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Glycemic regulation is a negative feedback control system with multiple signals: pancreatic cells secrete insulin in response to plasma glucose (sensor-effector-effect); cells secrete glucagon in hypoglycemia; The liver does most of the gluconeogenesis controlled by the insulin/glucagon ratio.

Bergman's (1981) minimal model is the standard for quantifying insulin sensitivity (IS) and glucose disposition from the intravenous glucose tolerance test (IVGTT). It uses two compartments: plasma (G) and a 'remote insulin action compartment' (X). The SI = p/p is the insulin sensitivity index; AIRg (acute insulin response to glucose) measures -cell function.

HbA1c reflects the average glycemia of the previous 23 months (erythrocyte half-life): the glycation rate is proportional to the glucose concentration (first-order kinetics). Each 1% of HbA1c mean blood glucose of an additional 28.7 mg/dL. It is the marker of glycemic control in diabetes and the goal of treatment (< 7% = 53 mmol/mol in most patients).

The hyperinsulinemic euglycemic clamp is the Gold Standard for measuring insulin resistance: insulin is infused at a supraphysiological dose and the glucose infusion rate (GIR) is adjusted to maintain constant blood glucose (4.55.5 mmol/L). The M-value = GIR/kg is insulin-mediated glucose uptake. In normal subjects, M 510 mg/kg/min; in severe insulin resistance, M < 23.

The PK-PD dynamics of insulin analogues allow the design of optimal dosing regimens: long-acting insulin (glargine, detemir) has a very slow absorption (t½ absorption > 12 h) that produces almost constant plasma levels (basal insulin); Rapid-acting insulin (lispro, aspart) has t½ absorption < 1 h to cover the postprandial peak. The closed loop system (artificial pancreas) implements a PID or MPC controller that adjusts insulin infusion in real time based on continuous blood glucose.

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