OBJECTIVEClinical studies evaluating the effects of medications on b-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of b-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve b-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT. RESEARCH DESIGN AND METHODSIn this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 6 1.9 years' duration and an A1C of 6.8 6 0.8% (51 6 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of b-cell function by Insulin SecretionSensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks. RESULTSThe primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 6 27.8 vs. 229.3 6 28.4, P = 0.008). Baseline-adjusted HbA 1c at 48 weeks was lower in the liraglutide group (6.2 6 0.1% vs. 6.6 6 0.1%, P = 0.055) (44 6 1.1 vs. 49 6 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA 1c £6.0% (42 mmol/mol) and glucose tolerance in the nondiabetic range. Despite this level of glycemic control, no difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups (P = 0.61). Two weeks after stopping treatment, however, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost (191.9 6 24.7 vs. 238.1 6 25.2, P = 0.20). CONCLUSIONSLiraglutide provides robust enhancement of b-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.The natural history of type 2 diabetes mellitus (T2DM) is characterized by rising glycemia and the need for increased antidiabetic medication over time (1). This clinical course is driven by the progressive deterioration of pancreatic b-cell function, a pathologic process that precedes the diagnosis of T2DM and continues

Kramer CK, Choi H, Zinman B, Retnakaran R. Determinants of reversibility of ␤-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes. Am J Physiol Endocrinol Metab 305: E1398 -E1407, 2013. First published October 15, 2013 doi:10.1152/ajpendo.00447.2013.-Short-term intensive insulin therapy (IIT) can improve pancreatic ␤-cell function when administered early in the course of type 2 diabetes mellitus (T2DM). However, the degree of improvement in response to this therapy varies between patients. Thus, we sought to characterize the determinants of improvement in ␤-cell function in response to short-term IIT in early T2DM. Sixty-three patients with mean 3.0 Ϯ 2.1 yr duration of T2DM and Hb A 1c of 6.8 Ϯ 0.8% underwent 4 wk of IIT consisting of basal insulin detemir and premeal insulin aspart, with oral glucose tolerance test administered at baseline and 1 day post-IIT. ␤-Cell function before and after IIT was assessed by Insulin Secretion Sensitivity Index-2 (ISSI-2). Reversibility of ␤-cell dysfunction was defined as percentage change in ISSI-2 of Ն25%. Overall, the study population experienced an increase in ISSI-2 from baseline to post-IIT (P ϭ 0.01), with one-third of participants achieving Ն25% improvement in ISSI-2. Compared with their peers, those with increases in ISSI-2 of Ն25% had greater decrements in fasting glucose (P Ͻ 0.0001), Hb A 1c (P ϭ 0.001), ALT (P ϭ 0.04), AST (P ϭ 0.02), and HOMA-IR (P Ͻ 0.0001). On logistical regression analysis, baseline Hb A 1c (OR ϭ 2.83, 95% CI 1.16 -6.88, P ϭ 0.02) and change in HOMA-IR (OR ϭ 0.008, 95%CI 0.0004 -0.16, P ϭ 0.001) emerged as independent predictors of reversibility of ␤-cell dysfunction. Indeed, reversibility of ␤-cell dysfunction was achieved in only those participants in whom IIT yielded an improvement in HOMA-IR. In conclusion, decline in HOMA-IR may be a key determinant of improvement of ␤-cell function in response to short-term IIT, suggesting a fundamental contribution of insulin resistance to the reversible component of ␤-cell dysfunction in early T2DM.intensive insulin therapy; type 2 diabetes; ␤-cell function; insulin resistance; remission THE NATURAL HISTORY OF TYPE 2 DIABETES MELLITUS (T2DM) is characterized by the progressive deterioration of pancreatic ␤-cell function over time, a pathological process that occurs irrespective of lifestyle and current pharmacological interventions (13, 32). In recent years, however, several studies have shown that temporary administration of short-term intensive insulin therapy (IIT) early in the course of T2DM can improve ␤-cell function and insulin resistance (4 -6, 17, 33). Indeed, this 2-to 4-wk treatment can induce a "glycemic remission," wherein patients are subsequently able to maintain euglycemia without antidiabetic medications for up to 2 yr (15,22,25,31).These promising effects were recently confirmed in a metaanalysis of seven studies involving Asian populations (15), which highlighted the potential of this treatment strategy and also the need for...

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OBJECTIVEIncreased glycemic variability has been reported to be associated with the risk of hypoglycemia and possibly diabetes complications and is believed to be due to b-cell dysfunction. However, it is not known whether improvement in b-cell function can reduce glycemic variability. Because short-term intensive insulin therapy (IIT) can improve b-cell function in early type 2 diabetes (T2DM), our objective was to determine whether the b-cell functional recovery induced by this therapy is associated with decreased glycemic variability. RESEARCH DESIGN AND METHODSSixty-one patients with T2DM of 3.0 years mean duration underwent 4 weeks of IIT, which consisted of basal insulin detemir and premeal insulin aspart. Glucose variability was assessed in both the first and the last week by the coefficient of variation of capillary glucose on daily 6-point self-monitoring profiles. b-Cell function before and after IIT was assessed with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). RESULTSBetween the first and the last week on IIT, 55.7% of patients had a reduction in glucose variability. Change in glucose variability was negatively correlated with the change in b-cell function (ISSI-2) (r = 20.34, P = 0.008). On multiple linear regression analyses, percentage change in ISSI-2 emerged as the only factor independently associated with the change in glucose variability (standardized b = 20.42, P = 0.03). Moreover, patients with an increase in ISSI-2 ‡25% experienced a reduction in glucose variability compared with their peers who had almost no change (20.041 6 0.06 vs. 20.0002 6 0.04, respectively; P = 0.006). CONCLUSIONSIn early T2DM, glycemic variability is a modifiable parameter that can be reduced by improving b-cell function with short-term IIT.

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