5 - Pharmacology of Diabetic Ketoacidosis

What is glycogen?

The stored form of glucose, primarily in the liver and muscles

What is glycogenolysis?

Breakdown of glycogen into glucose to increase blood glucose

What is glycogenesis?

Formation of glycogen from glucose for storage

What is gluconeogenesis?

Production of new glucose from non-carbohydrate sources

How do insulin and glucagon regulate glucose homeostasis?

Insulin → Lowers blood glucose; promotes glycogenesis

Glucagon → Raises blood glucose; promotes glycogenolysis and gluconeogenesis

Glucose?

Important energy source

It gets stored as a starch →

Gluα1-4Glu with branching Glcα1-6 linkages

How does starch get broken down into glucose in the gut?

The starch gets broken down via glycosidases →

Pancreatic α-amylase and α-glucosidases

How does the glucose enter enterocytes after the starch gets broken down?

It gets transported into enterocytes via sodium glucose cotransport 1 → SGLT-1

What happens after glucose enters cells via SGLT-1?

It gets transported into the blood stream by GLUT2

GLUT2?

Insulin independent

Is responsible for transporting glucose into most cells

GLUT4?

Insulin dependent

Is responsible for transporting glucose into the liver, muscle and fat

How is glucose metabolized?

By cellular respiration by glycolysis and the citric acid cycle to generate energy

What happens to excess glucose?

It enters the liver hepatocytes and gets stored as a polysaccharide → glycogen and linked to a protein called glycogenin

This happens through the process of → glycogenesis

What are the steps for converting glucose into UDP-glucose?

1. Glucose → glucose-6-phosphate

2. Glucose-6-phosphate → glucose-1-phosphate

3. Glucose-1-phosphate → UDP-glucose

What is the role of glycogenin in glycogen synthesis?

Glycogenin has a tyrosine residues on each subunit → which gets modified by glucose

Glucose is added α1-4 chain on glycogenin until each tyrosine residue has approx. 8 glucose residues

What does glycogen synthase do?

Extends the glycogen chain by adding glucose through α-1,4 linkages

What does glycogen branching enzyme do?

Creates branches by adding α-1,6 glucose linkages to the polymer

Glycogenolysis?

Is the opposite of glycogenesis

The breakdown of glycogen

How does glycogenolysis start?

Glycogen phosphorylase cleaves terminal glucose units from α-1,4 linkages by adding a phosphoryl group

Turning the glycogen into → glucose-1-phosphate

What is released when glycogen's α-1,4 vs. α-1,6 bonds are broken?

α-1,4 bonds: Release mostly G1P, which converts to G6P.

α-1,6 bonds: Release a smaller amount of free glucose at branch points.

What happens after the phosphoryl group is added during glycogenolysis?

Glucose-1-phosphate is then converted into glucose-6-phosphate by the enzyme → phosphoglucomutase

When does trimming stop on G1Ps during glycogenolysis?

It occurs until its 4 residues before a glucose that is branched with an α-1,6 linkage

Glycogen debranching enzyme moves 3 of those 4 remaining residues onto the end of a nearby glycogen branch

Then α-1,6-glucosidase hydrolyzes the branching point → releasing free glucose

Gluconeogenesis?

The generation of glucose from certain non-carbohydrate substrates

One of the main mechanisms used by humans and many other animals to maintain blood glucose levels

Where does gluconeogenesis take place?

Mainly in the liver and to the lesser extent in the cortex of the kidneys

It is often associated with ketosis

It is a pathway consisting of a series of 11 enzyme catalyzed reactions

How does gluconeogenesis begin?

Begins in the mitochondria → withe the formation of oxaloacetate via the carboxylation of pyruvate catalyzed by pyruvate carboxylase

Pyruvate carboxylase is stimulated by → High acetyl-CoA

Pyruvate carboxylase is inhibited by → High ADP and glucose

What happens after the formation of oxaloacetate during gluconeogenesis?

The oxaloacetate is then decarboxylated and phosphorylated to form phosphoenolpyruvate

The rest of the steps are just essentially the reverse of glycolysis

Fructose-6-phosphate → glucose-6-phosphate

Glucose-6-phosphatase in the lumen of the ER converts G6P → free glucose

What happens to insulin, glucagon, and fuel use during fasting?

