6. diabetes pathopharmacology

body has trouble moving glucose from blood into cells -> high levels in blood -> cells starve for energy

body controls glucose with insulin ( and glucagon (↑)

- both are made by islet of langerhans in pancreas: beta cells make insulin, alpha cells make glucagon

Diabetes mellitus is diagnosed when the blood glucose levels get too high -> 10% of world population, 10% have type 2 and 90% have type 2

Insulin reduces amount of glucose in the blood by binding to insulin receptors embedded in the cell membrane of various insulin-responsive tissues (muscle cells and adipose tissue).-> when activated the insulin receptors cause vesicles containing glucose transporters that are inside cell to fuse with cell membrane, allowing glucose to be transported into the cell.

Glucagon exactly the opposite, gets liver to generate new molecules of glucose from other molecules, and also break down glycogen into glucose.

⁃  Body doesn’t make enough insulin -> type 4 hypersensitivity response (cell-mediated) where own T-cells attack pancreas

⁃  Genetic abnormality that results in a loss of self-tolerance among T-cells that specifically target the beta cell antigens -> means that T-cells are allowed

to recruit other immune cells and coordinate an attack on these beta cells

⁃  Losing beta cells -> less insulin -> glucose piles up in blood because cannot enter body cells.

⁃  Beta cell destruction happens early in life -> 90% destroyed before symptoms show

⁃  Symptoms: polyphagia, glycosuria, polyuria, polydipsia

⁃  Since glucose doesn’t go in cells they are starved -> in response adipose tissue breaks down fat + muscle starts breaking down protein -> weight loss + hungry = polyphagia

⁃  When blood gets filtered through kidneys some of it starts to spill into urine = glycosuria (glucose in urine)

⁃  Since glucose is osmotically active, water follows it -> increase in urination = polyuria

⁃  Because there’s so much urination -> dehydrated + thirsty = polydipsia

⁃  Even tho cannot make own insulin, they can respond to insulin -> lifelong Tx of insulin

diabetic ketoacidosis = when fat is broken down into free fatty acids (because cells have no energy), liver turns them into ketone bodies (acetoacetic acid + B-hydroxybutyric acid), they are used by cells for energy, but also increase acidity of blood -> major effects throughout body = kussmaul respiration (deep/labored breathing to try and move CO2 out of blood),

⁃ Insulin also stimulates sodium-potassium ATPases which helps K+ get into cells -> without insulin -> more K+ stays in fluid outside cells -> goes into blood -> hyperkalemia

can still happen even if undergoing Tx -> under stress -> release epinephrine -> release glucagon -> increase blood glucose -> loss of glucose + water in urine -> dehydration -> need for alternative energy -> generation of ketone bodies -> ketoacidosis (nausea, vomiting, mental status changes

⁃ Tx of DKA : fluids, insulin to lower, electrolytes (K+)

⁃  Body makes insulin but tissue doesn’t respond (isn’t fully understood)

⁃  Cells don’t move glucose transporters to membranes to bring glucose into cells -> insulin resistant

⁃  Risk factors for insulin resistance: obesity, lack of exercise, hypertension, genetics

⁃  An excess of adipose tissue is thought to cause the release of free fatty acids and adipokines -> causes inflammation -> related to insulin resistance

⁃  Since body doesn’t respond to insulin -> body produces more insulin through beta cell hyperplasia + hypertrophy to try and pump out more -> works for

a while

⁃  Eventually beta cells become so tired -> hypoplasia and hypotrophy -> hyperglycemias -> same clinical signs as type 1

⁃  Unlike type 1 there is still some circulating insulin in blood -> diabetic ketoacidosis does not happen in type 2

⁃  Hyperosmolar hyperglycaemic state is common -> increased plasma osmolarity from dehydration and increased concentration -> when levels of glucose

are super high in blood, water leaves cells to go into blood, leaving cells dry and shrivled -> increased urination because so much water in blood -> total body dehydration (mental status changes) ALSO sometimes mild ketonemia and acidosis

⁃  Pregnant women have high blood glucose

⁃  Usually in 3rd trimester

⁃  Tried to be related to pregnancy hormones that interfere with insulin receptors

⁃  Medication side effects -> increase blood glucose

⁃  Mechanism related to insulin resistance (type 2) not autoimmune (type 1)

⁃  Fasting glucose test = 100-125 mg/dL is pre diabetes, >126mg/dL is diabetes

⁃  Non fasting glucose test = >200mg/dL is diabetes

⁃  Oral glucose tolerance (given glucose + measured at intervals) = 140-199 mg/dL is pre diabetes and >200mg/dL is diabetes

⁃  HbA1C (proportion of Hb with glucose stuck to it) = 5.7-6.4% is pre diabetes and >6.5 % is diabetes

⁃  C peptide tests (byproducts of insulin production)

