free fatty acids and triglycerides in adipose tissue.

Also stimulates potassium uptake by cells (role in potassium homeostasis).

The Insulin Receptor As we previously saw, the insulin receptor is

composed of two subunits, and has intrinsic tyrosine kinase activity.

Activation of the receptor results in a cascade of phosphorylation events:

phosphorylation ofinsulin responsive substrates (IRS) RAS

MAP-KMAP-KK Final

actions

Specific Targets of Insulin Action: Carbohydrates

Activation of glycogen synthetase. Converts glucose to glycogen.

Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis.

Increased activity of glucose transporters. Moves glucose into cells.

Specific Targets of Insulin Action: Lipids Activation of acetyl CoA carboxylase.

Stimulates production of free fatty acids from acetyl CoA.Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell.

lipoproteinlipase

Regulation of Insulin Release Major stimulus: increased blood glucose

levels- after a meal, blood glucose increases

- in response to increased glucose, insulin is released

- insulin causes uptake of glucose into tissues, so blood glucose levels decrease.- insulin levels decline as blood glucose declines

Glucose

Insulin

InsulinSecretion

Insulin Effects

Pancreas

Restrain of HGO Uptake of

glucose

Storage In Fat DepotsInhibition of Lipolysis

Effect of Glucose on Insulin Release Glucose enters beta cell through a

glucose transporter. Glucose is utilized to generate ATP. ATP closes a potassium channel,

depolarizing the beta cell membrane (normally, K+ leaks out of cell).

Depolarization activates a voltage-dependent calcium channel, increasing intracellular calcium levels.

Increased calcium triggers insulin release.

The synthesis and release of insulin is modulated

by:1. Glucose (most

important), AAs, FAs and ketone bodies stimulate release.

2. Glucagon and somatostation inhibit relases

3. α-Adrenergic stimulation inhibits release (most important).

4. β-Adrenergic stimulation promotes release.

5. Elevated intracellular Ca2+ promotes release.

Insulin secretion - Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter, the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio. This rise inactivates the potassium channel that depolarizes the membrane, causing the calcium channel to open up allowing calcium ions to flow inward. The ensuing rise in levels of calcium leads to the exocytotic release of insulin from their storage granule.

Mechanism of Insulin Action

Insulin binds to specific high affinity membrane receptors with tyrosine kinase activity

Phosphorylation cascade results in translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane.

It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis.

Insulin promotes the uptake of K+ into cells.

Other Factors Regulating Insulin Release

Amino acids stimulate insulin release (increased uptake into cells, increased protein synthesis).

Keto acids stimulate insulin release (increased glucose uptake to prevent lipid and protein utilization).

Insulin release is inhibited by stress-induced increase in adrenal epinephrine- epinephrine binds to alpha adrenergic receptors on beta cells

- maintains blood glucose levels Glucagon stimulates insulin secretion (glucagon

has opposite actions).

Structure and Actions of Glucagon Peptide hormone, 29 amino acids Acts on the liver to cause breakdown of

glycogen (glycogenolysis), releasing glucose into the bloodstream.

Inhibits glycolysis Increases production of glucose from amino

acids (gluconeogenesis). Also increases lipolysis, to free fatty acids for

metabolism. Result: maintenance of blood glucose levels

during fasting.

Mechanism of Action of Glucagon

Main target tissues: liver, muscle, and adipose tissue

Binds to a Gs-coupled receptor, resulting in increased cyclic AMP and increased PKA activity.

Also activates IP3 pathway (increasing Ca++)

Targets of Glucagon Action Activates a phosphorylase, which cleaves off a

glucose 1-phosphate molecule off of glycogen. Inactivates glycogen synthase by

phosphorylation (less glycogen synthesis). Increases phosphoenolpyruvate

carboxykinase, stimulating gluconeogenesis Activates lipases, breaking down triglycerides. Inhibits acetyl CoA carboxylase, decreasing

free fatty acid formation from acetyl CoA Result: more production of glucose and

substrates for metabolism

Regulation of Glucagon Release

Increased blood glucose levels inhibit glucagon release.

Amino acids stimulate glucagon release (high protein, low carbohydrate meal).

Stress: epinephrine acts on beta-adrenergic receptors on alpha cells, increasing glucagon release (increases availability of glucose for energy).

Insulin inhibits glucagon secretion.

Other Factors Regulating Glucose Homeostasis Glucocorticoids (cortisol): stimulate

gluconeogenesis and lipolysis, and increase breakdown of proteins.

Epinephrine/norepinephrine: stimulates glycogenolysis and lipolysis.

Growth hormone: stimulates glycogenolysis and lipolysis.

Note that these factors would complement the effects of glucagon, increasing blood glucose levels.

Hormonal Regulation of Nutrients

Right after a meal (resting):

- blood glucose elevated

- glucagon, cortisol, GH, epinephrine low

- insulin increases (due to increased glucose)

- Cells uptake glucose, amino acids.

- Glucose converted to glycogen, amino acids into protein, lipids stored as triacylglycerol.

