Mechanism of Secretion of Insulin, Functions of Insulin, and Diabetes Mellitus

INTRODUCTION

PART 1: MECHANISM OF SECRETION OF INSULIN

Structure of Insulin

Glucose-Stimulated Insulin Secretion (Primary Mechanism)

Biphasic Pattern of Insulin Secretion

1. First phase (rapid): Plasma insulin rises almost 10-fold within 3-5 minutes due to immediate release of pre-formed, stored insulin from granules already docked at the cell membrane. This phase is transient and falls back halfway within 5-10 minutes.
2. Second phase (sustained): Beginning around 15 minutes, a second rise occurs over 2-3 hours, reaching even higher levels. This represents additional release of stored insulin plus new insulin synthesis from activated enzyme systems.

Other Stimulants of Insulin Secretion

Inhibitors of Insulin Secretion

Pharmacological Note (Sulfonylureas)

PART 2: FUNCTIONS OF INSULIN

A. Effects on Carbohydrate Metabolism

1. Facilitates glucose uptake into skeletal muscle and adipose tissue by promoting translocation of GLUT4 transporters to the cell surface. (Note: glucose uptake in brain, liver, and RBCs is insulin-independent.)
2. Promotes glycogenesis - stimulates glycogen synthase, increasing glycogen storage in liver and muscle.
3. Inhibits glycogenolysis - suppresses glycogen phosphorylase, reducing breakdown of glycogen.
4. Inhibits gluconeogenesis - reduces formation of glucose from amino acids and other substrates in the liver.
5. Stimulates glycolysis - increases utilization of glucose for energy.
6. Net effect: lowers blood glucose toward normal.

B. Effects on Fat Metabolism

1. Promotes lipogenesis - stimulates synthesis of fatty acids and triglycerides in the liver and adipose tissue.
2. Inhibits lipolysis - strongly inhibits lipase in adipose tissue, preventing breakdown of stored fat and reducing plasma free fatty acids.
3. Inhibits ketogenesis - by reducing fatty acid availability for beta-oxidation in the liver. Without insulin, massive lipolysis leads to ketone body accumulation (ketoacidosis).
4. Increases VLDL synthesis - promotes triglyceride packaging and export from the liver.

C. Effects on Protein Metabolism

1. Promotes amino acid uptake into cells, especially muscle.
2. Stimulates protein synthesis (anabolic effect) - promotes translation and gene expression for proteins.
3. Inhibits protein catabolism - reduces breakdown of intracellular proteins.
4. Works synergistically with growth hormone to promote body growth.

D. Effects on Potassium

1. Stimulates Na+-K+ ATPase - drives K+ into cells.
2. This is physiologically important for handling dietary K+ after a meal, preventing hyperkalemia.
3. Clinical application: Insulin is used to treat hyperkalemia acutely by driving K+ intracellularly.

E. Effects on the Brain (CNS)

• Insulin stimulates POMC neurons of the hypothalamus to reduce food intake.
• May regulate hepatic glucose production and systemic lipolysis via central pathways.

Summary Table of Insulin Functions

PART 3: NOTE ON DIABETES MELLITUS

Definition

• Lack of insulin secretion, or
• Decreased sensitivity of tissues to insulin (insulin resistance), or both.

Classification

Type 1 Diabetes Mellitus (IDDM - Insulin-Dependent DM)

• Pathogenesis: Autoimmune destruction of beta cells in the islets of Langerhans, leading to absolute insulin deficiency.
• Prevalence: ~3-5% of all diabetes; typically presents in children and young adults.
• Mechanism: T-cell mediated destruction of beta cells; autoantibodies (anti-islet cell antibodies, anti-GAD antibodies) are found.
• Key feature: Patients are completely dependent on exogenous insulin for survival.
• Without insulin, patients develop diabetic ketoacidosis (DKA).

Type 2 Diabetes Mellitus (NIDDM - Non-Insulin-Dependent DM)

• Pathogenesis: Combination of insulin resistance in peripheral tissues and progressive beta cell failure (insufficient compensatory insulin secretion).
• Prevalence: ~90-95% of all diabetes; presents typically in overweight/obese adults, but increasingly in children due to rising obesity.
• Mechanism: Insulin resistance is linked to obesity (especially visceral/abdominal fat), reduced GLUT4 activity, impaired insulin signaling pathways (lipotoxicity).
• Over time, beta cells fail to keep up with the demand, and relative insulin deficiency develops.
• Metabolic syndrome is often associated: obesity + insulin resistance + hyperglycemia + dyslipidemia + hypertension.

Gestational Diabetes Mellitus (GDM)

• Defined as hyperglycemia first detected during pregnancy.
• Due to placental hormones causing insulin resistance.

Pathophysiology (Consequences of Insulin Deficiency)

1. Reduced glucose entry into peripheral tissues (muscle, adipose) - cellular glucose deficiency despite hyperglycemia.
2. Increased hepatic glucose output via gluconeogenesis and glycogenolysis.

• Hyperglycemia - elevated blood glucose
• When blood glucose exceeds the renal threshold (~180 mg/dL), glucose spills into urine = glycosuria
• Glycosuria causes osmotic diuresis = polyuria (large urine volumes)
• Polyuria leads to dehydration = polydipsia (excessive thirst)

• Without insulin, lipolysis increases dramatically, releasing large amounts of free fatty acids.
• Liver converts these to ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, acetone) = ketonemia and ketonuria
• Accumulation of ketones (which are acids) causes metabolic acidosis = diabetic ketoacidosis (DKA) - primarily in Type 1 DM.
• Fat loss causes weight loss despite eating.

• Reduced amino acid uptake and increased protein catabolism.
• Results in muscle wasting, weakness, and cachexia (in untreated Type 1).
• Increased amino acids feed gluconeogenesis.

Clinical Features (The "Polys")

Diagnosis

• Fasting plasma glucose >= 126 mg/dL (on two separate occasions)
• Random plasma glucose >= 200 mg/dL with symptoms
• 2-hour OGTT (oral glucose tolerance test) >= 200 mg/dL
• HbA1c >= 6.5%

Complications

• Diabetic ketoacidosis (DKA) - mainly Type 1
• Hyperosmolar hyperglycemic state (HHS) - mainly Type 2
• Hypoglycemia (from insulin overdose)

Treatment

SUMMARY

• Insulin secretion from beta cells is primarily triggered by glucose through the GLUT2 → Glucokinase → ATP → K-ATP channel closure → Membrane depolarization → Ca2+ influx → Exocytosis pathway.
• Insulin secretion is biphasic: an immediate first phase and a sustained second phase.
• Insulin's main functions are glucose uptake, glycogenesis, lipogenesis, protein synthesis, and anti-lipolysis - all anabolic effects.
• Diabetes mellitus results from insulin deficiency (Type 1) or insulin resistance (Type 2), leading to the classic triad of polyuria, polydipsia, and polyphagia, along with hyperglycemia, glycosuria, and potentially ketoacidosis.
• Long-term complications target the kidney, retina, nerves, and blood vessels.