⁃  Weight loss

⁃  Exercise

⁃  Healthy diet

⁃  Antidiabetic meds (metformin)

⁃  Insulin

⁃  Hypoglycemias, especially if taken without meal

⁃  Weakness, hunger, shaking, loss of consciousness, seizures

⁃  Intranasal glucagon just approved

⁃  High glucose over time can cause damage to tiny blood vessels (microvasculature)

⁃  Hyaline arteriolosclerosis -> hyaline deposits in arterioles, make them hard and inflexible

⁃  Capillary -> basement memberane thickens -> harder for O2 to get to tissues -> hypoxia

⁃  Medium and large arterial wall damage: atherosclerosis -> heart attack and stroke

⁃  Retinopathy -> eventual blindness

⁃  Kidneys: afferent and efferent arterioles can get damaged -> nephrotic syndrome -> dialysis

⁃  Nerves: decreased sensation in toes and fingers, ANS malfunctions (sweating, passing gas)

⁃  Poor blood supply + nerve damage = ulcers (especially on feet)

Cell-Mediated Autoimmune Destruction of β-Cells → Insulin Secretion

↓

• Insulin-Dependent • Juvenile-Onset

• Prone to Ketoacidosis (DKA)

Excessive Insulin Secretion → Insulin Resistance Associated with Obesity; HTN & Dyslipidemia

Adult-Onset Form (But % childhood cases ↑)

• Prone to vascular damage

• Genetic defects in β-Cells or Insulin Action

Pancreatic diseases (Cystic Fibrosis; Pancreatitis; Infections)

Endocrine Disorders (Ex.: Hyperthyroidism; Acromegaly; Cushing’s

Type 1 (beta cell defect)

Incidence ≈ 1% worldwide (10% of DM)

Age of onset Peak = 11-13 years Rare ˂ 1 or 30+

Sex Similar

Ethnic Distribution Caucasian ≈ 2x ↑ Risk

Obesity Not an important factor

Heredity ≈ 5-10%

Antibodies Islet Cell & Insulin Autoantibodies

Insulin Resistance unusual

Type-II (Insulin resistance)

Incidence ≈ 9 % worldwide (90% of DM)

Age of onset Highest Risk between 40-70

Sex Similar

Ethnic Distribution ↑ Risk African-American & native Americans

Obesity Strong correlation

Heredity ≈ 10-15%

Antibodies UncommonInsulin Resistance at Dx

Unknown Pathophysiology

• Insulin Resistance + Hypoinsulinemia

Prevention

• Early Screening

• Glucose Monitoring Pre/Post/During

• Healthy Diet + Physical Activity Loading...

Pregnancy Complications

Baby puts on Extra weight → C-section

• ↑ T2DM risk for baby

↑ Early Delivery → Respiratory Distress

Complications for Mother

↑ T2DM risk & Future GDM↑ Risk Preeclampsia & Hypertension

complications of diabetes, secondary to Tx, specifically type 1

Insulin Shock

• Plasma glucose < 45 mg/dl (<30 newborns)

• T1DM Risk > T2DM• Preventable with monitoring

Treatments

• Exogenous Glucose

• Glucagon Injections

Neurogenic Sx = ↑ SNS Activation

Tachycardia + Tremor + Anxiety

brain starts freaking

Neuroglycopenic Sx = Brain Hypoglycemia

dizziness, confusion, seizures, coma

diabetic ketoacidosis (DKA) - type 1

hyperosmolar hyperglycaemic syndrome (HHS) - type 2

retinopathy

neuropathy

nephropathy

all type 2, can all lead to infections

↓ senses - ↓ Vision (DR) & Proprioception (DPN) = ↑ Injuries

↓ blood supply - Microvascular Angiopathy = ↓ Immune Cell Recruitment

hypoxia - Hgb A1C = ↓ Oxygen Release

↓ Wound Healing

↓ Immune Response

pathogen fuel - hyperglycemias = proliferation

Shared Primary Goal: Keep Glucose Levels in ‘Healthy’ Range

Diet & Physical Activity = Central Components

Physical Activity ↑ Glucose Uptake & Insulin-Sensitivity - > by muscle/fat hissues

Combine with cardiovascular drugs when necessary (ex.: ACE Inhibitors; Statins)

Specific Goal: Prevent Short-Term Complications (ex.: Ketoacidosis & Hypoglycemia)

Best Rx = Insulin

Requires extensive Patient EducationMust couple Insulin Replacement with Carb intake Weight Maintenance with Physical Activity

Specific Goal: Prevent Long-Term Complications (ex.: Micro & Macrovasculature Diseases)

Best Rx = Metformin & Insulin

Management of comorbidities = Crucial

Around-the-Clock Blood Glucose Level Maintenance Quite difficult to achieveRequires intensive insulin therapy: Avg. 4 x/day

