Diabetes Mellitus - Complete Explanation

1. Definition

• The leading cause of end-stage renal disease
• The leading cause of adult-onset blindness
• The leading cause of nontraumatic lower extremity amputations

2. Epidemiology

• Affects >30 million people (>11% of the US population)
• ~1.9 million have Type 1 diabetes (T1D); the rest have Type 2 (T2D)
• ~96 million US adults have "prediabetes" (impaired glucose tolerance not yet meeting the T2D threshold)
• Worldwide: 422 million people affected (WHO estimate)
• T2D rates in adolescents have increased dramatically in recent years
• Native Americans, African Americans, and Hispanics are 1.5-2x more likely to develop diabetes
• 7th leading cause of death in the US (2019); total yearly cost ~$327 billion

3. Diagnosis (ADA/WHO Criteria)

HbA1c (glycated hemoglobin) reflects average blood glucose over the preceding 2-3 months and is used to monitor long-term glycemic control.

4. Classification

5. Normal Insulin Physiology (Basis for Understanding Diabetes)

1. Glucose enters the β cell via GLUT-2 transporter
2. Glucokinase phosphorylates glucose → glucose-6-phosphate (rate-limiting step)
3. Increased ATP:ADP ratio closes K⁺-ATP channels → membrane depolarization
4. Voltage-gated Ca²⁺ channels open → insulin granule exocytosis

• Liver: inhibits gluconeogenesis and glycogenolysis; promotes glycogen synthesis
• Skeletal muscle: stimulates glucose uptake (via GLUT-4 translocation) and glycogen synthesis
• Adipose tissue: promotes lipogenesis; inhibits lipolysis

6. TYPE 1 DIABETES (T1D)

Pathogenesis

• Major linkage to MHC class II genes (HLA-DR3, HLA-DR4; especially DR3/DR4 heterozygotes have highest risk)
• Polymorphisms in CTLA4 and PTPN22 (both regulate T-cell activity)
• Insulin gene VNTR polymorphisms affect thymic insulin expression

• Concordance in identical twins is only ~50%, so environment is critical
• Viral infections (e.g., enteroviruses, Coxsackie B) may trigger autoimmunity via molecular mimicry (shared epitopes between viral proteins and islet antigens)
• Some infections are thought to be protective against T1D (hygiene hypothesis)

Three Stages of T1D

Mechanism of β-Cell Destruction

• Autoreactive T cells that escape clonal deletion in the thymus are activated in peripancreatic lymph nodes
• Th1 CD4+ cells secrete IFN-γ and TNF, causing β-cell injury
• CD8+ cytotoxic T cells directly kill β cells
• Target antigens include: insulin, glutamic acid decarboxylase (GAD65), IA-2, ZnT8
• Autoantibodies (anti-GAD65, anti-IA2, anti-ZnT8) are found at presymptomatic stages - useful for screening
• Insulitis: lymphocytic infiltration of islets (mainly T cells and macrophages)

Clinical Presentation of T1D

• Onset typically in childhood/adolescence (but can occur at any age)
• Patients are usually normal weight or underweight
• Abrupt onset of: polyuria, polydipsia, polyphagia, weight loss
• "Honeymoon period" in first 1-2 years - residual β-cell function transiently maintains some insulin production
• Diabetic ketoacidosis (DKA) is the hallmark acute complication
• Requires insulin therapy for life

7. TYPE 2 DIABETES (T2D)

Pathogenesis

In early T2D, insulin resistance is compensated by β-cell hyperfunction and hyperinsulinemia. Over years, β cells "burn out," secretory capacity falls, and frank hyperglycemia develops.

