Screening Methods for Antidiabetic Drugs

Scope, rationale & screening strategy

• What is screened — an experimental / methodology topic — the deliverable is the preclinical screening cascade used to detect and quantify the blood-glucose-lowering / antidiabetic activity of a candidate, NOT the clinical pharmacotherapy of diabetes. Two disease archetypes are modelled: type-1 / IDDM (β-cell loss → insulin deficiency) and type-2 / NIDDM (insulin resistance ± β-cell dysfunction, with obesity & hyperinsulinaemia).
• Core principle — because diabetes is diagnosed by glucose-tolerance tests, screening is directed at glucose metabolism; the most useful primary screen is depression of blood sugar in the intact animal, which retains all the mechanisms of blood-glucose regulation. An ideal agent normalises all metabolic derangements, so choosing the right physiologic endpoint is paramount.
• Two-tier cascade — (i) methods for discovering activity — primary high-throughput in-vivo blood-glucose screens; (ii) definitive mechanistic studies — secondary in-vitro assays localising the site of action (secretion vs uptake vs receptor).
• Historical milestones — von Mering & Minkowski (1890) — pancreatectomy diabetes in dogs; Banting & Best (1922) — pancreatic-extract lowering of blood sugar (proof of insulin); Houssay (1930) — hypophysectomy ameliorates pancreatic diabetes (pituitary counter-regulation).
• Vogel assay vocabulary — each method is described as Purpose & Rationale → Procedure → Evaluation → Modifications → Critical Assessment — a reusable skeleton for reproducing or critiquing any published screen.