Type-1 Diabetes

Benefits ˃˃ Risks & Challenge

Significant ↓ morbidity & mortality

Drawbacks :

↑ Hypoglycemia Risk & Weight Gain

↑ Cost/Complexity of Therapy

Type-2 Diabetes: Benefits limited to:

Younger & recent-onset patients

Otherwise, it increases mortality risks

Should be avoided in patients with:

History of Severe Hypoglycemia Advanced Vascular Complications

Self-Monitoring Frequency depends on treatment:

Metformin Monotherapy ≈ 1x/week Intensive Insulin for TGC ≈ 8-10x/day

Continuous Glucose Monitoring (CGM) = best when possible

Catabolic State: ↑ Breakdown of Fat, Glycogen & Proteins

↓

Gluconeogenesis: Fat & Amino Acids conversion to Glucose

+↓ Glucose Cellular Uptake & Usage

↓Hyperglycemia↓Signs & Symptoms of Diabetes

Synthesized via DNA Recombination

Shorter Action = Postprandial Control

Longer Action = Daily Baseline Control

Insulin = Protein → Digested by stomach acid

Only available parenteral

look at graph on slide

High-Alert Agent ↑ Medication Error Risks

clear, colourless solution

gently mix NPH insulin

verify/note date of penny

discard sub-standard solutions (coloured/cloudy)

U-100 or 200 : Routine Replacement Therapy

U-300 : Daily Basal Insulin Coverage

U-500 : Specifically for Insulin Resistant Patients

Only NPH Insulin can be mixed with Short-Acting Insulins

Premixed Preparations = Preferred to ↓ Errors

Abdominal = Faster

Legs = Slower

Subcutaneous = Preferred for all: Via syringe/pen/jet injectors

Pre-filled syringe stored in fridge upright: Gently agitate to re-suspend prior to injection

Admin IV: Emergency ketoacidosis

2x-daily premixed - only 2 injections but less needs based adjustments

intensive basal-bolus: good meal + basal coverage, perfect for T1DM

Continuous Subcutaneous Infusions (CSII):

Steady admin + Automated adjustments (TCG)

IV Infusions: Critical care cases (ex.: Ketoacidosis)

look at graphs

intense PA, pregnancy/childbirth, skipping meals, excessive alcohol

quick increases in sugar, juice, chocolate, short-term fix

hypokalemia (drop in K+)

allergic reactions

hypoglycaemic agents : alcohol

hyperglycaemic agents: glucocorticoids

beta-blockers: can hide early signs of complications

Must correct Hyperglycemia & Acidosis

IV Fluids & Electrolytes for rehydration

IV Insulin to gradually ↓ Blood Glucose

Rapid ↓ Blood Glucose can exacerbate condition

look at slide for MoA

this happens when there is poor glycemic control

When self-treatment with oral carbohydrates fails

• IV Glucose = Preferred option (Immediate effect)

• If impossible (Ex.: unconscious at home) →

Glucagon Subcut

T2DM - remember some insulin still present

block K+ channels in beta cells -> keeps K+ inside -> depolarization -> Ca2+ influx -> cue to release insulin

Orally AvailableMix of hepatic metabolism & kidney excretion

↑ Risk if Liver or Renal Impairment

Small Hypoglycemia risk

Weight Gain → ‘Weight-Positive’

Alcohol & Other Hypoglycemic Agents

Beta-Blockers (↓ Insulin release)

↑ Insulin Secretion (so ineffective for T1DM)

Most often a 2nd line option

Mechanism of Action & Adverse Effects

Same as Sulfonyureas

Pharmacokinetics

Shorter duration of acti than Sulfonylureas

Variable prescription pattern in North America due to GI Adverse (Ex.: Acarbose & Miglitol)

therapeutic use

2nd-line T2DM Glycemic Control↓ A1C levels & postprandial glucose peaks

kinetics

Only 2% absorbed → Very few systemic effects

Stays where it acts (in the gut!!)

Inactivated by GI enzymes & bacteria

adverse effects

GI Distress (ex.: Cramps, flatulence, diarrhea) ↓ Iron Absorption → ↑ Anemia Risks Low risk of HypoglycemiaVery rare risks of liver dysfunctions

1. @ GIT: Slight ↓ in Glucose absorption

2. @ Liver: ↓ glucose synthesis & release

3. ↑ organs’ sensitivity to Insulin

Orally AvailableNo Metabolism → 100% Kidney Excretion

↓ Vit. B12 & Folic Acid Absorption↓ Nausea, Diarrhea & Appetite → ‘Weight-Neutral’ Mitigation: Administration with meal

major toxicity = lactic acidosis:

50% mortality but very rare (0.003%/year)Risk factor: Renal Impairment

Contraindication: eGFR ≤ 30mL/min or any condition ↑ lactic acid

Early Signs: Hyperventilation, Myalgia & Somnolence

Treatment: Hemodialysis

Alcohol & Antihistamines → Increase LA risk

#1 drug of choice for long term T2DM management

glycemic control

- ↓ blood glucose without ↑ insulin

- hypoglycemia risk = low

- synergy w/other antidiabetic agents

- safe for individuals skipping meals

T2DM prevention

- delay T2DM development in high risk ppl

- not as much as diet + PA

gestational diabetes

- benefits = insulin

off label usage

- PCOS: ↓ androgens ↑ insulin sensitivity

- antipsychotic toxicity: ↓ weight gain

Drugs Empagliflozin & Canagliflozin

Action: ↓ Glucose Kidney Reabsorption Weight loss via urinary caloric loss

Specific Usage: T2DM: Best options for patients with CVD comorbidities already on Metformin

Heart Failure (new indication): Improves cardiovascular & renal outcomes

Common Adverse Effects

Orthostasis: ↑ risk with diuretics↑ UTIs & urination: Due to extra urinary glucose

Therapeutic Use Second-Line Drug to T2DM TherapySmall ↓ in A1C (≈ 0.5%) → yet clinically significant

Kinetics ≈ 100% Absorbed / ≈ 100% Kidney Excretion

Adverse Effects

Very few → Well toleratedSevere Pancreatitis (rare) → Monitor Unconfirmed Allergic Reactions → Monitor

Drug Interactions - Nothing significant!

Therapeutic Effects

Improve Glycemic Control of T2DM

Can induce weight-loss

Administration : 1 weekly injections for most

Kinetics:

Subcutaneous Injections = Best Absorption

≈ 100% Kidney Excretion

Adverse Effects

Common & Mild: GI Distress (constipation or diarrhea, nausea/vomiting, GI pain)

Rare & Severe: Hypoglycemia Pancreatitis & Acute Kidney Damage Thyroid Cancer & Allergic reactions

Drug Interactions

↓ Absorption of PO Drugs Ex.: Contraceptives & Antibiotics

approved in 2020, now also PO available

Ozempic:

Approved for T2DM management in 2017

During clinical trials:

Excess weight loss vs. Placebo @ 30 weeks 0.5mg = 2.6kg / 1mg = 3.5kg

Wegovy:

Approved for chronic weight management in 2021

not yet available in Canada

Indications:

Approved in 2022 for T2DM (Mounjaro) & Weight-Loss (Zepbound)

1st in class medication (‘Twincretin’)

Therapeutic Effects

Increased insulin secretions & adiponectin levels Evidence of superior Glycemic Efficacy & Weight- Loss vs. Glutides

Administration

5, 10 or 15mg once weekly injections

Kinetics

Affinity for Albumin

Half-Life = 5 days

Urine & Feces Excretion

Adverse Effects (AE) profile≈ GLP-1 Agonists

Most common = Dose-dependent GI Distress (constipation or diarrhea, nausea/vomiting, GI pain) AE-induced Drug discontinuation ≈ 10% at 15mg dosage

More Rare: Hypoglycemia, Pancreatitis & Cholecystitis

Contraindications: medullary thyroid cancer, multiple endocrine neoplasia syndrome

look at slides

Risk of Hypoglycemia with Insulin vs. Oral Antidiabetic Rx

• Oral Antidiabetic Rx do not influence insulin levels as much

• They ↓ glucose entry into the circulation so levels don’t drop drastically, they prevent blood glucose concentration from ↑ too much

• Insulin ↑ Uptake by almost all cells (Except Brain!!)

Pt often confuse the causal relationship between

meal intake and Insulin or Metformin admin

• Correct rationale: ‘I must eat because I took my insulin’ → to prevent hypoglycemia

• More common but less significant rationale ‘I take my insulin to prevent hyperglycemia from the meal I ate’

first you need to know who to screen -> look at drawing

screen FPG (fasted plasma glucose)

screen A1C = glycoslated hemoglobin -> Average blood glucose from previous 2-3 months, Cannot use to monitor acute, hour-to-hour glucose homeostasis

conditions that affect RBC lifespan will affect A1C: pregnancy, chronic kidney disease, severe bleeding, blood transfusions

IFG or Prediabetes:

No increased risk of diabetic microvascular complications, but... it is a potential sign of Hyperinsulinemia/Insulin-resistance!

↑ risk for T2DM → ↑ risk of other 3 Horsemen long-term

Via gradual vascular dammage & inflammation Can be mitigated via diet, exercise & Metformin

look at slide for A1C level to FPG conversion

A1C Level = ≈ 5.0

Plasma Glucose (mg/dL) = 100 or less

Plasma Glucose (mmol/L) = 5.5 or less

Achieve via lifestyle primarily (diet & exercise)