- Blood glucose maintained at moderate levels.

A few hours after a meal (active):- blood glucose levels decrease- insulin secretion decreases- increased secretion of glucagon, cortisol, GH, epinephrine - glucose is released from glycogen stores (glycogenolysis)- increased lipolysis (beta oxidation)- glucose production from amino acids increases (oxidative deamination; gluconeogenesis)- decreased uptake of glucose by tissues- blood glucose levels maintained

Hormonal Regulation of Nutrients

Turnover Rate

Rate at which a molecule is broken down and resynthesized.

Average daily turnover for carbohydrates is 250 g/day.

Some glucose is reused to form glycogen. Only need about 150 g/day.

Average daily turnover for protein is 150 g/day. Some protein may be reused for protein synthesis.

Only need 35 g/day. 9 essential amino acids.

Average daily turnover for fats is 100 g/day. Little is actually required in the diet.

Fat can be produced from excess carbohydrates. Essential fatty acids:

Linoleic and linolenic acids.

Regulation of Energy Metabolism

Energy reserves: Molecules that

can be oxidized for energy are derived from storage molecules (glycogen, protein, and fat).

Circulating substrates:

Molecules absorbed through small intestine and carried to the cell for use in cell respiration.

Insert fig. 19.2

Eating

Eating behaviors partially controlled by hypothalamus.

Lesions in vetromedial area produce hyperphagia (obesity).

Lesions in lateral hypothalamus produces hypophagia (weight loss).

Endorphins, NE, serotonin, and CCK affect hunger and satiety.

Regulatory Functions of Adipose Tissue

Adipostat regulatory system (negative feedback loops) to defend amount of adipose tissue. Differentiation of adipocytes require nuclear

receptor protein (PPAR which is activated when bound to 15-D PGJ2:

Stimulates adipogenesis by promoting development of preadipocytes into mature adipocytes.

Number of adipocytes increase after birth. Differentiation promoted by high [fatty acids].

Adipocytes store fat within large vacuoles. May secrete hormones involved in regulation of

metabolism.

Regulatory Functions of Adipose Tissue (continued)

Leptin: Hormone that signals the hypothalamus to indicate the

level of fat storage. Involved in long-term regulation of eating.

Satiety factor in obese have decreased sensitivity to leptin in the brain.

Neuropeptide Y: Potent stimulator of appetite. Functions as a NT within the hypothalamus.

These neurons are inhibited by leptin. TNF

Acts to reduce the sensitivity of cells to insulin. Increased in obesity.

May contribute to insulin resistance.

Regulation of Hunger

Adipose tissue secrete satiety factor: Acts through its regulation of hunger centers in

hypothalamus. Ghrelin:

Secreted by stomach. Secretions rise between meals and stimulate hunger.

CCK: Secretions rise during and immediately after a

meal. Produce satiety.

PYY3-36: Acts within the hypothalamus.

Decreases neuropeptide Y.

Obesity Obesity is often diagnosed by using using

a body mass index (BMI). BMI = w

w = weight in kilograms h = height in meters

Healthy weight as BMI between 19 – 25. Obesity defined as BMI > 30.

Obesity in childhood is due to an increase in both the size and the # of adipocytes.

Weight gains in adulthood is due to increase in adipocyte size in intra-abdominal fat.

Calorie Expenditures

3 components: Basal metabolic rate (BMR):

60% total calorie expenditure. Adaptive thermogenesis:

10% total calorie expenditure. Physical activity:

Contribution variable.

Balance Between Anabolism and Catabolism

The rate of deposit and withdrawal of energy substrates, and the conversion of 1 type of energy substrate into another; are regulated by hormones.

Antagonistic effects of insulin, glucagon, GH, T3, cortisol, and Epi balance anabolism and catabolism.

Insert fig. 19.4

Pancreatic Islets (Islets of Langerhans)

Alpha cells secrete glucagon. Stimulus is decrease in

blood [glucose]. Stimulates glycogenolysis

and lipolysis. Stimulates conversion of

fatty acids to ketones. Beta cells secrete insulin.

Stimulus is increase in blood [glucose].

Promotes entry of glucose into cells.

Converts glucose to glycogen and fat.

Aids entry of amino acids into cells.

Energy Regulation of Pancreas

Islets of Langerhans contain 3 distinct cell types: cells

Secreteglucagon. cells

Secreteinsulin. cells

Secrete somatostatin.

Regulation of Insulin and Glucagon

Mainly regulated by blood [glucose].

Lesser effect: blood [amino acid]. Regulated by negative feedback.

Glucose enters the brain by facilitated diffusion.

Normal fasting [glucose] is 65–105 mg/dl.

Regulation of Insulin and Glucagon (continued)

When blood [glucose] increases: Glucose binds to GLUT2 receptor

protein in cells, stimulating the production and release of insulin.

Insulin: Stimulates skeletal muscle cells and

adipocytes to incorporate GLUT4 (glucose facilitated diffusion carrier) into plasma membranes.

Promotes anabolism.

