Diabetes Mellitus

Overview

Diabetes mellitus (DM) is a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to disordered carbohydrate, fat, and protein metabolism with wide-ranging systemic consequences. (Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus, p. 1)

Classification

Type	Mechanism	Key Features
Type 1 DM	Autoimmune destruction of pancreatic β-cells	Absolute insulin deficiency; insulin required for survival
Type 2 DM	Insulin resistance + relative insulin secretory defect	Most common (~90–95% of cases); often manageable without insulin initially
Gestational DM (GDM)	Resembles T2DM; placental hormones cause resistance	Affects ~17% of pregnancies; major risk factor for future T2DM
Other specific types	Monogenic (MODY), drug-induced, pancreatic disease, endocrinopathies	Varied mechanisms

Pathophysiology

Type 1 DM

T-cell mediated autoimmune attack on β-cells (HLA-DR3/DR4 associations)
Leads to near-total loss of insulin secretion
Requires exogenous insulin for glucose uptake, prevention of ketoacidosis, and survival

Type 2 DM

The pathophysiology involves two core defects:

Insulin resistance — peripheral tissues (muscle, fat, liver) fail to respond normally to insulin
β-cell dysfunction — the pancreas cannot compensate with adequate insulin secretion

The diagram below illustrates the insulin signaling pathway and how disruption at multiple steps (PI3K, AKT, GLUT-4 translocation) leads to impaired glucose uptake:

Insulin Signaling Pathway & Glucose Uptake

Insulin binds its receptor → phosphorylation of IRS → PI3K/AKT cascade → GLUT-4 exocytosis → glucose uptake. Defects anywhere in this chain produce insulin resistance.

Diagnosis

ADA Diagnostic Criteria (any one of the following, confirmed on repeat testing unless unequivocal hyperglycemia):

Test	Diagnostic Threshold
Fasting plasma glucose (FPG)	≥ 126 mg/dL (7.0 mmol/L)
2-hour plasma glucose (75g OGTT)	≥ 200 mg/dL (11.1 mmol/L)
HbA1c	≥ 6.5% (48 mmol/mol)
Random glucose + symptoms	≥ 200 mg/dL (11.1 mmol/L)

Prediabetes (increased risk):

FPG: 100–125 mg/dL (impaired fasting glucose)
2h OGTT: 140–199 mg/dL (impaired glucose tolerance)
HbA1c: 5.7–6.4%

Clinical Presentation

Classic symptoms ("3 Ps"):

Polyuria — osmotic diuresis from glucosuria
Polydipsia — secondary to fluid loss
Polyphagia — cellular starvation despite hyperglycemia

Additional findings: weight loss, blurred vision, fatigue, recurrent infections, slow wound healing

T2DM is often asymptomatic at diagnosis; T1DM may present acutely with diabetic ketoacidosis (DKA).

Management

Individualized Glycemic Targets

HbA1c < 7% is the general target for most non-pregnant adults
Less stringent (< 8%) for elderly, limited life expectancy, or frequent hypoglycemia
More stringent (< 6.5%) in younger, newly diagnosed with no hypoglycemia risk

Type 1 DM

Insulin therapy is mandatory (basal-bolus regimens or continuous subcutaneous insulin infusion)
Carbohydrate counting, continuous glucose monitoring (CGM)

Type 2 DM — Stepwise Approach

Lifestyle modification — Medical nutrition therapy, physical activity, weight loss (first-line)
Metformin — First-line pharmacotherapy (reduces hepatic glucose output, low cost, weight-neutral)
Add-on agents based on comorbidities:

Drug Class	Benefit Beyond Glucose	Notes
GLP-1 agonists (e.g., semaglutide)	CV protection, weight loss	Injectable (oral semaglutide available)
SGLT-2 inhibitors (e.g., empagliflozin)	CV & renal protection, HF benefit	Preferred in CKD/HF
DPP-4 inhibitors	Weight-neutral	Well tolerated
Sulfonylureas	Low cost	Hypoglycemia risk
Insulin	Universal efficacy	Required when other agents fail

Insulin therapy when HbA1c targets not met with oral/injectable non-insulin agents (Eye Care of the Patient with Diabetes Mellitus, p. 23)

Cardiovascular & Other Risk Factor Management

Blood pressure control (target < 130/80 mmHg in most)
Statin therapy (high-intensity in those with CVD or high risk)
Antiplatelet therapy (aspirin) in established CVD

Complications

Microvascular

Complication	Mechanism	Manifestation
Diabetic nephropathy	Mesangial expansion, hyperfiltration	Proteinuria → CKD → ESRD
Diabetic retinopathy	Pericyte loss, neovascularization	Leading cause of adult blindness
Diabetic neuropathy	Axonal degeneration, demyelination	Distal symmetric polyneuropathy, autonomic neuropathy

Macrovascular

Accelerated atherosclerosis → coronary artery disease, stroke, peripheral artery disease
Leading cause of mortality in T2DM patients

Acute Metabolic

Emergency	Type	Key Features
DKA	Primarily T1DM	Hyperglycemia, anion-gap acidosis, ketonemia; pH < 7.3
HHS	T2DM	Extreme hyperglycemia (> 600 mg/dL), hyperosmolarity, no significant ketosis
Hypoglycemia	Any treated DM	BG < 70 mg/dL; symptoms: tremor, diaphoresis, confusion

Monitoring

HbA1c every 3 months until stable, then every 6 months
Self-monitoring of blood glucose (SMBG) or CGM
Annual: urine albumin-to-creatinine ratio, eGFR, lipid panel, ophthalmologic exam, foot exam
Immunizations: influenza, pneumococcal, hepatitis B (for adults with DM)

Special Populations

Gestational DM: Screen at 24–28 weeks; managed with diet ± insulin (metformin/glyburide as alternatives); risk of macrosomia, neonatal hypoglycemia
Elderly: Hypoglycemia is particularly dangerous; de-intensify therapy as needed
CKD: Adjust drug doses; prefer SGLT-2 inhibitors and GLP-1 agonists with proven renal benefit

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