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Diabetes Mellitus

Normal blood glucose range

  • body “loves” blood glucose in the range of 70–100 mg/dL

Insulin and glucagon dynamics

  • insulin and glucagon levels change because each other’s pathways are activated (overly)

Beta islet cell: glucose sensing and insulin secretion

Key features

  • in beta islet cells, GLUT2 is insulin-insensitive
  • glucose enters and (with glucokinase, the “glucose sensor”) goes down glycolysis

Stimulus–secretion coupling (sequence)

  1. glucose enters via GLUT2
  2. glycolysis increases ATP
  3. ATP blocks ATP-sensitive K\(^+\) channel
  4. cell membrane depolarizes
  5. voltage-gated Ca\(^{2+}\) channels open
  6. Ca\(^{2+}\) stimulates exocytosis of insulin vesicles

Biphasic insulin release

  • first large peak: pre-formed vesicles
  • second small peak: fewer/no pre-formed vesicles; need to build protein

Insulin: structure and processing

  • insulin has an A chain with intra-disulfide bond
  • produced as a pre-prohormone

Processing steps :

  1. ER cleaves signal sequence
  2. forms disulfide bonds
  3. Golgi cuts C-peptide

C-peptide vs insulin

  • C-peptide is a sign of beta health; half-life ~30 min

  • type 1 has much lower C-peptide level

  • insulin half-life: 1–2 min

Insulinoma

  • tumor within beta cells

Findings :

  • low blood glucose
  • high insulin
  • high C-peptide

Diabetes (general)

  • multiple genes and factors

Type 1 diabetes mellitus (T1DM)

  • absolute deficiency of insulin
  • autoimmune disease
  • less common than type 2

Mechanism :

  • CD8 cytotoxic T cells with B cells attack the host (beta cells)

Contributions :

  • mostly genetic
  • ~12% environmental

Examples / associations :

  • insulin gene
  • MHC presentation (HLC-DQ and HLC-DR)
  • CTLA4 (T cell off switch; ligand receptor protein)
  • trans-fat
  • pesticide

Symptoms (often sudden after clinical threshold)

  • polyuria: increased urination (osmotic pressure due to high blood glucose)
  • polydipsia: increased thirst
  • polyphagia: increased hunger (lack of glucose in insulin-dependent cells)
  • weight loss

Diagnosis

Overnight fasting:

  • 126 mg/dL blood glucose

Random:

  • 200 mg/dL blood glucose

2-hour post-prandial:

  • 200 mg/dL blood glucose

Antibody testing:

  • determine type 1 (positive) vs type 2 (negative)

Glycated hemoglobin (HbA\(_{1c}\))

  • glycation = non-enzymatic addition of glucose to a target
  • glucose added to hemoglobin (glycation of A\(_1\)C)
  • reflects average glycemia over ~3 months
  • DCCT (%): ok 5.7, pre 6.4, diabetic

Metabolic changes in uncontrolled T1DM

  • glucagon and epinephrine “win”
  • high glycogenolysis
  • high gluconeogenesis
  • high lipolysis
  • low liver glycolysis

Key transporter note:

  • GLUT4 is on the surface of muscle and adipose cells only with insulin

Ketones and acidosis

  • ketonemia from ketogenesis
  • fatty acids → acetoacetate + \(\beta\)-hydroxybutyrate → released into blood
  • pK\(_a\) of ketones is lower than blood pH → causes acidosis
  • lowers blood pH; “steals” protons from blood

Chronic impact:

  • glycation forms AGE (advanced glycation end products), which are inflammatory

Treatment note :

  • inject insulin and bicarbonate (if ketonemia)

Type 2 diabetes mellitus (T2DM)

  • insulin resistance
  • inflammatory; closely related to fat

Progression model :

  • as insulin resistance increases, beta cells compensate by secreting more insulin
  • over time insulin levels drop (can fall below normal) and glucose rises (beta cell exhaustion)

Diet implication :

  • low GI food is better because it protects beta cells from sudden high insulin demand

Risk factors

  • number 1: obesity

  • white fat cells are inflammatory and produce leptin and NCP-1 (recruits monocytes)

  • monocytes turn into macrophages
  • macrophages secrete IL-6 and TNF-\(\alpha\)
  • these block insulin pathways
  • TCF7L2 influences
  • PPAR influences

Symptoms

  • later onset than type 1
  • slower healing than type 1
  • neuropathy worse than type 1
  • also with PPP

Diagnosis:

  • same diagnostic methods as type 1

Ketones:

  • no ketonemia (some insulin still working)

Management focus

  • diet
  • exercise
  • removal of fat tissue

Treatments / drug mechanisms

Metformin (hepatocyte)

Effects:

  • inhibits gluconeogenesis
  • increases glucose uptake
  • increases insulin sensitivity

Mechanistic notes :

  • inhibits complex I of ETC (other pathways convert NADH to NAD\(^+\))
  • lowers AMP and then activates AMPK
  • phosphorylation leads to GLUT being sent to the surface of the cell

Insulin

  • insulin therapy (general)

Sulfonylurea

  • increases insulin secretion
  • binds ATP-sensitive K\(^+\) channel

Alpha-glucosidase inhibitor

  • blocks carbohydrate absorption

Thiazolidinedione

  • enhances insulin signaling