Oral Glucose Tolerance Test

Measurement of the ability of cells to secrete insulin.

Ability of insulin to lower blood glucose.

Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs.

Insert fig. 19.8

Regulation of Insulin and Glucagon

Parasympathetic nervous system: Stimulates insulin secretion.

Sympathetic nervous system: Stimulates glucagon secretion.

GIP: Stimulates insulin secretion.

GLP-1: Stimulates insulin secretion.

CCK: Stimulates insulin secretion.

Regulation of Insulin and Glucagon Secretion (continued)

Glucose homeostasis

Figure 26.8

Insulin

Beta cellsof pancreas stimulatedto release insulin intothe blood

Bodycellstake up moreglucose

Blood glucose leveldeclines to a set point;stimulus for insulinrelease diminishes

Liver takesup glucoseand stores it asglycogen

High bloodglucose level

STIMULUS:Rising blood glucoselevel (e.g., after eatinga carbohydrate-richmeal) Homeostasis: Normal blood glucose level

(about 90 mg/100 mL) STIMULUS:Declining bloodglucose level(e.g., afterskipping a meal)

Alphacells ofpancreas stimulatedto release glucagoninto the blood

Glucagon

Liverbreaks downglycogen and releases glucoseto the blood

Blood glucose levelrises to set point;stimulus for glucagonrelease diminishes

Hormonal Regulation of Metabolism

Absorptive state: Absorption of energy. 4 hour period after eating. Increase in insulin secretion.

Postabsorptive state: Fasting state. At least 4 hours after the meal. Increase in glucagon secretion.

Absorptive State

Insulin is the major hormone that promotes anabolism in the body.

When blood [insulin] increases: Promotes cellular uptake of glucose. Stimulates glycogen storage in the liver and

muscles. Stimulates triglyceride storage in adipose

cells. Promotes cellular uptake of amino acids and

synthesis of proteins.

Postabsorptive State

Maintains blood glucose concentration.

When blood [glucagon] increased: Stimulates glycogenolysis in the liver

(glucose-6-phosphatase). Stimulates gluconeogenesis. Skeletal muscle, heart, liver, and

kidneys use fatty acids as major source of fuel (hormone-sensitive lipase).

Stimulates lipolysis and ketogenesis.

Insert fig. 19.10

Effect of Feeding and Fasting on Metabolism

Diabetes Mellitus

Chronic high blood [glucose]. 2 forms of diabetes mellitus:

Type I: insulin dependent diabetes (IDDM).

Type II: non-insulin dependent diabetes (NIDDM).

Comparison of Type I and Type II Diabetes Mellitus

Insert table 19.6

Type I Diabetes Mellitus

cells of the islets of Langerhans are destroyed by autoimmune attack which may be provoked by environmental agent. Killer T cells target glutamate decarboxylase in

the cells (see next slide). Glucose cannot enter the adipose cells.

Rate of fat synthesis lags behind the rate of lipolysis.

Fatty acids converted to ketone bodies, producing ketoacidosis.

Increased blood [glucagon]. Stimulates glycogenolysis in liver.

GAD (expressed by β cells)

Glucagon secretionfrom α cells

Glc in blood andinsulin release

Without GAD

Glucagon secretion andblood glc, but no increasedinsulin because β cells aredestroyed. So, glc accumulates.

GABAwhich regulatesglucagon secretionfrom α cells

Virusβ cells p69 Killer T cells

GAD epitope(in β cells) ~p69 epitope

infects express

Consequences of Uncorrected Deficiency in Type I Diabetes Mellitus

Insert fig. 19.11

Type II Diabetes Mellitus Slow to develop. Genetic factors are

significant. Occurs most often in

people who are overweight.

Decreased sensitivity to insulin or an insulin resistance.

Obesity. Do not usually

develop ketoacidosis. May have high blood

[insulin] or normal [insulin].

Insert fig. 19.12

Treatment in Diabetes

Change in lifestyle: Increase exercise:

Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells.

Weight reduction. Increased fiber in diet. Reduce saturated fat.

Hypoglycemia

Over secretion of insulin.

Reactive hypoglycemia:

Caused by an exaggerated response to a rise in blood glucose.

Occurs in people who are genetically predisposed to type II diabetes.

Insert fig. 19.13

Metabolic Regulation

Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary. Insulin, T3, and GH can act

synergistically to stimulate protein synthesis.

Metabolic Effects of Catecholamines

Metabolic effects similar to glucagon. Stimulate glycogenolysis.

Stimulate release of glucose from the liver. Stimulate lipolysis and release of fatty acids.

NE stimulates 3 receptors in brown fat. Contains uncoupling protein that dissociates

electron transport from ATP production.

Metabolic Effects of Catecholamines (continued)

Metabolic Effects of Glucocorticoids

Glucocorticoids secreted in response to release of ACTH.

Support the effects of increased glucagon.

Promote lipolysis and ketogenesis. Promote protein breakdown in the

muscles. Increases blood [amino acids].

Promote liver gluconeogenesis.

The Endocrine Pancreas

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