TYPE 1 DIABETES MELLITUS

Diagnosis

• Definition: Diabetes mellitus is established when:
  1. Typical hyperglycemia symptoms (polyuria, polydipsia, weight loss)
  2. Fasting plasma glucose ≥126 mg/dL OR Random plasma glucose ≥200 mg/dL (confirmed on another occasion)
• Three general types of diabetes mellitus:
  1. Type 1 DM
  2. Type 2 DM
  3. Gestational DM
• Prevalence: Type 1 DM <10% of all diabetes cases.
• Pathophysiology: Pancreatic β-cell destruction → absolute insulin deficiency → if untreated, fatal catabolic disorder. All patients require insulin replacement therapy.

Incidence and Risk Factors

• Geographic variation:
  • Highest incidence in northern Europe (~30/100,000 persons/year).
  • Lowest in China (~1/100,000 persons/year).
• Typical onset: children/young adults (though can occur at any age).
• Family risk:
  • Offspring of diabetic mother: 3% risk.
  • Offspring of diabetic father: 6% risk.
• Environment + genetics: Only ~50% of identical twins both develop T1DM → environmental triggers (e.g., infections/toxins) + genetic predisposition.

Genetic Associations

• HLA class II (DQ, DR):
  • 95% of patients have HLA-DR3, HLA-DR4, or both (vs. ~50% in controls).
  • Some DQ alleles (e.g., DQA10102, DQB10602) → decreased risk.
• Non-HLA genes: e.g., polymorphisms in PTPN22, promoter region of insulin gene → increased susceptibility.

Autoimmune Mechanisms

• Autoimmune basis in >95% of type 1 cases.
• Loss of tolerance → immune system targets β-cell proteins with “molecular mimicry.”
• Autoantibodies (present in most new T1DM):
  • Islet cell antibody
  • Anti–glutamic acid decarboxylase (GAD)
  • Anti–tyrosine phosphatases (IA2)
  • Zinc transporter
  • Insulin autoantibody

Natural History

• Chronic autoimmune β-cell destruction over months/years.
• Latent period: normal glucose tolerance while β-cells are being lost.
• Impaired glucose tolerance → overt diabetes when >90% β-cell mass destroyed.
• Toxic hyperglycemia accelerates remaining β-cell apoptosis.
• Honeymoon period: short-term partial recovery after exogenous insulin started.

Histopathology

• Early: “hydropic” changes (actually glycogen infiltration).
• Selective β-cell destruction; islets show:
  • Chronic inflammatory infiltrate (insulitis) with T lymphocytes (CD8>CD4).
  • Eventually islets become hyalinized, partially or completely replaced.

Clinical Presentation

• Classic hyperglycemia signs: polyuria, polydipsia, blurred vision (osmotic effect), weight loss.
• Volume depletion → postural hypotension.
• Hyperglycemic neurotoxicity → paresthesias.
• Severe insulin deficiency → diabetic ketoacidosis (DKA).

TREATMENT OF TYPE 1 DIABETES MELLITUS

Importance of Tight Glycemic Control

• Reduces risk of:
  • Retinopathy
  • Nephropathy
  • Neuropathy
  • Cardiovascular disease
• Glycemic goals:
  • HbA1c <7% (<6% is optimal if achievable safely).
  • Fasting/premeal glucose 70–130 mg/dL.
  • 2-hr postprandial <180 mg/dL.

Insulin Therapy

• Absolute requirement for exogenous insulin.
• Two main regimens:
  1. Multiple daily injections (MDI)
  2. Continuous subcutaneous insulin infusion (CSII) (insulin pump)

Types of Insulin

1. Rapid-acting analogues (lispro, aspart, glulisine):
   • Onset ~15 minutes
   • Peak ~1 hour
2. Short-acting (regular insulin):
   • Onset 30–60 minutes
   • Peak 2–4 hours
3. Intermediate-acting (NPH):
   • Onset 1–3 hours
   • Peak 6–8 hours
4. Long-acting (glargine, detemir):
   • Onset ~1 hour
   • Minimal peak
   • Duration ~24 hours

Modifications (Analogs)

• Rapid-acting:
  • Lispro: Invert β-28 (Lys) and β-29 (Pro)
  • Aspart: Replace β-28 (Pro) with Asp
  • Glulisine: Replace β-3 (Asn) with Lys, β-29 (Lys) with Glu
• Long-acting:
  • Glargine: Replace α-21 (Asn) with Gly + add 2 Arg to β-chain → forms microprecipitates in subQ.
  • Detemir: Remove β-30 (Thr) + attach C14 fatty acid at β-29 → prolongs absorption.

Amylin Analogues

• Amylin is normally cosecreted with insulin by β-cells (deficient in T1DM).
• Pramlintide: amylin analogue, subQ before meals; helps improve glycemic control by:
  • Delaying gastric emptying
  • Reducing appetite
  • Suppressing glucagon

Intensive Insulin Programs

1. MDI:
   • Long-acting analog (glargine/detemir) at bedtime for basal coverage
   • Rapid-acting analogs before meals
2. CSII (Insulin pump):
   • Continuous rapid-acting insulin via subQ catheter
   • Preprogrammed basal rate + patient-activated boluses premeal
   • Adjust basal profile for circadian changes

Hypoglycemia is a major complication:

• Risk of falls, accidents, seizures
• Autonomic neuropathy → “hypoglycemic unawareness” (loss of adrenergic warning signs)
• Essential to have readily available carbs (glucose tablets) + injectable glucagon kit