INTERMITTENT INTENSIVE INSULIN THERAPY FOR TYPE 2 DIABETES: EFFECTS ON HYPOGLYCEMIA, WEIGHT GAIN, AND QUALITY OF LIFE OVER 2 YEARS.

Objective: In early type 2 diabetes (T2DM), the administration of short-term intensive insulin therapy (IIT) can induce glycemic remission for a year thereafter, but this effect ultimately wanes. In this context, intermittently repeating short-term IIT could provide a strategy for maintaining the otherwise transient benefits of this intervention. However, the viability of this strategy would be contingent upon not inducing undesirable effects of insulin therapy such as excessive hypoglycemia and fat deposition. We thus sought to evaluate the effect of administering short-term IIT every 3 months on hypoglycemia, weight gain, and quality of life in early T2DM. Methods: In this 2-year pilot trial, 24 adults with T2DM of 2.0 ± 1.7 years duration and hemoglobin A1c of 6.4 (46 mmol/mol) ± 0.1% were randomized to 3 weeks of IIT (glargine, lispro) followed by either (1), repeat IIT for up to 2 weeks every 3 months or (2), daily metformin. IIT was titrated to target near-normoglycemia (premeal glucose 4 to 6 mmol/L; 2-hour postmeal <8 mmol/L). Participants were assessed every 3 months, with quality of life (QOL) evaluated annually. Results: The rate of hypoglycemia (<3.5 mmol/L) was low in the metformin and intermittent IIT arms (0.37 versus 0.95 events per patient-year; P = .28). There were no differences between the groups in changes over time in overall, central, or hepatic fat deposition (as reflected by weight [P = .10], waist-to-hip ratio [P = .58], and alanine aminotransferase [P = .64], respectively). Moreover, there were no differences between the groups in QOL at 1- and 2-years. Conclusion: Intermittent short-term IIT may be safely administered in early T2DM without excessive adverse impact on hypoglycemic risk, anthropometry, or QOL. Abbreviations: ALT = alanine aminotransferase; HbA1c = hemoglobin A1c; IIT = intensive insulin therapy; ISSI-2 = insulin secretion-sensitivity index-2; OGTT = oral glucose tolerance test; QOL = quality of life; SF-36 = medical outcomes study 36-item short-form health survey; T2DM = type 2 diabetes.

Effect of chronic liraglutide therapy and its withdrawal on time to postchallenge peak glucose in type 2 diabetes.

Delayed timing of peak serum glucose following an oral glucose challenge can predict declining ß-cell function and worsening glucose tolerance over time. Accordingly, postchallenge peak glucose is typically delayed in patients with type 2 diabetes (T2DM). However, little is known about the capacity of antidiabetic medications to reverse this delay. Thus, we sought to evaluate the effect of the glucagon-like peptide-1 agonist liraglutide on time to peak glucose in early T2DM. In this secondary analysis of a double-blind placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 yr duration were randomized to daily subcutaneous liraglutide or placebo injection for 48 wk, with oral glucose tolerance test (OGTT) performed every 12 wk while on therapy and after a 2-wk washout. On each OGTT, time to peak glucose was determined from venous glucose measurements at 0, 10, 20, 30, 60, 90, and 120 min. At randomization, most patients in both arms exhibited peak glucose at 90 min postchallenge. By 12 wk, 65.4% of the liraglutide arm had shifted to an earlier peak (vs. 36% on placebo; P = 0.19), with little change thereafter at 24, 36, and 48 wk. After the 2-wk washout, however, 57.7% of those who had been on liraglutide reverted to a later peak (vs. 4.5% on placebo; P < 0.001). This shift was associated with declining ß-cell function ( P = 0.001), resulting in higher 2-h blood glucose at washout in the liraglutide arm compared with placebo ( P = 0.001). Thus, although liraglutide possibly might improve the delay in peak glucose, its cessation yielded a worsening thereof and higher glycemia. The mechanisms underlying these observations and their clinical implications warrant further investigation.

Two-year trial of intermittent insulin therapy vs metformin for the preservation of ß-cell function after initial short-term intensive insulin induction in early type 2 diabetes.

