Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver

Abstract

Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1 . 5, 3, 6, and 9 U/day) over 7 days.Insulinopenic-untreated rats and 6U-and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U-and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/ glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.

Diabetes-related alterations in the enteric nervous system and its microenvironment

“…Hyperglycemia may also activate matrix-degrading metalloproteinases, enzymes implicated in plaque rupture and arterial remodeling, inducing similar responses in vascular smooth muscles [128] . Although intensive glycemic control has reduced the risks of micro-and macrovascular complications, this strategy is not successful in all patients; therefore, cardiovascular events remain the leading risk factor for mortality of diabetic patients worldwide [129][130] . Glycemic control in the context of type 2 diabetes, as well as pre-diabetes, is also intertwined with cardiovascular risk factors such as obesity, hypertriglyceridemia and blood pressure contidemia and blood pressure control [131][132][133] .…”

“…Therefore, knowing the mechanisms by which diabetes inflicts structural, functional and molecular changes in these capillaries may open new directions in diabetes research and then offer alternative mechanisms to treat the complications associated with hyperglycemia. Due to the growing incidence of insulin resistance, it is becoming increasingly important for clinicians to introduce alternative therapies and be aware of diabetes-related vascular complications [130] . In our ongoing research, we provided evidence [25] that endothelial cells in capillaries adjacent to the MP are direct targets of diabetic damage.…”

Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes

“…At least in theory, recovery from hypoglycaemia may be impaired despite glucagon counterregulation if the liver glycogen content is low because of a previous bout of hypoglycaemia, poor diabetes control or prolonged exercise. Poorly controlled diabetes in rats, even without exercise, dramatically diminishes liver glycogen stores [45], while intensive insulin treatment can help recover glycogen content to some degree [46], but can also increase hypoglycaemia risk. These findings are confirmed in our study as the non-diabetic rats had much higher baseline liver glycogen concentrations compared with the diabetic rats not treated with insulin (Fig.…”

Low-dose Insulin Treatment Ameliorate Glucose Metabolism in Type 1 Diabetic Rats

“…However, long term exposure to high concentration of insulin may suppress the glucose transporter 4 (GLUT-4) gene expression [33]. The development of insulin resistance in hyperinsulinized subjects may cause disruption at different branch points of the insulin-mediated phosphatidylinositol 3-kinase/ protein kinase B (PI-3kinase/Akt) pathway [34]. These include reduction in tyrosine autophosphorylation of insulin receptor (IR), phosphorylation of glycogen synthase kinase (GSK-3), translocation of GLUT-4 to the plasma membrane of muscle tissue as well as deregulated FOXO1 transcription factor [34,35].…”