Long-acting insulin analogs in type 1 diabetes : effects on metabolic control, endogenous insulin production and the GH-IGF-axis

The treatment goal in type 1 diabetes is to achieve near-normal glycemia. Despite of the advancements of subcutaneous insulin therapy and glucose monitoring, metabolic control is not fully normalized and secondary endocrine disturbances in the growth-hormone (GH) - Insulin-like Growth Factor (IGF)-axis are important for the deterioration of metabolic control, particularly in children at puberty. The long-acting insulin analogs, glargine and detemir, have prolonged effect duration compared to intermediate-acting NPH insulin. Sustained nightly insulin actions could be particularly important in pubertal children with type 1 diabetes by opposing the low IGF-I production and increase feedback inhibition of elevated GH. Even the successive decline in endogenous insulin production could be affected. The purpose of this thesis was to evaluate if glargine or detemir, compared to NPH, could improve metabolic control, prolong endogenous insulin production and reverse the abnormalities in the GH-IGF-axis in children and adolescents with type 1 diabetes.

In Paper I we studied the effects of changing insulin therapy from NPH to glargine for up to 12 weeks on the GH-IGF-axis and metabolic control in 12 pubertal subjects with type 1 diabetes. A fifty percent increase in IGF-I levels, decreased overnight IGFBP-1 secretion and unchanged overnight GH secretion were associated with a 1 % unit (10 mmol/mol) lower (P= 0.008) 12-week HbA1c. These findings indicate that glargine reverses some of the abnormalities in the GH-IGF-axis and improves metabolic control. Suppression of IGFBP-1 suggests that hepatic insulin sensitivity is improved.

In Paper II we retrospectively compared the first 49 children and adolescents that we treated with glargine from diagnosis of type 1 diabetes with 49 patients treated with NPH, for up to one year. We found 0.8 % unit (8 mmol/mol) lower (P < 0.01) 12-month HbA1c and lower insulin requirements in the glargine treated subjects without affecting weight gain. These findings support a long-term improvement of HbA1c in children and adolescents treated from diagnosis with glargine. We hypothesized that improved metabolic control and lower insulin requirements could result from normalization of the GH-IGF-axis and/or improved endogenous insulin production.

In Paper III we randomized children and adolescents stratified for puberty to treatment with glargine or detemir vs. NPH from diagnosis of type 1 diabetes. We found 9 mmol/mol (0.9 % unit) lower (P = 0.008) 12-month HbA1c and lower fasting-glucose with glargine or detemir in pubertal children, with no difference in prepubertal children. Meal-stimulated C-peptide AUC or glucose variability by CGM did not differ. These findings demonstrate that long-term improvement of metabolic control is obtained with glargine or detemir treatment but not associated with improved preservation of beta cell function.

In Paper IV we reported changes in the GH-IGF-axis in the subjects studied in paper III. We found lower 12-month IGFBP-1 with glargine or detemir in pubertal subjects. IGF-I SDS was subnormal from diagnosis throughout the 12 months study, particularly low in the pubertal individuals, and did not differ among the treatment groups. Lower IGFBP-1 suggests that hepatic insulin action is improved, which may have contributed to the improved 12-month HbA1c. However, the improved hepatic insulin action with long-acting insulin analogs was not sufficient to normalize IGF-I.

In summary, this thesis supports that long-acting insulin analogs, glargine or detemir, are used from diagnosis of type 1 diabetes in pubertal children with insulin injection therapy to improve metabolic control. Although endogenous insulin secretion is not better preserved and IGF-I remains subnormal, hepatic insulin sensitivity may be improved as indicated by lower IGFBP-1. Given the link between abnormalities in the GH-IGF-axis associated with subcutaneous insulin therapy and the development of diabetic complications new treatment strategies are needed until beta-cell function can be fully preserved.

List of scientific papers

I. Ekström K, Salemyr J, Zachrisson I, Carlsson-Skwirut C, Örtqvist E, Bang P. Normalization of the IGF-IGFBP Axis by Sustained Nightly Insulinization in Type 1 Diabetes. Diabetes Care. 2007 Jun;30(6):1357-63
https://doi.org/10.2337/dc06-2328

II. Salemyr J, Bang P, Örtqvist E. Lower HbA1c after 1 year, in children with type 1 diabetes treated with insulin glargine vs. NPH insulin from diagnosis: a retrospective study. Pediatric Diabetes. 2011 Aug;12(5):501-5
https://doi.org/10.1111/j.1399-5448.2010.00723.x

III. Salemyr J, Örtqvist E, Ekström K, Carlsson-Skwirut C, Pulkkinen M-A. Brorsson A-L, Bang P. Lower HbA1c with long-acting insulin analogs versus NPH insulin from diagnosis of type 1 diabetes in pubertal children - a Randomized Controlled Trial. [Manuscript]

IV. Salemyr J, Ekström K, Carlsson-Skwirut C, Brismar K, Örtqvist E, Bang P. Lower IGFBP-1 is a marker of improved hepatic insulin sensitivity in pubertal children treated from diagnosis of type 1 diabetes with long-acting insulin analogs versus NPH insulin. [Manuscript]