Diabetes Overview

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Diabetes Mellitus - Overview

Definition

Diabetes mellitus (DM) is a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Persistent hyperglycemia leads to dysfunction, damage, and failure of multiple organ systems - particularly the eyes, kidneys, nerves, heart, and blood vessels.

Classification

The American Diabetes Association (ADA) recognizes four major clinical types:

Type	Key Feature
Type 1 DM (T1DM)	Autoimmune beta cell destruction → absolute insulin deficiency
Type 2 DM (T2DM)	Progressive loss of beta cell insulin secretion, often with insulin resistance
Gestational DM (GDM)	Diabetes first diagnosed during pregnancy, not clearly overt prior to gestation
Other specific types	Monogenic (MODY, neonatal DM), exocrine pancreas disease, drug/chemical-induced

Source: Creasy & Resnik's Maternal-Fetal Medicine and ROSEN's Emergency Medicine

Prediabetes is now recognized as a distinct category: fasting plasma glucose 100-125 mg/dL or HbA1c 5.7-6.4%, representing high risk for progression to T2DM. The pathogenesis is thought to be related to insulin resistance.

Historical Classification Note

Early classification (1979, National Diabetes Data Group) used the terms:

Type I = insulin-dependent diabetes mellitus (IDDM)
Type II = non-insulin-dependent diabetes mellitus (NIDDM)

The ADA revised this in 1997, switching to "type 1" and "type 2" to base classification on etiology rather than treatment dependency. The terms IDDM and NIDDM are now obsolete.

Tietz Textbook of Laboratory Medicine, 7th Edition

Epidemiology

Diabetes is a rapidly growing global health burden. The IDF Diabetes Atlas projects a dramatic rise in the total number of adults with diabetes across all regions, particularly in Southeast Asia and Western Pacific regions. T2DM accounts for the vast majority (~90-95%) of all cases. T1DM comprises approximately 5-10% of all diabetes cases.

Risk factors for T2DM include:

Obesity (especially central/visceral adiposity)
Physical inactivity
Family history and genetic predisposition
Age >45 years
History of gestational diabetes
Ethnicity (higher rates in South Asian, African, and Hispanic populations)

Pathogenesis

Type 1 DM

T1DM is a chronic autoimmune disease in which immune-mediated destruction of beta cells in the islets of Langerhans leads to absolute insulin deficiency. Key features:

Autoantibodies are present in 85-90% of patients: islet cell autoantibodies (ICA), anti-insulin antibodies, anti-GAD65, anti-IA-2
Genetic susceptibility involves over 60 loci - many implicating the immune system (particularly HLA region)
Environmental triggers (e.g., enteroviruses) likely initiate immune destruction in susceptible individuals
Destruction occurs over months to years before clinical onset; only ~30% of children present initially with diabetic ketoacidosis (DKA)
Late-onset T1DM (LADA - Latent Autoimmune Diabetes of Adults) has a more indolent course with longer preservation of beta cell function
Creasy & Resnik's Maternal-Fetal Medicine

Type 2 DM

T2DM is multifactorial. The two core defects are:

Insulin resistance - peripheral tissues (particularly muscle and liver) are resistant to insulin's actions; defects in muscle glycogen synthesis play an important role
Progressive beta cell failure - pancreatic beta cells initially compensate with increased insulin output, but gradually fail to maintain euglycemia

Additional contributing factors include:

Increased hepatic glucose production
Impaired incretin effect (reduced GLP-1/GIP response)
Increased glucagon secretion
Renal glucose reabsorption abnormalities
Adipokine dysregulation (inflammation from visceral fat)

No autoimmune markers or HLA associations are seen in T2DM. Ketosis is rare because residual insulin secretion suppresses lipolysis and ketogenesis.

ROSEN's Emergency Medicine; Basic Medical Biochemistry - A Clinical Approach, 6e

Gestational DM

Pathogenesis resembles T2DM - driven by placental hormones inducing insulin resistance that normal beta cells cannot compensate for. Screening is performed at 24-28 weeks using a 75-g oral glucose load.