Insulin decreases and glucagon increases

Most tissues use fatty acids for energy, sparing glucose for the CNS

The brain relies primarily on glucose because it cannot effectively use fatty acids

CNS glucose needs remain around 2 mg/kg/min

How does the liver maintain blood glucose during fasting?

Glycogenolysis → Breaks down stored glycogen

Gluconeogenesis → Makes glucose from lactate, alanine, and glycerol

How do insulin and glucagon affect liver glucose metabolism?

Insulin → Inhibits glycogenolysis and gluconeogenesis → promotes glycogenesis

Glucagon → Stimulates glycogenolysis and gluconeogenesis → inhibits glycogenesis

What are normal fasting plasma glucose and fatty acid concentrations?

Glucose: 4.4–5 mM → less than 100 mg/dL

Fatty acids → approximately 400 μM

What happens to glucose and insulin during the fed state?

Plasma glucose increases to 120–140 mg/dL

Gut incretins and neural signals stimulate insulin secretion

Insulin promotes glucose uptake by the → liver, skeletal muscle, and adipose tissue

How does insulin affect glucose, fat, and protein metabolism during feeding?

Glucose → Inhibits hepatic glycogenolysis and gluconeogenesis.

Fat → Inhibits lipolysis; promotes fat storage through lipoprotein lipase synthesis and adipocyte glucose uptake.

Protein → Increases amino acid uptake and protein synthesis; inhibits protein breakdown.

How does the body maintain glucose during exercise?

Muscle glycogen is used at the start of activity

Most glucose support comes from hepatic gluconeogenesis

Catecholamines (epinephrine and norepinephrine) → increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis

How do catecholamines affect insulin, glucagon, and fat metabolism during exercise?

Insulin → Decreases secretion

Glucagon → Increases release

Fat → Stimulates lipolysis, releasing fatty acids for muscle energy and glycerol for gluconeogenesis

Lipogenesis?

Is the conversion of acetyl-CoA to fatty acids and triglycerides to store energy as fats

How are triglycerides transported from the liver into the blood?

Packaged into very-low-density lipoproteins (VLDL)

What is lipolysis?

Breaks down triglycerides into glycerol and free fatty acids

What happens to triglycerides in VLDL during lipolysis?

Cellular lipases break them down, releasing free fatty acids and some glycerol for tissue uptake

How are free fatty acids transported in the blood after TGs are broken down?

Available for direct cellular uptake

Fatty acids not immediately used bind to albumin for transport to other tissues

What happens to glycerol released during lipolysis?

Enters the bloodstream and travels to the liver or kidneys

Converted into glycerol-3-phosphate

Can enter glycolysis or gluconeogenesis

Ketogenesis?

Occurs when there is low glucose levels in the blood and when glycogen stores are exhausted

What does ketogenesis do?

Produces ketone bodies → acetoacetate, acetone, D-β-hydroxybutyrate

Due to the breakdown of atty acids and ketogenic amino acids

What does ketogenesis normally do?

Normally is just process that supplies energy to the brain during fasting

But excessive production of ketone bodies leads to ketoacidosis → when ketone body accumulation makes the blood too acidic

How are ketone bodies produced?

1. Fatty acids undergo β-oxidation → producing acetyl-CoA.

2. When oxaloacetate (OAA) is low → acetyl-CoA cannot efficiently enter the citric acid cycle

3. So then the excess acetyl-CoA is used to make ketone bodies

What conditions can trigger ketogenesis?

Fasting

Vigorous exercise

High-fat diets

Lack of insulin in type 1 diabetes

When does the liver produce ketone bodies?

Fasting or starvation

Low-carbohydrate diets

Prolonged exercise

Untreated type 1 diabetes

How long does it take for liver glycogen stores to become depleted during fasting?

Approximately 24 hours

How do extrahepatic tissues use ketone bodies for energy?

Convert acetoacetate and D-β-hydroxybutyrate into acetyl-CoA

Acetyl-CoA enters the citric acid cycle to generate ATP → ENERGY!

Why can't the liver use ketone bodies for energy?

The liver lacks the enzyme needed to convert ketone bodies back into acetyl-CoA

β-ketoacyl-CoA transferase or thiophorase

What is acetone, and why is it important?

