The Endocrine Pancreas/Intermediary Metabolism

Objectives

Endocrine Control of Metabolism

____ = all chemical reactions that occur within the cells of the body

the sum of the processes in the buildup and destruction of ____; specifically: the chemical changes in living cells by which energy is provided for vital processes and activities and new material is assimilated

___ (Fuel) Metabolism - reactions involving the degradation synthesis and transformation of proteins, carbohydrates, & fats.

the intracellular process by which nutritive material is converted into ___ components

Glycogenesis = glucose to ____

Glycogenolysis = glycogen to ___

Gluconeogenesis = Amino acids to ___

Protein synthesis = AA's to ____

Protein degradation = Protein to ___

Fat synthesis (lipogenesis/triglyceride synthesis) = Fatty acids & glycerol to ____

Fat breakdown (lipolysis/triglyceride degradation) = Triglycerides to ___ & ___

Anabolism:
– Build-up of ___ organic molecules from smaller organic molecules

Catabolism

- ___ of large, energy-rich organic molecules within cells

->Excess glucose transformed to ___ and ___ to form triglycerides

->Excess a.a. transformed to glucose and fatty acids, eventually ending up as ____

ADsorptive State
(FED State)

->Carbs = ___ as major energy source (glycogen synthesis and storage)
->Excess converted and stored as ___ fat

->Fats = triglyceride ___ and storage

->Protein - protein synthesis
->Excess converted and stored as triglyceride ___

Postadsorptive State (FASTED State)

->Carbs = glycogen ___ & depletion glucose sparing for ___ use
(New glucose through ____)

->Fats = triglyceride ___ energy for non-glucose using tissues

->Protein - protein catabolism
(___ ___ for gluconeogenesis)

Tissues involved in adsorptive and post-adsorptive metabolic states:

–Liver
•Primary role in [glucose]blood maintenance
–Stores ___
–Site of _____ & other metabolic interconversions

–Adipose tissue
•Primary site of energy ___
•Regulates [fatty acid]blood

–Muscle
•Site of amino acid ___
•Major energy user

–Brain
•Can only use ___
•Cannot __ glucose
(NEED for [glucose]blood maintenance)

Other Organic Intermediaries Are Energy Sources

•Glycerol
–Backbone of triglyceride (1 glyceride + 3 Fatty acids)
–Converted to glucose by __

•Lactate
–Result of ___ glucose metabolism in muscle
–Converted to glucose by ___

•Ketone bodies (acetate acetoacidic acid β-hydroxybutyric acid)
–Produced by liver during glucose ___

•Liver cannot completely catabolize fatty acids
–Oxidation of fatty acids in liver yields ___
–Released to blood where other body cells use ketones for energy production via ___ ___ ___

•In long-term starvation:
–Brain shifts fuel metabolism to use ___
»Prevents gluconeogenesis from depleting protein
•Death due to starvation usually due to protein ___, not hypoglycemia

•High levels of ketones lead to brain use and directly inhibit protein ____

Endocrine Pancreas (Insulin and Glucagon)

______ =
Released in response to glucose and amino acids

___ digestion of nutrients, preventing excess in plasma

____ secretion of insulin, glucagon & SS itself (i.e. paracrine and autocrine actions)

INSULIN

Insulin ___ blood glucose, amino acids, and fatty acids by

–Altering transport of nutrients into cells
–Altering activity of enzymes involved in specific pathways
•Ex: ↑ glycogen synthase -> ↑ glucose to glycogen rate
•Ex: ↓ hormone-sensitive lipase -> ↓ lipolysis (conversion of triglycerides to FFA+glycerol)

Control of carbohydrates:

•Circulating glucose concentration based on balance of:
–Glucose absorption from GI tract

–Glucose transport into cells
(Only these two are subject to control)

–___ glucose production
(Only these two are subject to control)

–Urinary excretion of glucose

Glucose Transporters

1.) ___ facilitated diffusion into cell (through ___)

2.) Glucose -> glucose-6-phosphate
–Phosphorylation
»Traps glucose inside cell
»Keeps intracellular glucose concentration __

Glucose transporters

GLUT-1
Blood-brain barrier

GLUT-2
->Kidney and intestinal cells
->Na-glucose cotransporter

GLUT-3
____

GLUT-4
->Most cells of body
->ONLY transporter that is sensitive to ___
->Normally cells are relatively impermeable to glucose
->Abundant in resting ___ muscle & ___ ___
->Recruitment triggered by insulin

Insulin lowers blood glucose levels and promotes carbohydrate storage

Insulin facilitates glucose transport into cells by insertion of __ at the cell membrane.

***Brain, exercising muscle, liver are NOT dependent on ___ for glucose uptake***

-Brain = GLUT 1 and GLUT3
-Exercising = contraction-induced glut-4 insertion
-Liver = Not Glut4 dependent

Insulin actions on Fat

1. Insulin increases the transport of __ ___ and glucose (via GLUT4) into ___ cells

2. Insulin promotes reactions that use fatty acids and glucose for ___
synthesis

3. Insulin ___ lipolysis

Insulin actions on protein

1. Insulin promotes the active transport of ___ ___ from the blood into
muscles and other tissues

2. Insulin increases the rate of amino acid incorporation into protein by stimulating the cell's protein-___ machinery

3. Insulin ___ protein degradation

CONTROL OF INSULIN SECRETION

Blood glucose is primary stimulus of insulin secretion, but also by:

↑ blood amino acids
Amino acid uptake enhanced
↑ protein synthesis
Stimulates insulin via excitation-secretion coupling

Food intake:
____: glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide (GLP)

