Combined Exam 2 Lecture Slides - Biotech

Starting in the 1980s, what was biotechnology inspired by Insulin applied to?

Applied to purifying (i.e., Peptide Chromatography) and characterizing (i.e., Sanger Sequencing) many new peptide hormones

What would molecular biology revolution allow for in the 1980s?

Allowed for making Peptide Hormone Analogs to be superior drugs

What are Peptide Hormone Analogs?

Hormones that differ in the AA sequence from the Natural Hormone to be made into superior drugs

What does the 2026 Review Paper "The evolving landscape of drug targets" target?

How many total drugs did it look at?

What percent of these drugs were Biologics?

Targeted 686 biomolecular targets

Looked at 1,702 total approved drugs

20% of the total were Biologics

What is the most striking shift in the landscape of drug targets since 2000 according to the slides?

Includes a 7.2-fold increase in the number of endogenous peptide targets

When did the Obesity Epidemic begin?

What did it cause an explosion in?

Began in 1990

Caused an explosion in Type 2 Diabetes

What did Type 2 Diabetes become a major driver of in the U.S. following the Obesity Epidemic?

What did this lead to a search for?

Major driver of Morbidity and Mortality

Led to a search for Type 2 Diabetes Drugs

What was the first GLP-1 Agonist drug introduced to the market?

What did it help cause?

Exenatide (brand name Byetta) in 2005 for Type 2 Diabetes

Helped control Insulin and Glucose level, but was also the first antidiabetic drug to cause real weight loss in patients

What is Tirzepatide?

When was it introduced to the market?

Dual Agonist GLP / GIP drug

Introduced in 2022

Which two drugs became the best selling drugs in the world in 2025?

What manufacturer produces these medications?

What drug class are these medications?

Mounjaro and Zepbound

Produced by Eli Lilly

GLP-1 Agonist Peptide Drugs

What is the 2026 estimate of U.S. adults who currently take a GLP-1 Agonist Peptide Drug?

What do most of them take it for (indication)?

Estimated 11% of U.S. adults

Most take it for Weight Loss

What is the average weight loss on Tirzepatide?

15-21% of Total Body Weight

How are GLP-1 Agonists changing society?

U.S. Life expectancy has increased for the first time in several years as of 2025

Food shopping and other economic activity are changing

- Average GLP-1 Agonist patient spends $500 less on food

Patient behavior changes

What other disease states unrelated to Type 2 Diabetes are also positively affected by GLP-1 Agonists?

Improvement in CV Disease

Addictive Behaviors

Psychiatric Disorders

About what percent of positive effects of GLP-1 Drugs are considered independent of weight loss?

~60% of the positive effects are estimated to be independent of weight loss

What is most of the unexpected success of GLP-1 Agonists due to?

What did they demonstrate?

Most unexpected success due to not fully understanding the biology of GLP-1s and other Peptide Hormones

Demonstrated that injectable peptide drugs have mass market appeal

What has the success of GLP-1 Agonists kicked off a rush for?

Rush into other peptide hormone drugs, including many that have NOT had studies for FDA approval (i.e., Peptide Stacks)

What are the four main advantages of the Peptide Hormone as a drug formulation?

1. Strong biological effect

2. Good specificity for the target

3. Good toxicity profiles and is easy to metabolize

4. Easy to produce and modify

What are the two main disadvantages of the Peptide Hormone as a drug formulation?

1. Native hormones are rapidly degraded and must be modified to increase half-life

2. Only injectable forms can be made

What are the four main Peptide Hormones involved in Glucose Homeostasis?

How many AAs does each Hormone contain?

