Accelerated Insulin Degradation: An Alternate Mechanism for Insulin Resistance

Abstract

We have examined insulin and glucagon degrading activities of muscle and fat tissues in 11 subjects (4 lean controls, 3 insulin-resistant obese subjects, 2 non-insulin-dependent diabetic subjects, and 2 insulin-treated diabetic subjects) and correlated degrading activity with (1) basal insulin level and (2) state of insulin resistance. We found hyperinsulinemia and insulin resistance to be significantly correlated with accelerated insulin and glucagon degrading activity. Weight reduction in an insulin-resistant obese patients results in parallel reduction in both basal insulin level and insulin-glucagon degrading activity. These data are consistent with the hypothesis that an alternative mechanism for insulin resistance may be an accelerated insulin degradation at the level of target tissues.

Insulin degrading enzyme activity and insulin binding of erythrocytes in normal subjects and Type 2 (non-insulin-dependent) diabetic patients

“…These observations appear to agree with findings in the literature, where increased insulin degradation has been described in muscle from insulin-deficient, streptozotocin-diabetic rats, while insulin binding to muscle was increased at the same time, a phenomenon which reverted to normal after one week of insulin treatment [25]. An association of basal plasma insulin values with insulin degrading activities of muscle and fat tissue has also been shown in a previous study in some non-diabetic and diabetic insulin-resistant subjects [27]. These data have been interpreted as suggesting that insulin degrading enzymes are inducible and thereby influencing insulin metabolism or action respectively, with increased insulin degradation going along with a state of both insulin deficiency and insulin resistance [20,25,27].…”

“…An association of basal plasma insulin values with insulin degrading activities of muscle and fat tissue has also been shown in a previous study in some non-diabetic and diabetic insulin-resistant subjects [27]. These data have been interpreted as suggesting that insulin degrading enzymes are inducible and thereby influencing insulin metabolism or action respectively, with increased insulin degradation going along with a state of both insulin deficiency and insulin resistance [20,25,27].…”

“…Although increased insulin degradation has been recognized for many years as a theoretical cause of an impaired response to insulin, only recently have a few diabetic patients been described with extreme resistance to subcutaneous insulin and markedly elevated insulin degrading activity of adipose or muscle tissue [26][27][28][29][30][31]. The present study now demonstrates more generally elevated and fluctuating IDEA of erythrocytes in a variety of subgroups of patients with Type 2 diabetes.…”

“…In streptozotocin-diabetic rats, increased insulin degradation by intact muscle has been observed which could be restored to near-normal by insulin treatment [25]. Furthermore, studies in some rare cases of diabetic patients with excessive insulin resistance have suggested that accelerated insulin degradation at the level of target tissues might be a possible alternate explanation for their severe insulin-resistant state [26][27][28][29][30][31].…”

Inhibition of insulin degradation by hepatoma cells after microinjection of monoclonal antibodies to a specific cytosolic protease.

“…This degradation has been proposed to function either in the termination of the response of the cell to insulin (2) or possibly in the generation of the signal for the insulin response (3). Also, in several cases insulin-resistance has been reported to occur as a result of excessive insulin degradation (4)(5)(6)(7)(8).…”