Feed-__ notification of impending rise in blood nutrients
(Stimulates insulin via cAMP -> Ca2+)

Nervous input to _-islets:
->Parasympathetic (vagal) stimulation
(ACh stimulates via IP3/Ca2+)
(Also feed-forward)

->Sympathetc inhibition & Epinephrine -> ↓cAMP

REVIEW

Abnormalities in insulin secretion

->Diabetes - “siphon” or “running through”

reference to the large volume of urine output characteristic of diabetes

1.) Diabetes Mellitus
Mellitus = ____

___glycemia - reduced cellular glucose uptake, liberation of glucose into the circulation from the liver

2. Diabetes insipidus

Insipidus = ___
->Due to lack of ___

1. Diabetes mellitus - hyperglycemia

A. Type 1 (insulin-___ or juvenile-onset)

Lack of insulin ____

~5% of all diabetes mellitus cases

Autoimmune process involving the erroneous destruction of pancreatic -> cells by activated T lymphocytes

Individuals require ___ insulin for survival

1. Diabetes mellitus - hyperglycemia

B. Type 2 (non-insulin-dependent or ___ onset)

Lack of ___ to insulin

~__ of all diabetes mellitus cases

____ is a major risk factor and can lead to inadequate insulin secretion & down-regulation of cellular insulin receptors.

90% of T2 Diabetics are overweight to obese

Gestational Diabetes

- abnormally elevated glucose levels during pregnancy as a result of decreased insulin ___ that occurs in approximately 4% of pregnancies

similar to Type _

Cause unknown, but goes ___ following delivery.

Associated with greater incidence of Type 2 diabetes ___ in life

Obesity and Type 2 Diabetes

Metabolic Syndrome (Syndrome X) – obesity, high triglycerides, low HDL, high blood glucose, high blood pressure

Adipokines:
->___ – interferes with insulin actions, increased in obesity

->____ – enhances insulin sensitivity, decreased in obesity

Inflammation – obesity is an “inflammatory state” and increases in things such as TNFα can decrease ___ to insulin

___ fatty acid levels
- accumulation in muscle can interfere with actions of insulin
- accumulation in liver can lead to increased hepatic glucose production
- can trigger apoptosis of ___ cells

Insulin Deficiency

Long-term Consequences

Diabetic Retinopathy: Vision ___

A.) Nonproliferative (most common)
Pouch formation of capillaries in the back of the eye, leaking fluid and causing the eye to be unable to focus (__ __).

B.) Proliferative (less common)
Damaged vessels completely close off and new ones form, but are weak and leak blood (__ ___).
->Scar tissue can also form causing more damage to eyesight

Neuropathy: Sensorimotor and Autonomic Neuropathy

Sensorimotor Neuropathy:
Malfunction in nerves fibers that supply sensory input, leading to ___ and/or pain occurring typically at the extremities. Due to damage of blood supply to these nerves in a ___ environment.

Autonomic Neuropathy:
Malfunction in nerve fibers that control the heart, ___ tract, and urinary function.

Common problem in diabetics is the inability to control ___ ___ and pressure to keep blood flowing normally to the brain when they stand up and as a result ___. Also due to damaged blood vessels around the nerves.

3. Diabetic Nephropathy: Kidney Failure

Destruction of the glomerular capillaries in the kidney which eventually leads to kidney failure and death; characterized by increased plasma ___ in the ___.

Treatment of Diabetes

Type 1:
Very controlled regimen of insulin ____ timed around meals

Management of the types and amounts of foods consumed

Exercise (remember that glucose uptake in exercising muscle is NOT insulin-____)

Treatment of Diabetes

Type 2:

Dietary control and exercise may be all that’s necessary

->10% weight __ can improve sensitivity to insulin significantly

Pharmacological Intervention:
Stimulation of insulin secretion by β cells (____)

Suppressing liver output of glucose (__)

Blocking enzymes that digest carbohydrates (α glycosidase inhibitors)

Increasing sensitivity to insulin (thiazolidinediones)

Mimicking the ____ (GIP, GLP)

Increasing endogenous GLP-1 (Dipeptidyl peptidase or DPP-4 inhibitors)

**If Type 2 persists, it can become __ _ due to depletion of β-cells

Insulin Excess

Consequences are primarily manifestations of the effects of ___ on the brain

Insulin Shock:
Can occur in a diabetic patient when too ___ insulin is injected
Symptoms: largely due to effects at brain
Treatment: ___ at first signs

Reactive Hypoglycemia:
beta-cell ___ or over-responsive beta-cells
Insulin secretion ___ in response to elevated blood glucose and thus too much glucose is driven into cells

Symptoms: tremor, sleepiness, inability to concentrate

Treatment: limited ___ diet

Glucose maintenance also involves α-cells of the islets

Glucagon promotes ↑ blood glucose during ____ state

Amino acid paradox (i.e. high protein meal)

↑ amino acids stimulate both α and β-cells

If ONLY insulin is stimulated -> ___

Would promote further storage of already limited carbohydrate

Parallel simulation of glucagon ensures glucose availability via hepatic glucose production

Ultimately, glucose remains normal

Abnormalities of Glucagon Secretion

There are __ __ clinical abnormalities associated with oversecretion or under secretion of glucagon

Glucagon is usually elevated during diabetes and exaggerates the issue

Insulin is necessary for glucose to enter ___ cells

Thus, glucose ___ inhibit glucagon secretion

For this reason, some Type 1 diabetics respond better to insulin in combination with ___, which inhibits ___ secretion

Other Hormones play role in glucose homeostasis

REVIEW