Factors associated with improvement of fasting plasma glucose level by mealtime dosing of a rapid-acting insulin analog in type 2 diabetes

Abstract

This study investigated whether strict control of plasma glucose levels with mealtime dosing of a rapid-acting insulin analog improves early morning fasting plasma glucose (FPG) levels in patients with type 2 diabetes.

A rapid-acting insulin analog was administered at each mealtime to 40 Japanese patients with type 2 diabetes whose existing antidiabetic medication was discontinued. Approximately one-half (52.5%) of the patients achieved a minimum early morning FPG levels achievable (nadir FPG) of <120 mg/dL with mealtime dosing of a rapid-acting insulin analog alone; no basal insulin replacement was needed in these patients. Nadir FPG levels were independent of duration of diabetes, baseline body mass index (BMI) or glycemic control. All patients who had been treated with sulfonylureas needed basal insulin replacement. Low responses of insulin to glucagon and to arginine, and high response of glucagon to arginine may explain the failure to improve FPG levels with postprandial insulin replacement alone.

In conclusion, approximately one-half of the patients with type 2 diabetes achieved appropriate control of FPG by rapid-acting insulin analog monotherapy. Basal insulin secretory defects in type 2 diabetes may be estimated by the responses of insulin to glucagon and to arginine and the response of glucagon to arginine. This study contributes to a better understanding of the pathophysiology contributing to the heterogeneity in the characteristics of insulin secretion in type 2 diabetes.

Introduction

Diabetes, especially postprandial hyperglycemia, is associated with accelerated systemic arteriosclerosis, leading to macroangiopathy including ischemic heart disease and cerebrovascular accidents. Type 2 diabetes develops largely because of an absolute or relative deficiency of insulin secretion [1], [2]. Glucose-responsive insulin secretion is frequently impaired prior to the onset of type 2 diabetes [3]. In addition, considering reduced pancreatic β-cell mass in patients with type 2 diabetes [4], [5], defects in insulin secretion appear heterogeneous in patients with type 2 diabetes. In some patients, only glucose-responsive insulin secretion appears impaired, while in others, basal insulin secretion is also affected.

The presence of persistent postprandial hyperglycemia aggravates preexisting insulin secretory defects and/or insulin resistance, leading to further hyperglycemia [6]. This may be irreversible ‘glucose toxicity’, possibly caused by genetic damage to pancreatic β-cells, or reversible ‘glucose desensitization’, possibly caused by temporary β-cell exhaustion. Correcting hyperglycemia in cases of glucose desensitization improves insulin secretory capacity and/or insulin resistance [7].

Studies have demonstrated that treatment targeting postprandial hyperglycemia, which improves glucose-responsive insulin secretion in patients with glucose desensitization, improves not only postprandial, but also early morning fasting plasma glucose (FPG) in such patients [8], [9], [10]. Patients whose FPG levels remain high even after postprandial hyperglycemia is improved are presumed to have defects in basal insulin secretion.

Early treatment of type 2 diabetes is focused on oral hypoglycemics. However, these drugs cannot completely mimic a physiologic pattern of insulin secretion. In general, postprandial glycemic control is inadequate and there is a risk of fasting hypoglycemia. Insulin preparations have been developed to provide insulin replacement that more closely reflects physiologic insulin secretion; the introduction of rapid-acting insulin analogs and long-acting soluble insulin analogs has been a further step in this direction. Rapid-acting insulin analogs have been particularly effective at targeting postprandial hyperglycemia [11], [12], [13]. They can, therefore, effectively reduce postprandial plasma glucose even if administered immediately before a meal, and minimize the risk of hypoglycemia prior to the next meal [12], [13]. We evaluated the effect of a mealtime, rapid-acting insulin analog on the minimum early morning plasma glucose levels (nadir FPG) in patients with type 2 diabetes.

Mealtime dosing of rapid-acting insulin analogs strictly controls postprandial and daytime plasma glucose levels, and thereby improves glucose desensitization and glucose-responsive insulin secretion. The study aimed to characterize the heterogeneous nature of insulin secretion and the presence of basal insulin secretory defects in some patients with type 2 diabetes, by analyzing the nadir FPG levels attained with mealtime rapid-acting insulin analog dosing. The study also evaluated the clinical and biochemical factors that may correlate with specific types of insulin secretory defects.