Insulin Treatment in Type 2 Diabetes
Year: 2001
Type: dissertation
Study design: Clinical Trial
Abstract: Background and aims. Given that the pathogenesis of type 1 and 2 diabetes are markedly different, it is possible that patients with type 2 diabetes should not be treated with insulin following the principles used for treatment of type 1 diabetes. The present studies were undertaken to define 1) the optimal insulin treatment regimen for type 2 diabetic patients with secondary failure to oral anti-diabetic drugs (OAD), 2) causes of inter-individual variation in insulin requirements in type 2 diabetic patients and 3) how improvement of glycemic control by insulin therapy influences markers of endothelial activation as measured by serum concentrations of the soluble adhesion molecules sE-selectin and vascular cell adhesion molecule (sVCAM-1). Subjects, study designs and methods. 153 poorly controlled type 2 diabetic patients who were treated with maximal doses of sulfonylurea alone or in combination with metformin were randomized to treatment for 3 months with either continued OAD and NPH insulin in the evening or continued OAD and NPH insulin in the morning, a 2 insulin injection regimen without OAD or a multiple insulin injection regimen without OAD. The goal was to achieve similar glycemic control with all insulin regimens and to compare effects of various regimens on insulin requirements, body weight, serum lipids and lipoproteins and episodes of hypoglycemia (study I). Study II was designed to determine what bedtime NPH insulin should be combined with, a sulfonylurea, metformin, both drugs or another injection of NPH insulin. Ninety-six type 2 diabetic patients who were treated with a maximal dose of sulfonylurea, were randomized to treatment for one year with bedtime NPH insulin and glibenclamide, or bedtime NPH insulin and metformin, or bedtime NPH insulin and glibenclamide and metformin, or bedtime NPH insulin and morning NPH insulin. The patients were taught to self adjust their insulin doses. In study III, 20 type 2 diabetic patients with stable glucose control and insulin dose, who were treated with combination therapy with bedtime NPH insulin and metformin for at least 1 year were studied. In each subject, the following measurements were performed: 1) measurement of action of intravenous insulin on endogenous glucose production (EGO) and utilization, (euglycemic insulin clamp combined with [3-H]glucose) 2) measurement of absorption (increase in free insulin and total insulin over 8 h after subcutaneous dose of regular insulin) and action of subcutaneous insulin (glucose infusion rate required to maintain euglycemia and suppress FFA) and 3) measurement of liver (proton spectroscopy) and intra-abdominal (magnetic resonance imaging) fat content and in addition, body weight, body composition, and the thickness of subcutaneous abdominal (ultrasound) fat were determined. In study IV, 81 type 2 diabetic patients, who participated in study II and 41 normal subjects were studied. In these groups, concentrations of serum sE-selectin and sVCAM-1 concentrations were determined. In the type 2 diabetic patients, the measurements were repeated at 3 and 12 months. Results. Study I: The mean insulin doses of NPH insulin in the two groups receiving an OAD and NPH insulin were similar and 60 % lower than in the 2-injection or multiple injection group. The total doses of insulin were comparable in the 2and multiple insulin injection groups. HbA1c concentrations decreased from approximately 8 to 10 % in all the insulintreatment groups. All groups receiving insulin therapy gained weight. The smallest increment in body weight occurred in the OAD and evening NPH insulin group and the largest in the multiple-injection group (p < 0.05). The frequency of hypoglycemia was similar in all insulin treated groups. The concentration of serum VLDL triglycerides decreased by 13 to 28 % in the insulin treatment groups with no differences between the groups who used insulin. The concentrations of total, LDL, and HDL cholesterol remained unchanged. Study II: Patients receiving bedtime insulin and metformin showed a progressive decrease in HbA1c concentrations over time. At 12 months, HbA1c values in this group averaged 7.2 % ± 0,2 %; which differed significantly from that in the other groups. Patients receiving bedtime insulin and metformin did not gain weight unlike the other groups. The frequency of hypoglycemic episodes in patients receiving bedtime insulin and metformin was significantly lower (p < 0.05) than that in patients receiving bedtime and morning insulin. Hypoglycemia limited adequate titration of the insulin dose in the group using NPH insulin and glibenclamide. Serum triglyceride concentrations decreased similarly in all groups. Study III: The amount of insulin absorbed was significantly correlated with glucose infusion rate required to maintain euglycemia ( r = 0.74, p < 0.001) and suppression of FFA ( r = -0.63, p < 0.005). On the other hand, the actions of intravenous and subcutaneous insulin were so closely correlated that the contribution of variation in insulin absorption to interindividual variation in insulin action was maximally 30 %. Of the relationships of measures of overall adiposity and fat distribution, the % liver fat was the best correlate of the % suppression of EGO by intravenous insulin. In multiple linear regression, 61.3% of variation in the daily insulin dose (units per day) could be explained by variation in the ability of subcutaneous insulin to suppress FFA (p < 0.001) and by insulin antibodies (p = 0.05). Of all measures of adiposity, the % liver fat was the parameter best correlated with the insulin dose. Study IV. Serum sE-selectin concentrations were 71 % higher in the type 2 diabetic patients than in the normal subjects before insulin therapy. During insulin therapy, sE-selectin concentrations decreased significantly compared to 0 month but the concentration at 12 months was still 55 % higher than in the normal subjects. Serum sVCAM-1 decreased transiently during the first 3 months and then increased back to baseline by 12 months. The change in HbA1c, both in diabetic men and women, was significantly correlated with the change in sE-selectin concentrations. Conclusions. In poorly controlled type 2 diabetic patients receiving OAD therapy, the addition of NPH insulin in the evening improves glycemic control in a similar manner as a two-insulin-injection therapy regimen and multiple-insulin-therapy regimen, but induces less weight gain and hyperinsulinemia. Combination therapy with bedtime insulin and metformin prevents weight gain and seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia. Self-adjustment of the insulin dose is critically important to achieve glycemic targets. The major reason for interindividual variation in insulin requirements in type 2 diabetes is variation in insulin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitivity of EGO to insulin. Improvement in glycemic control by insulin alone or insulin combined with either glibenclamide, metformin, or both agents induces a sustained decrease in sE-selectin, the magnitude of which seems to be dependent on the degree of improvement in glycemic control. Serum sE-selectin might provide a marker of effects of treatment of chronic hyperglycemia on endothelial activation.
Source: Työväentutkimus Vuosikirja
Author: L. Ryysy
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1520139708