AIMS: To test the hypothesis that "induction" intensive insulin therapy (IIT) needs to be followed by "maintenance therapy" to preserve ß-cell function, and to evaluate the impact on ß-cell function over 2 years of two approaches to maintenance therapy: intermittent short-term IIT every 3 months vs daily metformin. MATERIALS AND METHODS: In this trial, 24 adults with a mean type 2 diabetes mellitus (T2DM) duration of 2.0 ± 1.7 years and glycated haemoglobin (HbA1c) levels 6.4 ± 0.1% (46 ± 1.1mmol/mol) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by either repeat IIT for up to 2 weeks every 3 months or daily metformin. Participants underwent serial assessment of ß-cell function using the Insulin Secretion-Sensitivity Index-2 (ISSI-2) on an oral glucose tolerance test every 3 months. RESULTS: The primary outcome of baseline-adjusted ISSI-2 at 2 years was higher in the metformin arm compared with intermittent IIT (245.0 ± 31.7 vs 142.2 ± 18.4; P = .008). Baseline-adjusted HbA1c at 2 years (secondary outcome) was lower in the metformin arm (6.0 ± 0.2% vs 7.3 ± 0.2%; P = .0006) (42 ± 2.2 vs 56 ± 2.2mmol/mol). At study completion, 66.7% of participants randomized to metformin had an HbA1c concentration ≤ 6.0% (≤42mmol/mol), compared with 8.3% of those on intermittent IIT (P = .009). There were no differences in insulin sensitivity. CONCLUSION: After induction IIT, metformin was superior to intermittent IIT for maintaining ß-cell function and glycaemic control over 2 years. The strategy of induction and maintenance therapy to preserve ß-cell function warrants exploration in early T2DM.

Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUCGLP-1 at 12 weeks ( P < .001), 24 weeks ( P < .001), 36 weeks ( P = .03) and 48 weeks ( P = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology.

Determinants of reversibility of ß-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes.

Short-term intensive insulin therapy (IIT) can improve pancreatic ß-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 ß-cell function in response to short-term IIT in early T2DM. Sixty-three patients with mean 3.0 ± 2.1 yr duration of T2DM and Hb A1c of 6.8 ± 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. ß-Cell function before and after IIT was assessed by Insulin Secretion Sensitivity Index-2 (ISSI-2). Reversibility of ß-cell dysfunction was defined as percentage change in ISSI-2 of ≥25%. Overall, the study population experienced an increase in ISSI-2 from baseline to post-IIT (P = 0.01), with one-third of participants achieving ≥25% improvement in ISSI-2. Compared with their peers, those with increases in ISSI-2 of ≥25% had greater decrements in fasting glucose (P < 0.0001), Hb A1c (P = 0.001), ALT (P = 0.04), AST (P = 0.02), and HOMA-IR (P < 0.0001). On logistical regression analysis, baseline Hb A1c (OR = 2.83, 95% CI 1.16-6.88, P = 0.02) and change in HOMA-IR (OR = 0.008, 95%CI 0.0004-0.16, P = 0.001) emerged as independent predictors of reversibility of ß-cell dysfunction. Indeed, reversibility of ß-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 ß-cell function in response to short-term IIT, suggesting a fundamental contribution of insulin resistance to the reversible component of ß-cell dysfunction in early T2DM.

Impact of the Glucagon Assay When Assessing the Effect of Chronic Liraglutide Therapy on Glucagon Secretion.

Context: Glucagon-like peptide-1 agonists acutely lower serum glucagon. However, in the Liraglutide and ß-Cell Repair (LIBRA) Trial, 48-week treatment with liraglutide yielded lower/unchanged fasting glucagon but, surprisingly, enhanced postchallenge glucagonemia [measured by R&D Systems (Minneapolis, MN) assay]. Objective: Because differences between glucagon assays potentially could explain these unexpected findings, we have remeasured glucagon in all 1222 samples from this trial using the highly-sensitive/specific Mercodia assay to compare the findings between assays. Design/Setting/Participants/Intervention: In LIBRA, 51 patients with type 2 diabetes of 2.6 ± 1.9 years duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial oral glucose tolerance test (OGTT) every 12 weeks (with liraglutide/placebo last administered ∼24 hours earlier). Outcome: Serum glucagon was measured every 30 minutes on each OGTT, enabling determination of the area under the glucagon curve (AUCglucagon). Results: With the Mercodia assay, fasting glucagon was higher in the liraglutide arm than placebo at 12 weeks (P = 0.01), with no between-group differences at 24, 36, and 48 weeks. There was no difference in AUCglucagon between the groups at any visit. Mercodia and R&D Systems glucagon measurements correlated at postchallenge time points but not at fasting. Conclusion: The Mercodia assay did not replicate the R&D Systems glucagon findings. Although neither assay demonstrated lower postchallenge glucagonemia with chronic liraglutide last administered ∼24 hours earlier, the differential response reported by these assays precludes definitive conclusion and highlights the critical role of assay selection when measuring glucagon in clinical studies.

Predictors of sustained drug-free diabetes remission over 48†weeks following short-term intensive insulin therapy in early type 2 diabetes.

