Clinical predictors and time course of the improvement in ß-cell function with short-term intensive insulin therapy in patients with Type 2 diabetes.

AIMS: In patients with Type 2 diabetes, a short course of intensive insulin therapy can improve ß-cell function and even induce transient remission of diabetes. However, not all patients respond to this therapy. Although the achievement of fasting glucose  < 7.0 mmol/l one day after stopping intensive insulin therapy can identify patients in whom ß-cell function has improved, we sought to determine clinical predictors for the early identification of such responders and the time course of response. METHODS: We pooled data from two studies in which 97 patients with Type 2 diabetes mellitus (median 3 years duration) and HbA1c 51 ± 8.7 mmol/mol (6.8 ± 0.8%) underwent 4-8 weeks of intensive insulin therapy, consisting of basal detemir and pre-meal insulin aspart. They were classified as responders (n = 74) or non-responders (n = 23), defined by the achievement of fasting glucose  < 7.0 mmol/l after stopping intensive insulin therapy. RESULTS: On logistic regression analyses, duration of diabetes (odds ratio [OR] = 0.72, 95% confidence interval [CI] 0.56-0.92, P = 0.009) and baseline fasting glucose (OR = 0.40, 95% CI 0.24-0.68, P = 0.001) emerged as predictors of the likelihood of responding. Ninety per cent of patients with duration ≤ 4 years and fasting glucose ≤ 8.0 mmol/l responded to intensive insulin therapy. Despite having lower glucose levels during intensive insulin therapy, responders had less hypoglycaemia than non-responders (median 0.3 vs. 1.6 episodes/week, P < 0.0001), with rates of hypoglycaemia diverging sharply from the third week onwards. CONCLUSION: At baseline, shorter duration of diabetes and lower fasting glucose can identify patients most likely to benefit from short-term intensive insulin therapy. Most importantly, during therapy, responders had less hypoglycaemia from the third week onwards, despite lower glycaemia, suggesting that 2 weeks of intensive insulin therapy may be needed to improve endogenous islet function.

Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of beta-cell function with oral antidiabetic medications: a pilot study with sitagliptin.

AIM: Studies evaluating the effects of oral antidiabetic drugs (OADs) on beta-cell function in type 2 diabetes mellitus (T2DM) are confounded by an inability to establish the actual baseline degree of beta-cell dysfunction, independent of the deleterious effects of hyperglycaemia (glucotoxicity). Because intensive insulin therapy (IIT) can induce normoglycaemia, we reasoned that short-term IIT could enable evaluation of the beta-cell protective capacity of OADs, free from confounding hyperglycaemia. We applied this strategy to assess the effect of sitagliptin on beta-cell function. METHODS: In this pilot study, 37 patients with T2DM of 6.0 + 6.4 years duration and A1c 7.0 + 0.8% on 0-2 OADs were switched to 4-8 weeks of IIT consisting of basal detemir and premeal insulin aspart. Subjects achieving fasting glucose <7.0 mmol/l 1 day after completing IIT (n = 21) were then randomized to metformin with either sitagliptin (n = 10) or placebo (n = 11). Subjects were followed for 48 weeks, with serial assessment of beta-cell function [ratio of AUC(Cpep) to AUC(gluc) over Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (AUC(Cpep/gluc) /HOMA-IR)] on 4-h meal tests. RESULTS: During the study, fasting glucagon-like-peptide-1 was higher (p = 0.003) and A1c lower in the sitagliptin arm (p = 0.016). Nevertheless, although beta-cell function improved during the IIT phase, it declined similarly in both arms over time (p = 0.61). By study end, AUC(Cpep/gluc) /HOMA-IR was not significantly different between the placebo and sitagliptin arms (median 71.2 vs 80.4; p = 0.36). CONCLUSIONS: Pretreatment IIT can provide a useful strategy for evaluating the beta-cell protective capacity of diabetes interventions. In this pilot study, improved A1c with sitagliptin could not be attributed to a significant effect on preservation of beta-cell function.

The response to short-term intensive insulin therapy in type 2 diabetes.

AIM: Although a short course of intensive insulin therapy (IIT) can improve beta-cell function and glycaemic control in most patients with newly diagnosed type 2 diabetes (T2DM), the impact of this intervention in diabetes of longer duration has not been carefully studied. Thus, we sought to evaluate the effect of short-term IIT in patients with established T2DM. METHODS: Thirty-four patients, with diabetes of mean 5.9 +/- 6.6 years duration, underwent 4-8 weeks of IIT, with 4-h meal test administered at baseline and at 1 day post-IIT. A positive clinical response was defined as fasting glucose < 7.0 mmol/l off any antidiabetic therapy at the latter test. RESULTS: A positive response was achieved in 68% (n = 23) of the subjects. At baseline meal test, the responders had lower glucose levels than the non-responders from 120 to 240 min (all timepoints p < or = 0.0008) and higher late incremental area-under-the-C-peptide-curve (AUC(Cpep)), particularly from 60 to 150 min (all p < 0.005). Beta-cell function (ratio of AUC(Cpep) to AUC(gluc) divided by HOMA-IR) was similar between the groups at baseline (median 54.1 vs. 51.3, p = 0.62) but after IIT was significantly higher in the responders (109.3 vs. 57.4, p = 0.009). At baseline, the strongest predictors of the change in beta-cell function were glucose levels between 180 and 240 min (all r = -0.5, p = 0.005) and incremental AUC(Cpep) from 120 to 180 min (all r > or = 0.66, p < or = 0.0001), both reflecting late-phase insulin secretion. CONCLUSIONS: The clinical response to short-term IIT is variable, consistent with the heterogeneity of T2DM. However, preserved late-phase insulin secretion may identify those patients who can benefit from this intervention with improved beta-cell function.