Acetone is formed when acetoacetate loses CO₂ (decarboxylation)

It cannot be converted back into acetyl-CoA

It contributes to the fruity or nail-polish-remover smell of ketosis and ketoacidosis

Ketolysis?

Is the conversion of ketone bodies into energy

How much energy does acetoacetate produce when oxidized?

2 GTP and 22 ATP per molecule when oxidized via the citric acid cycle

How is acetone detoxified in the liver?

At low concentrations → it enters the methylglyoxal pathway → which ultimately produces lactate

What fuel does the heart preferentially use under normal conditions versus ketosis?

Normal → Fatty acids

Ketosis → Can effectively use ketone bodies

When does the brain use ketone bodies for energy?

When glucose is less available, such as during fasting, strenuous exercise, low-carbohydrate diets, and in neonates

How does the brain's use of ketone bodies change during prolonged fasting?

After 3 days: About 25% of energy comes from ketone bodies

After 4 days: About 70% comes from ketone bodies

The brain still requires some glucose

What potential benefit may ketones from omega-3 fatty acids have?

They may help reduce cognitive deterioration with aging

How are ketone bodies normally produced and used in healthy individuals?

The liver produces ketone bodies → which are used for energy by extrahepatic tissues

What are normal blood and urine ketone levels?

Blood: Approximately 1 mg/dL

Urine: Undetectable

Ketonemia?

When ketone production by the liver exceeds ketone utilization by peripheral tissues → causing blood ketone levels to rise

Ketonuria?

The presence and excretion of ketone bodies in urine

What causes diabetic ketoacidosis (DKA) in type 1 diabetes?

Insufficient or absent insulin

High glucagon levels

Can be triggered by infection, heart attack, physical trauma, or missed insulin

How do low insulin and high glucagon cause ketone body production in DKA?

1. The liver increases glucose production

2. Fatty acids undergo β-oxidation, producing acetyl-CoA

3. Excess acetyl-CoA is converted into ketone bodies

4. Ketones accumulate, contributing to ketoacidosis

What happens to blood ketone levels and pH during pathological ketoacidosis?

Ketones rise to approximately 15–25 mM

Acetoacetic acid and β-hydroxybutyric acid lower blood pH

Kidneys excrete acidic urine

What is commonly detected in the urine during diabetic ketoacidosis (DKA)?

Both glucose (glycosuria) and ketones (ketonuria)

Why does DKA cause severe dehydration?

High blood glucose causes glucose to spill into urine

Glucose pulls water and electrolytes into the urine (osmotic diuresis)

This can cause potentially fatal dehydration

What is nutritional ketosis, and what ketone levels does it cause?

Ketosis from a low-carbohydrate diet → typically with plasma ketones around 0.5–5 mM

How does alcoholic ketoacidosis differ from diabetic ketoacidosis?

Triggered by binge drinking

Increased blood ketones

Typically has negative glycosuria (no glucose in the urine)

Should ketones normally be detectable in urine?

No

Normal urine should have undetectable ketone levels

Which patients are frequently screened for ketonuria?

Acutely ill patients

Pre-surgical patients

Pregnant women

When should diabetic patients be tested for urinary ketones?

When blood and urine glucose are elevated

During acute infections or other illnesses

When switching from insulin to oral hypoglycemic agents

Why are urinary ketones monitored in patients with acidosis?

To assess the severity of acidosis and monitor response to treatment

What conditions can cause ketonuria?

Starvation or fasting

High-protein or low-carbohydrate diets

Prolonged vomiting

Anorexia

Why are urine ketones useful in emergency situations?

Urine ketones may appear before a significant increase in blood ketones

What does ketonuria within 24 hours of insulin withdrawal indicate?

A potentially poor response to oral hypoglycemic agents

What does the nitroprusside dipstick test detect?

Acetoacetate in urine → producing a purple color

How are urine acetoacetate levels classified by the nitroprusside test?

Small: Less than 20 mg/dL

Moderate: 30–40 mg/dL

Large: 80 mg/dL or greater

What are the limitations of the nitroprusside test?

Detects acetoacetate only

Does not detect β-hydroxybutyrate or acetone

Can underestimate ketone levels during severe ketoacidosis

Why can the nitroprusside test underestimate ketones during severe ketoacidosis?

The β-hydroxybutyrate-to-acetoacetate ratio increases dramatically, but the test only measures acetoacetate