Dataset Information

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

ABSTRACT:

Objective

In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity.

Research design and methods

For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide.

Results

In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion.

Conclusions

In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

SUBMITTER: Rother KI

PROVIDER: S-EPMC2782986 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

Rother Kristina I KI Spain Lisa M LM Wesley Robert A RA Digon Benigno J BJ Baron Alain A Chen Kim K Nelson Patric P Dosch H-Michael HM Palmer Jerry P JP Brooks-Worrell Barbara B Ring Michael M Harlan David M DM

Diabetes care 20091006 12

<h4>Objective</h4>In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity.<h4>Research design and methods</h4>For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label ...[more]

PMID: 19808924

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Project description:Type 1 diabetes (T1DM) is associated with an increased fracture risk, specifically at nonvertebral sites. The influence of glycemic control and microvascular disease on skeletal health in long-standing T1DM remains largely unknown. We aimed to assess areal (aBMD) and volumetric bone mineral density (vBMD), bone microarchitecture, bone turnover, and estimated bone strength in patients with long-standing T1DM, defined as disease duration ≥25 years. We recruited 59 patients with T1DM (disease duration 37.7 ± 9.0 years; age 59.9 ± 9.9 years.; body mass index [BMI] 25.5 ± 3.7 kg/m2 ; 5-year median glycated hemoglobin [HbA1c] 7.1% [IQR 6.82-7.40]) and 77 nondiabetic controls. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT) at the ultradistal radius and tibia, and biochemical markers of bone turnover were assessed. Group comparisons were performed after adjustment for age, gender, and BMI. Patients with T1DM had lower aBMD at the hip (p < 0.001), distal radius (p = 0.01), lumbar spine (p = 0.04), and femoral neck (p = 0.05) as compared to controls. Cross-linked C-telopeptide (CTX), a marker of bone resorption, was significantly lower in T1DM (p = 0.005). At the distal radius there were no significant differences in vBMD and bone microarchitecture between both groups. In contrast, patients with T1DM had lower cortical thickness (estimate [95% confidence interval]: -0.14 [-0.24, -0.05], p < 0.01) and lower cortical vBMD (-28.66 [-54.38, -2.93], p = 0.03) at the ultradistal tibia. Bone strength and bone stiffness at the tibia, determined by homogenized finite element modeling, were significantly reduced in T1DM compared to controls. Both the altered cortical microarchitecture and decreased bone strength and stiffness were dependent on the presence of diabetic peripheral neuropathy. In addition to a reduced aBMD and decreased bone resorption, long-standing, well-controlled T1DM is associated with a cortical bone deficit at the ultradistal tibia with reduced bone strength and stiffness. Diabetic neuropathy was found to be a determinant of cortical bone structure and bone strength at the tibia, potentially contributing to the increased nonvertebral fracture risk. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Project description:AimsTo evaluate the effects of separate and combined use of the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin and the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on measures of kidney function.MethodsIn this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16-week randomized double-blind placebo-controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24-hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C-estimated glomerular filtration rate (GFR) and kidney injury molecule-1:creatinine ratio (KIM-1:Cr).ResultsAt week 16, the mean UACR change from baseline was -39.6% (95% confidence interval [CI] -58.6, -11.9; P = 0.001) in the combined exenatide-dapagliflozin group, -18.1% (95% CI -43.1, 18.0; P = 0.278) in the dapagliflozin group, -15.6% (95% CI -41.4, 21.6; P = 0.357) in the exenatide group and - 11.0% (95% CI -39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide-dapagliflozin group was -32.2% (95% CI -60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide-dapagliflozin group, an acute dip in estimated GFR was observed with creatinine-estimated GFR (-4.0 mL/min/1.73 m2 [95% CI -9.3, 1.2]; P = 0.129) and cystatin C-estimated GFR (-10.4 mL/min/1.73 m2 [95% CI -14.9, -5.8]; P < 0.001). The mean KIM-1:Cr difference in the combined treatment arm versus placebo was -43.8% (95% CI -73.5, 18.9; P = 0.129).ConclusionThis prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes.

Project description:This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1 mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55 kg for body weight. Potential treatment-by-subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least-squares mean reductions of -23.6 vs -19.0 mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0 mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9 mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range -2.56 to -3.98 kg vs -0.56 to -2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

Dataset Information

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

Objective

Research design and methods

Results

Conclusions

Publications

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

Similar Datasets

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