OBJECTIVE: In early type 2 diabetes (T2DM), short-term intensive insulin therapy (IIT) for 2-4 weeks can decrease insulin resistance, reduce glucagonemia, improve ß-cell function, and even induce a remission of diabetes that can last up to 1 year in some patients. However, little is known about the predictors of such a sustained remission. METHODS: We evaluated data from the placebo arm of a double-blind randomized controlled trial in which patients with early T2DM (≤7 years duration) underwent 4 weeks of IIT (basal detemir, bolus aspart), followed by placebo therapy for 48 weeks (n=25). Participants underwent an oral glucose tolerance test every 12 weeks, enabling serial assessment of insulin sensitivity, α-cell response, and ß-cell function. Diabetes remission was defined as A1c<6.5% on no medication for T2DM. RESULTS: At 48 weeks post-IIT, 56% of the participants remained in remission. Comparison of remitters to non-remitters revealed no differences in waist, body mass index, insulin sensitivity (Matsuda index), or glucagon profile, either at baseline or over 48 weeks. Compared to non-remitters, the remission group had lower baseline A1c (p=0.006) and better baseline ß-cell function (Insulin Secretion-Sensitivity Index-2) (p=0.01) that was then sustained across 48 weeks post-IIT (p=0.006). On logistic regression analyses, however, shorter duration of diabetes supplanted baseline A1c (p=0.24) and ß-cell function (p=0.19) as an independent predictor of remission (p=0.04). In particular, diabetes duration <2 years predicted persistence of remission (p=0.006). CONCLUSIONS: The key determinant of the likelihood of inducing sustained drug-free diabetes remission with short-term IIT is early intervention, particularly within the first 2 years after diagnosis. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov NCT01270789; Post-results.

Effect of Short-term Intensive Insulin Therapy on Post-challenge Hyperglucagonemia in Early Type 2 Diabetes.

CONTEXT: Hyperglucagonemia is a characteristic feature of type 2 diabetes (T2DM) that has been postulated to be due to ß-cell dysfunction and the resultant loss of insulin-mediated α-cell suppression. When administered in early T2DM, short-term intensive insulin therapy (IIT) can improve ß-cell function, resulting in reduced glycemic variability. OBJECTIVE: To evaluate the impact of IIT on hyperglucagonemia and its associations with ß-cell function and glycemic variability. Design/Setting/Participants/Intervention: Sixty-two patients with T2DM of mean 3.0 ± 2.1 years duration and glycated hemoglobin of 6.8 ± 0.7% underwent 4 weeks of IIT, consisting of basal detemir and premeal insulin aspart. MAIN OUTCOME MEASURES: Glucagon response was measured by area under the glucagon curve (AUCglucagon) on oral glucose tolerance test at baseline and 1 day post-IIT. ß-Cell function before and after IIT was assessed by Insulin Secretion-Sensitivity Index-2 and ΔISR0-120/Δglucose0-120*Matsuda index (where ISR is the prehepatic insulin secretion rate determined by C-peptide deconvolution). Glucose variability was assessed in both the first and last weeks by the coefficient of variation of capillary glucose on daily six-point self-monitoring profiles. RESULTS: Both Insulin Secretion-Sensitivity Index-2 and ΔISR0-120/Δglucose0-120*Matsuda index demonstrated improvement in ß-cell function after IIT (both P ≤ .02), accompanied by reduced glycemic variability (P = .05). There was a marked reduction in AUCglucagon after IIT, as compared to baseline (P < .001). However, the decrease in AUCglucagon was not associated with the change in either ß-cell measure (both P ≥ .34) or glucose variability (P = .37). CONCLUSIONS: Short-term IIT can reduce post-challenge hyperglucagonemia in early T2DM, but this effect does not appear to be due to improved ß-cell function.

The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in Type 2 Diabetes: Insight From the LIBRA Trial.

