Diabetes

Disease definition & pathophysiology

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia resulting from impaired insulin secretion, insulin action, or both.
Two main types exist: Type 1 diabetes (T1DM) involves autoimmune destruction of pancreatic beta-cells, leading to absolute insulin deficiency.
Type 2 diabetes (T2DM) is characterized by insulin resistance combined with progressive beta-cell dysfunction, influenced by genetic, lifestyle, and environmental factors.

Commonly used Pharmacodynamic (PD) Models

• Glucose-insulin homeostasis models (minimal model, insulin-glucose feedback models).
• Disease progression models describing beta-cell function decline over time (HbA1c progression).
• Indirect-response or target-engagement models evaluating insulin secretion or sensitivity.

Typical patient population

T1DM commonly presents in childhood or adolescence (<20 years), though adult-onset is possible.
T2DM usually appears after age 40 but increasingly occurs earlier due to rising obesity rates.
T2DM is more prevalent, accounting for >90% of diabetes cases globally.

Risk factors & disease progression indicators

Risk factors for T1DM include genetics and autoimmunity.
T2DM risk factors include obesity, sedentary lifestyle, poor diet, family history, age, hypertension, and dyslipidemia.
Disease progression indicated by rising HbA1c, decreasing beta-cell function (lower insulin secretion), increasing insulin requirements, and presence of diabetes complications (retinopathy, nephropathy, neuropathy).

Key Clinical Biomarkers

Diagnosis relies primarily on blood glucose criteria: - Fasting plasma glucose (FPG) ≥126 mg/dL (≥7.0 mmol/L) - 2-hour plasma glucose ≥200 mg/dL (≥11.1 mmol/L) after oral glucose tolerance test (OGTT) - HbA1c ≥6.5% - Random plasma glucose ≥200 mg/dL (≥11.1 mmol/L) with classical symptoms

HbA1c is key for monitoring glycemic control over time.

Disease Severity Classification

Severity often described by glycemic control level and presence of complications: - Well-controlled: HbA1c <7% - Moderately controlled: HbA1c 7–8.5% - Poorly controlled: HbA1c >8.5%

Treatment aim (PD-targets)

The main treatment aims are normalization of blood glucose, preservation of beta-cell function, and reduction of long-term diabetic complications.
PD-targets include insulin secretion, insulin sensitivity, glucose absorption, and renal glucose excretion.

Common Drug Classes & Regimens

Commonly used PK-models

• Population PK models describing insulin kinetics and dynamics, considering factors like body weight, renal function, and insulin resistance.
• Physiologically-based PK (PBPK) models used to characterize absorption and disposition of oral anti-diabetic drugs.
• PK-PD models linking drug exposure to glycemic endpoints (HbA1c, fasting glucose), insulin sensitivity, and beta-cell function.