Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2)

Abstract

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A 1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.

Interim report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using “Neo-Islets,” aggregates of adipose stem and pancreatic islet cells (INAD 012-776)

“…Importantly, the omentum’s venous drainage facilitates the physiological delivery of secreted insulin and other islet hormones directly into the portal system of the liver, i.e., a route that is identical to that of the pancreatic veins. Since the liver inactivates up to 50% of received insulin, the post-hepatic concentrations of insulin that other insulin-sensitive tissues are exposed to is significantly lower than those insulin levels that are generated by the s.c. injection of insulin that, particularly in higher doses, may have adverse systemic effects [41–43].…”

Mechanisms of hyperinsulinaemia in apparently healthy non-obese young adults: role of insulin secretion, clearance and action and associations with plasma amino acids

“…Unfortunately, due to the cross-sectional nature of our work, this distinction could not be determined. However, there is strong evidence in animals [34–40] and humans [11–13, 41] to support a causal role of excess insulin in driving insulin resistance, and that suppression of high plasma insulin levels enhances insulin action [42–44]. In this regard, it is of interest to note the recent work of Tricò et al [8], which suggests that hyperinsulinaemia can arise due to primary insulin hypersecretion independent of insulin resistance.…”

In vitrocharacterization of the effects of chronic insulin stimulation in mouse 3T3-L1 and human SGBS adipocytes

“…Several studies have explored in vitro models of insulin resistance using stressors of different nature (pro-inflammatory agents, lipids, cytokines, hormones) and discerned their distinct roles in a range of cell types, including adipocytes [ 1 , 3 , 10 , 12 , 24 - 26 ]. However, the studies evaluating the specific effects of high insulin concentrations in adipose cell lines have been limited: only 3T3-L1, and not SGBS, have been assessed as adipose cellular model, and the treatment with insulin was often conducted with a low concentration of the hormone (10 nM 11 , 26 , a concentration that, according to our phospho-Akt experiments, is close to insulin EC 50 thus it does not trigger maximal Akt phosphorylation), for a brief period of time (minimum 12 hours [ 12 ] maximum 24 hours [ 10 , 13 , 26 ]) and with shorter starvation period (between 2 hours [ 11 , 13 ]and 8 hours [ 26 ]).…”

“…As examples, transgenic mice carrying extra copies of insulin gene display glucose intolerance [1]. Similarly, 40 h-continuous infusion of insulin resulted in reduced glucose utilization in humans [2], and more recently hyperinsulinemia has been demonstrated to be the predominant causative factor leading to insulin resistance in type 1 diabetic subjects [3].…”

“…3T3-L1 have widely been used to model in vitro insulin-induced insulin resistance. Various publications consistently showed that prolonged exposure to high or even physiological concentrations of insulin causes an inhibition of insulin signalling, with a consequent reduction in glucose uptake [ 1 , 3 , 10 - 12 ] despite no changes highlighted in either basal or insulin-mediated inhibition of lipolysis.…”