The only new
pharmaceutical therapy for Type 2 (non-
insulin-dependent) diabetes that has become available for clinical use in the last 40 years is the
alpha-glucosidase inhibitor,
acarbose, which reduces postprandial
glucose levels by retarding digestion of complex
carbohydrates in the gut. It has proved difficult to find other new metabolically active drugs that lack toxicity. Agents that reduce
insulin resistance include the
thiazolidinediones, which are very effective in animals. Of these, the only one that has been maintained in clinical evaluation appears from preliminary data to have an effect that although still useful, is not greater than that reported for current oral agents. Agents that reduce non-
esterified fatty acid levels by inhibiting lipolysis, thereby allowing increased peripheral uptake of
glucose, have so far given minimal reduction in glycaemia. The development of
fatty acid oxidation inhibitors to reduce gluconeogenesis in the liver has been hampered by toxicity, but additional new agents are being studied. The most promising new approach for enhancing insulin secretion has been suggested by the demonstration that pharmacological doses of
GLP-1 (7-36 amide), a natural enteric
incretin hormone, improves pancreatic beta-cell and alpha-cell sensitivity to
glucose and can induce normal basal
glucose levels in diabetic man. The future development of
GLP-1 agonists will be of great interest. This is timely as other
insulin secretogogues, such as alpha 2
adrenergic blockers have proved relatively ineffective.
Anti-obesity agents would in theory be beneficial, but have either had limited efficacy or have been avoided because of concern about long-term safety. Until new
pharmaceutical agents become available, if near-normal glycaemia is to be achieved, many more Type 2 diabetic patients will need
insulin therapy. When full
insulin replacement
therapy is not feasible, reducing the fasting
blood glucose level towards normal with a single daily basal
insulin supplement, either alone or in combination with oral agents, could become a more widely used
therapy.