1. GLP-1 = 31 AAs

2. GIP = 42 AAs

3. Glucagon = 29 AAs

4. Amylin = 37 AAs

What is the source cell for each of the four main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Beta Cells

GLUCAGON - Alpha Cells

GLP-1 - L Cells (in the Gut)

GIP - K Cells (in the Gut)

AMYLIN - Beta Cells (with Insulin)

What is the primary job for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Store Glucose

GLUCAGON - Release Glucose

GLP-1 - Incretin + Satiety

GIP - Incretin

AMYLIN - Blunt the meal peak

What is the effect on Insulin Secretion for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Nothing (is Insulin)

GLUCAGON - Opposes Insulin

GLP-1 - Increases if Glucose high

GIP - Increases if Glucose high

AMYLIN - None

What is the effect on Glucagon for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Indirectly Decreases

GLUCAGON - Nothing (is Glucagon)

GLP-1 - Decreases if Glucose high

GIP - Increases if Glucose low

AMYLIN - Decreases postprandial

What is the effect on Hepatic Glucose output for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Decreases

GLUCAGON - Increases

GLP-1 - Falls via decreased Glucagon

GIP - Context-dependent

AMYLIN - Falls via decreased Glucagon

What is the Muscle / Fat uptake like for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Yes (GLUT4)

GLUCAGON - No

GLP-1 - No direct

GIP - No direct

AMYLIN - No direct

What is the effect on Gastric Emptying for each of the four main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - No

GLUCAGON - No

GLP-1 - Slows

GIP - Little

AMYLIN - Slows

What is the effect on Food Intake for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - No (weight gain)

GLUCAGON - No

GLP-1 - Decreases

GIP - Weak alone

AMYLIN - Decreases

What is the Hypoglycemia Risk for each of the four main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - High

GLUCAGON - Treats Hypoglycemia

GLP-1 - Low alone

GIP - Low alone

AMYLIN - High with Insulin

What is the Native Half-Life (t1/2) like for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Minutes (SC longer)

GLUCAGON - ~5 min IV

GLP-1 - 1-2 min

GIP - Few min

AMYLIN - ~13 min

What is the given example of a market product for each of the five main Peptide Hormones involved in Glucose Homeostasis + Glucagon?

INSULIN - Insulin Analogs

GLUCAGON - Glucagon rescue

GLP-1 - Semaglutide

GIP - Tirzepatide (dual)

AMYLIN - Pramlintide (Symlin)

Which three Peptide Hormones involved in Glucose Homeostasis are produced by the Pancreas?

1. Glucagon (via Alpha Cells)

2. Insulin (via Beta Cells)

3. Amylin (via Beta Cells)

Where are the Incretins involved in Glucose Homeostasis produced from?

(Incretins = GLP-1, GIP)

Produced in the Small Intestine

What is Metabolism?

Chemical processes that occur in an animal to sustain life, providing energy and the required building blocks

What is the Metabolic Contract?

What does it limit?

Animal organism will supply the individual cells a constant level of energy, in the form of Glucose

Limits the cells from trying to make their own energy, which could be toxic to the animal organism

What is the major energy-producing molecule form supplied to the physiology of an animal?

Glucose as a Carbohydrate

What is Glucose Homeostasis?

Constant, non-toxic supply of Glucose to the cells at all times

What does the metabolic system use as short-term energy?

Medium-term energy?

Long-term energy?

SHORT-TERM = ATP (reactive and unstable)

MEDIUM-TERM = Glycogen via Glucose (Glucose stable, but toxic over time; Glycogen is storage form)

LONG-TERM = Triglycerides (stable and compact, but must be metabolized back to Glucose to be used for energy)

What is responsible for controlling the continual Glucose supply that provides constant energy?

Controlled by Basal Insulin Excretion

What is Glucose converted into in cells when needing immediate energy needs at the Molecule level?

What is Glucose converted into for long-term storage?

IMMEDIATE ENERGY --> ATP in Cells

LONG-TERM STORAGE --> Fats / Triglycerides that can be changed back to Glucose when needed

What are the three given reasons for why Glucose is an ideal molecule for energy currency in the body?

1. Glucose is chemically stable, but also a source of large amounts of chemical energy

- Most high energy molecules are unstable (e.g., ATP)

2. Chemical energy can be unlocked via cellular metabolism (e.g., Glycolysis, ETC) and is used to make ATP

3. Can be stored for long-term energy energy through Polymerization to form the Polysaccharide molecule Glycogen, which allows for concentrated storage of Glucose

Why do animal organisms not attempt to always keep Glucose levels as high as possible in the cells for them to access as needed?

