Colorado State University, USA
Title: Why clinical trials that reduce glucose levels fail to prevent complications in diabetic patients: Tests support an alternative hypothesis for pathogenesis
Biography: Douglas N Ishii
Statement of Problem: Meta-analysis of outcomes on 34,533 Type 2 diabetic patients shows that intensive lowering of glucose levels
does not prevent neuropathy, retinopathy, nephropathy, cardiovascular death, nor excess mortality. Nor does lowering of glucose levels prevent complications in approximately 40% of type 1 patients. Exposing patients to adverse effects from unbeneficial drugs is unjustified, yet remains standard therapy. The development of meaningful novel treatments awaits an alternative hypothesis for
pathogenesis of diabetic complications.
Methodology & Theoretical Orientation: Insulin and insulin-like growth factors (IGFs) are neurotrophic factors. The inter-related
hypotheses were developed that diminished insulin and IGF activities is the dominant cause of neurological complications, and that replacement of such activities should ameliorate diabetic complications irrespective of unabated hyperglycemia. These hypotheses were tested by infusing IGFs, insulin, or their combination into diabetic rats to determine whether neuropathy is alleviated under conditions in which hyperglycemia remains unabated.
Conclusion & Significance: IGF mRNA levels are reduced in peripheral nerves, brain and spinal cord in diabetes. Replacement IGF infusion prevented impaired sensory and motor nerve regeneration, hyperalgesia, abnormal ultrastructure in autonomic axons, loss of epidermal nerve fiber density, and poor gastric wound healing despite undiminished hyperglycemia. Tiny doses of insulin
and/or IGF were infused into diabetic rat brains under conditions that did not reduce hyperglycemia. A decrease in total mRNA, protein, and DNA levels was associated with brain atrophy and impaired learning/memory in diabetic rats. Insulin and IGF i.c.v. infusion prevented all such disturbances despite unabated hyperglycemia. Insulin and IGFs are master switches controlling the levels of hundreds of proteins in brain; loss of protein regulation, not hyperglycemia, is proposed as the most likely pathogenic cause for diabetic complications. Governments should manufacture clinical grade IGF (off- patent). Clinical trials are urgently needed to test insulin/IGF therapy.