Glucose uptake is regulated by insulin in the case of high plasma glucose. Insulin is then secreted and stimulates the uptake and storage of glucose, as well as its metabolism in skeletal muscle and adipose tissue, in order to maintain a constant glucose level. In our study, the group with a longer disease duration had higher insulin requirements for metabolic control. Furthermore, a significant positive correlation was found between the time of disease and the dose of insulin required for treatment, which suggests that the appearance of insulin resistance occurs during the course of disease and becomes higher with longer duration of disease. The required insulin dose in patients with type 1 diabetes constitutes a marker of insulin resistance.10
Other factors which influence insulin action, such as suboptimal control, overweight, counter-regulatory hormone excess, or ketoacidosis, have been suggested as mechanisms for insulin resistance in patients with type 1 diabetes.12
In our study, there were no differences in BMI and metabolic control as assessed by the level of HbA1c
, which could explain the difference in insulin action in type 1 diabetic patients with different durations of diabetes.
The first mechanism of insulin action is mediated by cell surface receptors which were described in 1971.13
An alteration in the binding of insulin to its receptor could explain an impairment of insulin action in diabetic patients. Studies of insulin action in type 1 diabetes have observed normal restored insulin action in these individuals. Although muscle tissue is the major peripheral target organ of insulin, adipose tissue is another important one, and previous studies have demonstrated that glucose uptake induced by insulin in this tissue correlates with overall glucose utilization.10
Moreover, in vitro experiments show that a reversal of hyperglycemia normalizes the insulin action in fat cells following insulin treatment.14
In addition, normal insulin sensitivity has also been reported in patients with type 1 diabetes in the preclinical stage of the disease. In subjects with newly diagnosed type 1 diabetes, a transient normalization of insulin action may occur after initial insulin treatment. In patients with type 1 diabetes, partial recovery of C-peptide secretion has been observed during the honeymoon period.15
We measured C-peptide levels, both at baseline and six minutes after stimulation with glucagon 1 mg intravenously, and an absence of insulin secretion was confirmed. Therefore, our results support the hypothesis that factors other than endogenous insulin secretion must contribute to the increase in daily insulin requirements over the duration of the disease.
High glucose transport in adipocytes as the cause of the honeymoon period, without changes in insulin secretion, has been reported.17
An increase in basal glucose transport and maximally stimulated glucose transport during the early phase of diabetes could explain the low insulin requirement needed to achieve metabolic control during the first year of the disease. In conceptual agreement, we now report high glucose transport, both basal and maximal, in type 1 diabetic patients with a shorter duration of disease. We did not observe insulin resistance in our type 1 diabetic patients, because both basal and maximum insulin-stimulated glucose uptake were not decreased in type 1 diabetic patients when compared with the control group. Furthermore, we found a negative correlation between insulin action and duration of disease in type 1 diabetic patients.
A limitation of our study is the low number of patients. Our results indicate that a longer duration of diabetes could lead to a decrease in insulin action in type 1 diabetic patients. In the early phase of the disease, an increase in glucose transport and maximal insulin glucose transport could explain the lower dose of insulin needed in type 1 diabetic patients in clinical practice. Moreover, a normal insulin action explains the frequent hypoglycemia seen in type 1 diabetes versus type 2 diabetes patients with high levels of insulin and low episodes of hypoglycemia.
In summary, type 1 diabetic patients are not insulin-resistant, and the early phase of the disease is characterized by an increase in glucose transport, both basal and insulin-stimulated. Further studies with larger number of patients are needed to confirm our results.