Insulin Resistance

• Liver: fails to suppress gluconeogenesis → high fasting blood glucose
• Skeletal muscle: fails to uptake glucose post-meal → high postprandial glucose
• Adipose tissue: fails to suppress lipases → excess free fatty acids (FFAs) in circulation

Role of Obesity

• Excess FFAs overwhelm β-oxidation pathways → accumulation of diacylglycerol (DAG), ceramides - these "toxic lipids" inhibit insulin receptor signaling and activate inflammatory pathways in islets
• Adipokines: Adipose tissue in obese individuals secretes more resistin and TNF-α (pro-insulin resistance) and less adiponectin (which normally enhances insulin sensitivity)
• Chronic low-grade inflammation: macrophage infiltration of visceral fat releases IL-6, TNF-α → systemic insulin resistance

β-Cell Failure in T2D

• Genetic factors (~40% heritability), linked to TCF7L2, PPARG, FTO polymorphisms (not HLA)
• Chronic exposure to excess glucose (glucotoxicity) and FFAs (lipotoxicity) impairs β-cell function
• Amyloid deposition (islet amyloid polypeptide/IAPP) in islets - obliterates islet architecture in advanced T2D

Clinical Presentation of T2D

• Onset typically in adults (increasingly in adolescents)
• 80% are obese at diagnosis
• Often insidious and asymptomatic - detected incidentally on routine labs
• May present with complications (neuropathy, retinopathy) already established
• Nonketotic hyperosmolar coma (rather than DKA) is the characteristic acute crisis
• Circulating insulin is initially elevated (early) then normal or decreased (late)
• No islet autoantibodies

8. Comparison: Type 1 vs Type 2

9. Monogenic Forms (MODY)

• Glucokinase (GCK): Altered glucose "set point"; hyperglycemia but no typical complications
• HNF1α, HNF1β, HNF4α, PDX1 (various transcription factor mutations): cause β-cell dysfunction with typical complications
• Insulin gene mutations: directly reduce insulin production

10. Pathophysiology of Complications (Biochemical Mechanisms)

A. Advanced Glycation End Products (AGEs)

• Glucose non-enzymatically binds to proteins/lipids → AGEs
• AGEs cross-link collagen → thickened basement membranes (key in microangiopathy)
• AGEs bind RAGE receptors → activate NF-κB → inflammation and cytokine production
• AGEs trap plasma proteins in vessel walls

B. Polyol Pathway / Oxidative Stress

• Excess intracellular glucose → converted by aldose reductase to sorbitol (using NADPH as cofactor)
• NADPH also needed to regenerate reduced glutathione (GSH) - a key antioxidant
• Sorbitol accumulation depletes NADPH → less GSH → increased oxidative stress
• Sorbitol in the lens → cataracts

C. PKC Activation

• Hyperglycemia increases diacylglycerol (DAG) → activates Protein Kinase C (PKC)
• PKC signaling alters gene expression: increases VEGF (→ neovascularization), TGF-β (→ basement membrane thickening), endothelin-1 (→ vasoconstriction), and decreases eNOS (→ vasodilation)

D. Hexosamine Pathway

• Glycolytic intermediates shunted through hexosamine pathway → enhanced oxidative stress → insulin resistance and vascular complications

11. CHRONIC COMPLICATIONS

A. Macrovascular Disease (Large Vessels)

• Accelerated atherosclerosis of aorta, coronary, and peripheral arteries
• Diabetics have 2-4x higher risk of coronary artery disease
• 4-fold higher risk of dying from cardiovascular causes
• Risk elevated even in prediabetes
• Hypertension is present in ~75% of T2D patients
• Diabetic dyslipidemia: increased triglycerides and LDL, decreased HDL

B. Diabetic Nephropathy

• Leading cause of end-stage renal disease (ESRD) in the USA
• 30-40% of all diabetics develop clinical nephropathy
• Progression:
  1. Microalbuminuria (30-300 mg/day) = earliest sign
  2. Overt nephropathy (macroalbuminuria >300 mg/day) + hypertension
  3. ESRD requiring dialysis/transplant
• Pathology: Kimmelstiel-Wilson nodules (nodular glomerulosclerosis), diffuse glomerulosclerosis, arteriosclerosis, pyelonephritis