Too much Glucose in either the blood or the cells is toxic over time (Hyperglycemia ruh roh)

What is Glycogen?

Polysaccharide of Glucose for medium-term energy storage primarily in the Liver

How does Hyperglycemia cause Glucotoxicity via Mitochondria Metabolism?

Via Protein damage?

Overwhelms Mitochondria metabolism, causing formation of reactive molecules that cause cellular protein damage via Oxidative Stress

Directly damages Proteins, forming Advanced Glycation End-Products (AGEs)

What is the basis of the A1C Glucose Monitoring System, such as Accu-Check Guide Me Kits, Relion, ContourNext, etc....?

Advanced Glycation End-Products (AGEs)

What happens with Hyperglycemia in relation to Hemoglobin?

Glucose molecules will react with Amine side-chains on Hemoglobin, forming more Glycated Hemoglobin (Glucose bonded to protein portion of Hemoglobin)

What is D-Glucose's two forms in the equilibrium process?

What percent of aqueous solution does each form exist in?

1. D-Glucose open, linear form (has Aldehyde group at Carbon 1 --> ~0.01% in Aqueous Solution

2. D-Glucose closed, cyclic form (Glucopyranose; Aldehyde group gone and ring is closed via Ether linkage) --> ~100% in Aqueous Solution

What types of cells are especially sensitive to drops in Blood Glucose (Hypoglycemia)?

What are they fully dependent on for function and survival?

Why?

Brain Cells

Fully dependent on CONTINUAL Blood Glucose to function and survive

They are high energy-consuming cells with no Glycogen storage

What are some of the first physical signs of Hypoglycemia?

Sweating, Shaking, and Confusion

How does the body present when adapting to Hypoglycemia?

What is this condition called?

What can it lead to?

Presents as reduced shakiness or sweating after repeated bouts of Hypoglycemia

Condition is called Hypoglycemia Unawareness

Can lead to Confusion, Seizures, and Neurological Damage

Why is the Pancreas referred to as the Protein / Peptide Factory?

Serves as a major source of Peptide Hormones, including Insulin, Glucagon, Amylin, and others

What is the function of Insulin?

How does it help with Glucose Homeostasis?

Function is communication with cells in the body to take up Blood Glucose for metabolism; distributes and stores Glucose, especially during High Glucose spikes

Continually excreted (Basal levels) to encourage cellular Glucose uptake

What happens to Insulin levels during Digestion?

What do continual Insulin levels contribute to Glucose homeostasis?

Insulin levels are spiked in the blood during Digestion / postprandial to encourage increased Glucose uptake into cells and tissues

Continual Insulin levels signal the liver to convert the excess Glucose from meals into Glycogen

What is used to supply Blood Glucose in between meals?

Glycogen stored in the Liver

What is the main function of Glucagon?

Travels to the Liver and binds to its receptor, which triggers the conversion of Glycogen stored in the Liver into Glucose

Where does Glucose converted from Glycogen in the Liver go after conversion?

Excreted in the blood to maintain Basal blood sugar levels

How many AAs long is Glucagon?

What is the structure of Glucagon like?

29 AAs long

Long, highly flexible and unstructured peptide

Secondary Structure = N-terminal Beta-Sheet and C-terminal Alpha-Helix

Tertiary Structure = None in solution

When was Glucagon discovered?

When was it purified?

Discovered in 1920s from injecting pancreatic extractions into animals and recording an increase in Glucose

Purified in the 1950s (more challenging to purify than Insulin)

When did Glucagon finally become available as a medicine on the market?

What are some of the newer formulations like?

Available in 1960 as a dry powder that had to be dissolved and injected

Now available as pre-filled syringes (e.g., Gvoke HypoPen) and nasal inhalants

What are the main medicinal uses of Glucagon?

How does it accomplish this?

Mainly for severe Hypoglycemia

Causes the Liver to rapidly release Glucose into the blood

How is stored energy converted back into Glucose from the Liver?

How does Glucagon affect this process?