Diagnostic Criteria (ADA)

Any one of the following confirms diabetes:

Test	Diagnostic Threshold
HbA1c	≥ 6.5% (NGSP-certified method)
Fasting Plasma Glucose (FPG)	≥ 126 mg/dL (≥ 7.0 mmol/L); fasting = no caloric intake ≥ 8 hours
2-hour plasma glucose (OGTT)	≥ 200 mg/dL (≥ 11.1 mmol/L) using 75-g glucose load
Random plasma glucose	≥ 200 mg/dL with classic hyperglycemia symptoms

In the absence of unequivocal hyperglycemia, a result should be confirmed by repeat testing.

Creasy & Resnik's Maternal-Fetal Medicine; ROSEN's Emergency Medicine

Clinical Features

Acute / Symptomatic Presentation

Polyuria (osmotic diuresis from glycosuria)
Polydipsia (compensatory increase in fluid intake)
Polyphagia with weight loss (inability to utilize glucose; fat catabolism)
Blurred vision, fatigue, recurrent infections

T1DM acute emergencies:

Diabetic Ketoacidosis (DKA) - absolute insulin deficiency → uncontrolled lipolysis → ketone body accumulation → metabolic acidosis

T2DM acute complications:

Hyperosmolar Hyperglycemic State (HHS) - extreme hyperglycemia without significant ketosis; sufficient residual insulin prevents ketogenesis but not hyperglycemia

Pathophysiology of Hyperglycemia-Induced Damage

Chronic hyperglycemia causes tissue damage via several mechanisms:

Non-enzymatic glycation of proteins (e.g., HbA1c formation, collagen cross-linking in soft tissues) - alters protein structure and slows degradation
Polyol pathway activation - excess glucose is converted to sorbitol via aldose reductase; accumulates in nerves, lens, and retina
Advanced glycation end-products (AGEs) - accumulate in vessel walls and organs, promoting inflammation and fibrosis
Oxidative stress - overproduction of reactive oxygen species from mitochondria
Protein kinase C (PKC) activation - impairs vascular function

These mechanisms converge to produce microvascular and macrovascular complications.

Basic Medical Biochemistry - A Clinical Approach, 6e; Fuster and Hurst's The Heart, 15th Edition

Complications

Microvascular Complications

Complication	Main Feature
Diabetic Retinopathy	Leading cause of blindness in working-age adults; background → proliferative
Diabetic Nephropathy	Leading cause of end-stage renal disease; microalbuminuria → proteinuria → CKD
Diabetic Neuropathy	Peripheral (stocking-glove sensory loss), autonomic (gastroparesis, orthostasis)

Macrovascular Complications

Coronary artery disease (leading cause of mortality in diabetics)
Cerebrovascular disease (stroke)
Peripheral arterial disease (foot ulcers, gangrene, amputation)

Glycemic control, as shown by the DCCT and UKPDS trials, significantly reduces microvascular complications. Macrovascular risk requires multifactorial intervention (blood pressure, lipids, antiplatelet therapy).

Fuster and Hurst's The Heart, 15th Edition; Textbook of Family Medicine, 9e

Management Principles (Overview)

Domain	Key Interventions
Lifestyle	Medical nutrition therapy, regular physical activity, weight loss (T2DM)
Glycemic targets	HbA1c < 7% (individualized); FPG 80-130 mg/dL; 2-hr postprandial < 180 mg/dL
T1DM pharmacotherapy	Insulin replacement (basal-bolus or pump) - lifelong
T2DM pharmacotherapy	Metformin (first-line), followed by SGLT-2 inhibitors, GLP-1 agonists, DPP-4 inhibitors, sulfonylureas, insulin as needed
Cardiovascular protection	ACE inhibitor/ARB (nephroprotection), statins, aspirin, SGLT-2i / GLP-1 agonists with proven CV benefit
Monitoring	Self-monitoring of blood glucose (SMBG), HbA1c every 3 months, annual dilated eye exam, urinary albumin, foot exam

Key Summary Points

Diabetes is defined by chronic hyperglycemia from insulin deficiency, resistance, or both
T1DM is autoimmune; T2DM is multifactorial (insulin resistance + beta cell failure)
Diagnosis uses HbA1c ≥6.5%, FPG ≥126 mg/dL, or 2-hr OGTT ≥200 mg/dL
Complications are microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (CAD, stroke, PAD)
Intensive glycemic control reduces microvascular complications; multifactorial risk factor management is required for macrovascular disease
T1DM requires insulin; T2DM management is stepwise, beginning with lifestyle and metformin

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