C. Diabetic Retinopathy

• Affects 60-80% of patients - leading cause of adult blindness in USA
• Fundamental lesion: neovascularization driven by hypoxia-induced VEGF
• Treatment: anti-VEGF agents (e.g., bevacizumab, ranibizumab)
• Also: cataracts (sorbitol accumulation in lens), glaucoma

D. Diabetic Neuropathy

• Most common form: distal symmetric polyneuropathy of lower extremities (sensorimotor)
• "Glove-and-stocking" pattern when upper extremities involved
• Autonomic neuropathy: bowel/bladder dysfunction, erectile dysfunction, orthostatic hypotension
• Mononeuropathy: sudden footdrop, wrist-drop, cranial nerve palsies

E. Susceptibility to Infections

• Impaired neutrophil function (chemotaxis, phagocytosis) due to hyperglycemia
• Poor wound healing
• Predisposed to: mucormycosis, Candida, recurrent urinary tract infections, foot ulcers, gas-forming infections

12. ACUTE METABOLIC COMPLICATIONS

A. Diabetic Ketoacidosis (DKA) - primarily T1D

• Precipitated by insulin deficiency (+ stress, infection)
• Insulin lack → unrestrained lipolysis → excess FFAs → liver β-oxidation → ketone bodies (acetoacetate, β-hydroxybutyrate)
• Presents with: nausea, vomiting, abdominal pain, fruity breath, Kussmaul breathing, altered consciousness
• Labs: hyperglycemia, ketonemia, metabolic acidosis (anion gap), hypokalemia (after treatment)
• Treatment: IV fluids, insulin infusion, potassium replacement

B. Hyperosmolar Hyperglycemic State (HHS) - primarily T2D

• Extreme hyperglycemia (often >600 mg/dL) with severe dehydration
• No significant ketosis (residual insulin prevents ketogenesis)
• Presents with: profound dehydration, neurologic symptoms, coma
• Very high mortality if untreated

C. Hypoglycemia

• Most common acute complication in treated diabetics
• Causes: excess insulin/sulfonylurea, skipped meals, exercise
• Symptoms: sweating, tremor, palpitations (adrenergic), then confusion, seizures (neuroglycopenic)
• Treatment: glucose (oral or IV dextrose/glucagon if severe)

13. Morphological Changes in the Pancreas

• T1D: dramatic reduction in islet number and size; insulitis (lymphocytic infiltration); β-cell depletion
• T2D: subtle reduction in islet cell mass; amyloid deposition (IAPP) obliterating islets; no insulitis
• Nondiabetic newborns of diabetic mothers: islet hyperplasia (response to maternal hyperglycemia)

14. Diabetes and Pregnancy

• Gestational diabetes: new-onset during pregnancy (~5-9% of US pregnancies); pregnancy is "diabetogenic" due to placental hormones creating insulin resistance
• Pregestational diabetes: pre-existing diabetes complicating pregnancy - increased risk of congenital malformations and stillbirth
• Poorly controlled late-pregnancy diabetes → macrosomia (large newborn), neonatal hypoglycemia
• Gestational diabetes usually resolves postpartum but most affected women develop T2D within 10-20 years

Summary Chart

DIABETES MELLITUS
├── Type 1 (Autoimmune)
│   ├── HLA-linked → autoreactive T cells → insulitis → β-cell destruction
│   ├── Acute: DKA
│   └── Treatment: Insulin
│
├── Type 2 (Metabolic)
│   ├── Obesity → insulin resistance → β-cell compensation → β-cell failure
│   ├── Acute: Hyperosmolar nonketotic coma
│   └── Treatment: lifestyle, metformin, GLP-1 agonists, SGLT-2i, insulin
│
├── Monogenic (MODY, type A resistance)
├── Gestational
│
└── Chronic Complications (all types, 15-20 yrs)
    ├── Macrovascular: MI, stroke, peripheral vascular disease
    ├── Microvascular: Nephropathy, Retinopathy, Neuropathy
    └── Infections