How does Insulin affect this process?

Converted back into Glucose from Fats in the Liver via Lipolysis

GLUCAGON - triggers Lipolysis, signaling long-term storage of Glucose

INSULIN - blocks Lipolysis, signaling high blood glucose levels

What process does Glucagon initiate in the Liver?

In the Adipose Tissue?

LIVER - Gluconeogenesis

ADIPOSE TISSUE - Lipolysis

What process does Insulin initiate in the Skeletal Muscle?

Liver?

Adipose Tissue?

SKELETAL MUSCLE - Glucose uptake

LIVER - Glycogenesis

ADIPOSE TISSUE - Lipogenesis

What is Diabetes?

What are the two main causes of Diabetes (classifications)?

DIABETES - chronic metabolic disease of sustained high blood sugar (Hypoglycemia)

CLASSIFICATIONS:

- Type 1 Diabetes, caused by lack of Insulin produced by the Pancreas

- Type 2 Diabetes, where the body cannot correctly or efficiently use the Insulin that the body produces

What is the main cause of Type 1 Diabetes?

When is the typical onset?

About how many patients does it affect in the U.S.?

Caused by autoimmune destruction of Beta Cells, resulting in complete loss of Insulin production

Typical onset in Juvenile years, but can also be adult onset

Affects < 1.6 million U.S. patients

What is the main cause of Type 2 Diabetes?

About how many patients does it affect in the U.S.?

What percent of Type 2 Diabetics are considered overweight / obese?

Insulin is made, but overtime it becomes less effective and patient develops Insulin Resistance

Affects >34 million patients in the U.S.

>90% of Type 2 Diabetics are overweight or obese

Which of the two Diabetes classifications is considered more complex?

How does affect the number of treatment options?

Type 2 Diabetes is considered more complex, therefore there are more treatment options

What is Insulin Resistance?

What conditions are responsible for triggering Insulin Resistance?

Condition where the tissue in the body stops responding to Insulin, resulting in more and more Insulin being produced to signal cells and tissues to take up Glucose

- Point is eventually reached where the Pancreas cannot excrete any more Insulin and Insulin signaling stops working

- Causes Hyperglycemia

Obesity and other conditions that cause a constant level of Blood Glucose over time trigger this conditon

What is Glucose Homeostasis?

Physiological process that keeps blood Glucose at the ideal range at all times

What are the four Satiety-Promoting (Anorexigenic) Hormones?

What is the main Hunger-Promoting (Orexigenic) Hormones?

ANOREXIGENIC:

- Insulin (via Pancreas)

- Amylin (via Pancreas)

- Leptin (via White Adipose Tissue)

- GLP-1 (via Small Intestine)

OREXIGENIC:

- Ghrelin (via Stomach)

What is energy intake and storage / utilization largely regulated by?

Regulated by Peptide Hormones

What are Peptide Hormones sensed by?

What does sensation of these Hormones then determine?

Briefly describe the example of Insulin.

Sensed by structures in the Hypothalamus

Determines sensations of hunger, appetite, and Satiety

EXAMPLE:

- Insulin levels are sensed in the brain, which has an effect on appetite and satiety

What does the Hypothalamus use Peptide Hormones to balance between?

Hunger

Appetite Control

Satiety

What three things are Peptide Hormones major regulators of?

1. Glucose Homeostasis

2. Energy Intake (i.e., Hunger, Appetite, Satiety)

3. Energy Storage (i.e., Glycogen and Fat storage)

Where are Peptide Hormones excreted into?

How do they signal throughout the body?

Excreted into the Blood for systemic effects

Signal systemically via specific cell-membrane receptors on the outside of cells in many different tissue / cell types

What is Ghrelin?

What is its main function?

28 AA long peptide made primarily by the Stomach

Major driver of the sensation of Hunger, but also helps regulate Metabolism and Insulin release

Where did Ghrelin get its name from?

Named as Growth Hormone-Releasing Peptide, based on the fact that it triggers release of Human Growth Hormone from the Pituitary Gland

How is Ghrelin (GH) activated?