CONTEXT: In patients with type 2 diabetes (T2DM), impaired suppression of postprandial glucagonemia is a metabolic defect that contributes to hyperglycemia. Treatment with a glucagon-like peptide-1 agonist can reduce hyperglucagonemia in the acute setting, but little is known about the durability of this effect with long-term treatment. OBJECTIVE: The purpose of this study was to evaluate the impact of chronic liraglutide therapy on glucagon regulation in early T2DM. Design/Setting/Participants/Intervention: In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration were randomized to either daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial assessment of the glucose, insulin, C-peptide, and glucagon responses to a 75-g oral glucose tolerance test every 12 weeks. MAIN OUTCOME MEASURES: The glucagon response was assessed with the incremental area under the glucagon curve (iAUCglucagon) from measurements at 0, 30, 60, 90, and 120 minutes on each oral glucose tolerance test. RESULTS: As expected, compared with placebo, liraglutide induced a robust enhancement of the postchallenge insulin and C-peptide response at each of the 12-, 24-, 36-, and 48-week time points, with a concomitant reduction in glycemic excursion. However, liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12 weeks and persisted over the 48-week treatment period. Indeed, baseline-adjusted iAUCglucagon was significantly higher in the liraglutide group compared with placebo at 12 weeks (170.2 ± 34.9 vs 65.4 ± 36.4 pg/mL · 2 hours, P = .04), 36 weeks (162.2 ± 27.9 vs 55.7 ± 30.4 pg/mL · 2 hours, P = .01), and 48 weeks (155.5 ± 26.5 vs 45.7 ± 27.0 pg/mL · 2 hours, P = .006). CONCLUSION: In contrast to its acute glucagon-lowering effect, chronic treatment with liraglutide is associated with increased postchallenge hyperglucagonemia in patients with early T2DM.

Liraglutide and the preservation of pancreatic ß-cell function in early type 2 diabetes: the LIBRA trial.

OBJECTIVE: Clinical studies evaluating the effects of medications on ß-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of ß-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 ß-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT. RESEARCH DESIGN AND METHODS: In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration and an A1C of 6.8 ± 0.8% (51 ± 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of ß-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks. RESULTS: The primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 ± 27.8 vs. 229.3 ± 28.4, P = 0.008). Baseline-adjusted HbA1c at 48 weeks was lower in the liraglutide group (6.2 ± 0.1% vs. 6.6 ± 0.1%, P = 0.055) (44 ± 1.1 vs. 49 ± 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA1c ≤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 ± 24.7 vs. 238.1 ± 25.2, P = 0.20). CONCLUSIONS: Liraglutide provides robust enhancement of ß-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.

Emerging parameters of the insulin and glucose response on the oral glucose tolerance test: reproducibility and implications for glucose homeostasis in individuals with and without diabetes.

AIMS: Recent studies have suggested that novel parameters of the insulin and glucose response on the oral glucose tolerance test (OGTT) can provide metabolic insight beyond glucose tolerance, but have not evaluated their reproducibility. Thus, our aim was to evaluate the reproducibility of these parameters and, if confirmed, characterize their clinical/pathophysiologic relevance in healthy and diabetic individuals. METHODS: Thirty healthy adults each underwent 3 replicate OGTTs, enabling assessment of the reproducibility of the following 5 parameters: time to insulin peak, shape of the glucose curve, glucose nadir below baseline, 1-h post-challenge glucose, and time to glucose peak. The only reproducible parameter was then further evaluated in 63 patients with early type 2 diabetes (T2DM) before and after 4-weeks of intensive insulin therapy (IIT) designed to improve beta-cell function (measured by Insulin Secretion-Sensitivity-Index-2 (ISSI-2)). RESULTS: Of the five parameters, only time to glucose peak displayed reliable reproducibility on replicate testing (κ=0.76). Over 80% of controls had their glucose peak at 30-min post-load, whereas all but one of the diabetic patients had their peak at 60-min or later. ISSI-2 was lower in T2DM patients with peak at ≥90-min than in those with peak at ≤60-min (P=0.012). In patients in whom IIT improved beta-cell function by ≥20% from baseline, 39.1% had glucose peak on the post-therapy OGTT shift to an earlier timepoint, as compared to 15.4% with similar shift in those without such improvement(P=0.03). CONCLUSION: Time to glucose peak is a reproducible characteristic on the OGTT and associated with beta-cell function in early T2DM.

Glycemic variability in patients with early type 2 diabetes: the impact of improvement in ß-cell function.

OBJECTIVE Increased glycemic variability has been reported to be associated with the risk of hypoglycemia and possibly diabetes complications and is believed to be due to ß-cell dysfunction. However, it is not known whether improvement in ß-cell function can reduce glycemic variability. Because short-term intensive insulin therapy (IIT) can improve ß-cell function in early type 2 diabetes (T2DM), our objective was to determine whether the ß-cell functional recovery induced by this therapy is associated with decreased glycemic variability. RESEARCH DESIGN AND METHODS Sixty-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. ß-Cell function before and after IIT was assessed with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). RESULTS Between 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 ß-cell function (ISSI-2) (r = -0.34, 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 ß = -0.42, 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 (-0.041 ± 0.06 vs. -0.0002 ± 0.04, respectively; P = 0.006). CONCLUSIONS In early T2DM, glycemic variability is a modifiable parameter that can be reduced by improving ß-cell function with short-term IIT.