DIABETES MELLITUS

A Complete University Biochemistry Answer

I. DEFINITION

"Diabetes mellitus is a heterogeneous group of multifactorial, primarily polygenic syndromes characterized by elevated blood glucose caused by a relative or absolute deficiency in the hormone insulin."

• Lippincott Illustrated Reviews: Biochemistry, 8th Edition

II. CLASSIFICATION

III. EPIDEMIOLOGY

• Over 30 million people in the USA (~9.4% of population) have DM.
• ~8 million are undiagnosed.
• More than one-third of adults have prediabetes.
• DM is the 7th leading cause of death in the USA.
• Leading cause of adult blindness, amputation, and a major cause of renal failure, nerve damage, heart attacks, and strokes.

IV. TYPE 1 DIABETES MELLITUS (T1DM)

A. Etiology and Pathogenesis

• Absolute insulin deficiency
• Loss of inhibitory control on glucagon → elevated glucagon
• Unchecked hepatic gluconeogenesis, glycogenolysis, and ketogenesis

B. Characteristics

C. Metabolic Consequences

1. Carbohydrate metabolism: Glucose uptake by muscle and adipose is impaired → hyperglycemia. Glycogenolysis and gluconeogenesis are increased in the liver.
2. Fat metabolism: Hormone-sensitive lipase (HSL) in adipose tissue is activated → increased lipolysis → elevated free fatty acids (FFAs) in blood. In the liver, FFAs undergo β-oxidation → Acetyl CoA accumulates → Ketone body synthesis (acetoacetate, β-hydroxybutyrate, acetone).
3. Protein metabolism: Proteolysis increases → amino acids used for gluconeogenesis → muscle wasting.

V. TYPE 2 DIABETES MELLITUS (T2DM)

A. Pathogenesis - Two Core Defects

1. Insulin resistance - reduced sensitivity of target tissues (liver, skeletal muscle, adipose tissue) to insulin
2. β-cell dysfunction - progressive impairment of insulin secretion

B. Insulin Resistance

• Liver: Increased hepatic glucose production (elevated gluconeogenesis and glycogenolysis)
• Muscle: Decreased glucose uptake (reduced GLUT-4 translocation)
• Adipose tissue: Increased lipolysis → elevated FFAs → worsen insulin resistance

C. β-Cell Dysfunction

• Glucotoxicity (chronic hyperglycemia damages β-cells)
• Lipotoxicity (elevated FFAs are toxic to β-cells)
• Amyloid deposits in islets

D. Characteristics

VI. BIOCHEMICAL/METABOLIC ALTERATIONS IN DM

A. Glucose Metabolism

B. Lipid Metabolism

• Lipolysis increases (HSL activated by glucagon/epinephrine in absence of insulin)
• FFA levels rise in blood
• Ketogenesis increases in liver: Acetyl CoA → acetoacetate → β-hydroxybutyrate → acetone
• Hypertriglyceridemia occurs due to increased VLDL production from acetyl CoA

C. Protein Metabolism

• Protein synthesis decreases
• Proteolysis increases
• Amino acids mobilized for gluconeogenesis
• Results in negative nitrogen balance and muscle wasting

VII. DIAGNOSIS OF DIABETES MELLITUS

Prediabetes (Impaired Glucose Tolerance):

• FPG: 100-125 mg/dL (Impaired Fasting Glucose, IFG)
• 2-hr OGTT: 140-199 mg/dL (Impaired Glucose Tolerance, IGT)
• HbA1c: 5.7 - 6.4%

HbA1c (Glycated Hemoglobin):

• HbA1c is formed by the non-enzymatic glycosylation (glycation) of the N-terminal valine of the β-chain of hemoglobin.
• It reflects average blood glucose over the past 2-3 months (lifetime of an RBC).
• Normal value: < 5.7%
• Target in treated DM: < 7%

VIII. ACUTE COMPLICATIONS

1. Diabetic Ketoacidosis (DKA) - Primarily Type 1

• Triggered by absolute insulin deficiency + stress (infection, surgery)
• Biochemical cascade:

No Insulin → Increased Lipolysis → FFAs → β-Oxidation → Acetyl CoA → Ketone Bodies

• Blood ketone bodies can reach 90 mg/dL (normal < 3 mg/dL)
• Urinary ketones may reach 5,000 mg/24 hrs
• Ketone bodies (pKa ~4) release H⁺ in blood → metabolic acidosis
• Combined with dehydration (glycosuria, ketonuria) → severe acidosis
• Classic symptom: fruity breath (due to acetone)
• Kussmaul breathing (deep, rapid breathing to blow off CO₂)

2. Hyperosmolar Hyperglycemic State (HHS) - Type 2

• Severe hyperglycemia (often > 600 mg/dL), extreme dehydration
• No ketoacidosis (residual insulin suppresses ketogenesis)
• Altered mental status
• High mortality if untreated

3. Hypoglycemia

• Most common complication of insulin therapy
• Blood glucose < 70 mg/dL
• Symptoms: sweating, trembling, confusion, unconsciousness

IX. CHRONIC COMPLICATIONS

Mechanisms:

1. Polyol Pathway: Glucose → Sorbitol (by aldose reductase) → contributes to cataract, neuropathy, nephropathy
2. Glycation of Proteins (AGEs): Hyperglycemia promotes non-enzymatic glycation of cellular proteins → Advanced Glycation End Products (AGEs) → damage microvascular endothelium, reduce wound healing; AGEs bind RAGE receptor → release proinflammatory cytokines
3. Oxidative stress
4. Protein Kinase C activation

Macrovascular Complications:

• Atherosclerosis → Coronary artery disease (heart attack)
• Stroke
• Peripheral vascular disease

Microvascular Complications:

X. TREATMENT

Type 1 DM:

• Insulin replacement is mandatory (subcutaneous injection or insulin pump)
• Types: rapid-acting, short-acting, intermediate, long-acting insulin analogues

Type 2 DM:

• Lifestyle modification (medical nutrition therapy, weight loss, exercise) - first line
• Oral hypoglycemic drugs:

• Insulin therapy eventually required in > 90% of T2DM patients

Monitoring:

• Self-monitoring of blood glucose (SMBG)
• HbA1c every 3 months (target < 7%)
• Regular eye, kidney, and foot examinations

XI. PREVENTION

• Type 1 DM: No current preventive treatment
• Type 2 DM: Risk significantly reduced by:
  • Medical nutrition therapy
  • Weight loss (even 5-10% body weight reduction helps)
  • Regular physical exercise
  • Aggressive control of hypertension and dyslipidemia

XII. SUMMARY DIAGRAM (Metabolic Effects of Insulin Deficiency)

INSULIN DEFICIENCY
        |
   _____|_____
   |           |
Liver          Adipose/Muscle
   |                |
↑ Glycogenolysis    ↑ Lipolysis (FFAs)
↑ Gluconeogenesis   ↓ Glucose uptake
↑ Ketogenesis             |
   |               ↑ Blood Glucose
↑ Ketone Bodies  (HYPERGLYCEMIA)
   |
↓ Blood pH
(KETOACIDOSIS)

KEY POINTS FOR THE EXAM

1. DM is characterized by hyperglycemia due to relative/absolute insulin deficiency.
2. Type 1 = autoimmune β-cell destruction; Type 2 = insulin resistance + β-cell dysfunction.
3. The key biochemical finding in T1DM is DKA; in T2DM it is HHS.
4. HbA1c reflects glycemic control over 2-3 months; diagnostic at ≥ 6.5%.
5. Chronic hyperglycemia causes complications via polyol pathway, AGEs, and oxidative stress.
6. Metformin is the first-line drug for T2DM; it works by reducing hepatic gluconeogenesis.
7. Classic symptoms of DM: Polyuria, Polydipsia, Polyphagia, Weight loss ("3 Ps + weight loss").