Peripheral neuropathy and microangiopathy in rats with insulinoma: association with chronic hyperinsulinemia

Hypoglycemia can precipitate or worsen peripheral neuropathy in patients with insulinoma or in diabetic patients on an intensive insulin regimen. It still remains unclear as to whether hyperinsulinemia itself is involved in neuropathic changes in these patients. We, therefore, explored the possible isolated effects of chronic hyperinsulinemia on neuropathic changes in insulinoma-bearing rats (I-rats).

I-rats were generated by a combined treatment with nicotinamide and streptozotocin. At 15 months after the treatment, they showed a wide range of the plasma insulin (PI) level with or without a decrease in the blood glucose (BG) level and were divided into three groups on the basis of the presence of hypoglycemia (BG < 2.5 mmol/L) or hyperinsulinemia (PI > 100 mU/L): the first exhibited only hypoglycemia, the second exhibited only hyperinsulinemia, and the third exhibited neither. Peripheral nerve function and structure as well as microvasculature were evaluated among these groups in addition to age-matched untreated control rats (C-rats).

The first group of hypoglycemic I-rats showed a decrease (p < 0.05) in the axon/myelin ratio and an increase (p < 0.0001) in fibers undergoing axonal degeneration compared to C-rats, while the other two groups did not. On the other hand, the second group of hyperinsulinemic I-rats showed a decrease (p < 0.05) in the myelinated axonal size and an increase (all p < 0.05) in the F-wave latency and the densities of myelinated fibers and endoneurial microvessels exhibiting endothelial hyperplasia, vascular wall thickening, or pericytes debris compared to the third group of isoglycemic I-rats without hyperinsulinemia.

These results suggest that hypoglycemia is associated with increased myelinated axonal damage, while hyperinsulinemia is associated with increased densities of small myelinated axons and endoneurial microvessels with microangiopathic changes in I-rats. We, therefore, propose that the observed findings may be relevant to the complicated features of neuropathy in diabetic patients with chronic hyperinsulinemia.