Must undergo Acylation to be active and bind to its receptor

Ghrelin --(Octanoyl + Ghrelin O-Acyltransferase, GOAT)--> Active Ghrelin

What is Acylation?

Chemical reaction in which a FA is attached via an Ester bond

What are GH Agonists developed to do?

Increase hunger and energy intake, especially in Cancer-Related Cachexia

What are GH Antagonists and GOAT Inhibitors developed to do?

Suppress hunger

Are GH Inhibiting Therapeutics effective in suppressing hunger?

No, currently not shown to be effective in suppressing hunger to control eating and Glucose Homeostasis

What weird lab thing happened to lead to the discovery of Leptin?

1949 - Mutant lab mouse strain was discovered that causes dramatic mouse obesity phenotype and insatiable appetite

1994 - Was determined to be caused by a circulating factor in the blood and discovery of gene

What is Leptin?

What is it expressed?

What is the main function of Leptin?

167 AA long small protein

Expressed in White Adipose Tissue (WAT; aka Fat Cells)

Coordinates energy storage in Adipose Tissue with food intake

What does high Leptin levels lead to in Obesity?

Leads to Leptin resistance where the Brain does not respond to appetite suppression / satiety signals provided by WAT, leading to overeating

What are the only current Leptin therapeutics approved for focusing on?

Focus on replacing missing Leptin, making Leptin a good target for future research

What is Amylin?

What is the main function of Amylin?

How does it accomplish this?

Hormone made in the Beta Cells that is released alongside Insulin

Helps to control Glucose levels (i.e., Glycemic Control)

Slows stomach emptying, suppresses Glucagon secretion, and promotes feeling of Satiety

How was Amylin discovered?

Discovered based on Amylin-Forming Amyloid Fibril structures in the Pancreas of severe Type 2 Diabetes

How does Amylin excretion change with Insulin Excretion?

Increases as Insulin excretion increases (e.g., insulin excretion in Type 2 Diabetes and Insulin Resistance)

What happens when Amylin is present in high concentrations?

At high concentrations, Amylin interacts with itself to form Amyloid Fibrils that are similar to Protein pathology found in Alzheimer's Disease

What is an Amyloid?

What is a Fibril?

AMYLOID - insoluble protein aggregate characterized by an aggregation caused by Beta Sheets in the Secondary Structure of proteins / peptides becoming entangled

FIBTIL - rod-shaped protein aggregate

What was first thought to be the cause of Type 2 Diabetes?

Discovery of Amylin Amyloids in Diabetic Pancreas

What is Pramlintide?

What is the brand name for this medication and when was it first developed?

How is it used?

What is it approved for?

Synthetic peptide-drug based off Amylin that is designed to avoid the Amyloid problem of Amylin

Brand name is Symlim

Used as a therapeutic injectable alongside Insulin at mealtimes

Approved for both Type 1 and Type 2 Diabetes

How does Pramlintide (brand name Symlim) avoid the Amyloid problem of Amylin?

3 AA substitutions that alter the Beta Sheet secondary structure to produce a longer half-life than Amylin

What was the first Type 1 Diabetes drug approved since Insulin?

Pramlintide (brand name Symlim)

What led to the discovery of the Incretin Effect?

What are the two Incretin Hormones talked about in Lecture 13?

What is their main function?

More Insulin was released from the Pancreas after eating when compared to just injecting Glucose

Two Incretin hormones are GLP-1 and GIP

GLP-1 and GIP receptors help to signal Insulin release

How does the Digestive System help to regulate energy and Glucose Homeostasis?

Through Incretin hormones GIP and GLP-1

What does INCRETINs stand for?

When were the two Incretin hormones discovered?

INtestine seCRETion INsulin Hormones

GIP discovered in 1973

GLP-1 discovered in 1987

What is the genetic disease or other disease state linked to Incretin levels?

None, unlike Diabetes

What do Incretins have a secondary effect on?

What is responsible for targeting Incretins?

Secondary effect on Glucose and Insulin

Targeted by Peptidase Activity (i.e., DPP4), which quickly destroy active Peptides