The Endocrine Pancreas
Regulation of Carbohydrate Metabolism
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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.
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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.
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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.
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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
cycle
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
RAF-1
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
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Glucose
Insulin
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InsulinSecretion
Insulin Effects
FOOD
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.
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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.
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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
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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.
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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
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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.
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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.
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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.
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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.
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Obesity Obesity is often diagnosed by using using
a body mass index (BMI). BMI = w
h 2
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.
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Calorie Expenditures
3 components: Basal metabolic rate (BMR):
60% total calorie expenditure. Adaptive thermogenesis:
10% total calorie expenditure. Physical activity:
Contribution variable.
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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
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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.
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Energy Regulation of Pancreas
Islets of Langerhans contain 3 distinct cell types: cells
Secreteglucagon. cells
Secreteinsulin. cells
Secrete somatostatin.
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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.
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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.
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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
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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.
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Regulation of Insulin and Glucagon Secretion (continued)
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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
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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.
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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.
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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.
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Insert fig. 19.10
Effect of Feeding and Fasting on Metabolism
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Diabetes Mellitus
Chronic high blood [glucose]. 2 forms of diabetes mellitus:
Type I: insulin dependent diabetes (IDDM).
Type II: non-insulin dependent diabetes (NIDDM).
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Comparison of Type I and Type II Diabetes Mellitus
Insert table 19.6
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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.
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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
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Consequences of Uncorrected Deficiency in Type I Diabetes Mellitus
Insert fig. 19.11
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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
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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.
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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
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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.
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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.
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Metabolic Effects of Catecholamines (continued)
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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.