scholarly journals SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants with Type 1 Diabetes

2021 ◽  
Author(s):  
Schafer C. Boeder ◽  
Justin M. Gregory ◽  
Erin R. Giovannetti ◽  
Jeremy H. Pettus
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Sglt2 Inhibitor ◽  
Treatment Phase ◽  
Glycemic Variability ◽  
Hormone Response ◽  
Double Blind ◽  
Sodium Glucose Cotransporter ◽  
Sglt2 Inhibition

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (<i>n</i> = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia, and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on alpha cell function.

scholarly journals SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants with Type 1 Diabetes

2021 ◽  
Author(s):  
Schafer C. Boeder ◽  
Justin M. Gregory ◽  
Erin R. Giovannetti ◽  
Jeremy H. Pettus
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Sglt2 Inhibitor ◽  
Treatment Phase ◽  
Glycemic Variability ◽  
Hormone Response ◽  
Double Blind ◽  
Sodium Glucose Cotransporter ◽  
Sglt2 Inhibition

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (<i>n</i> = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia, and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on alpha cell function.

β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial

The Lancet ◽  
2001 ◽  
Vol 358 (9295) ◽  
pp. 1749-1753 ◽  
Author(s):  
Itamar Raz ◽  
Dana Elias ◽  
Ann Avron ◽  
Merana Tamir ◽  
Muriel Metzger ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cell Function ◽  
Phase Ii Trial ◽  
Β Cell ◽  
Double Blind ◽  
Β Cell Function ◽  
New Onset

scholarly journals Exploring the Potential of the SGLT2 Inhibitor Dapagliflozin in Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

Diabetes Care ◽  
2014 ◽  
Vol 38 (3) ◽  
pp. 412-419 ◽  
Author(s):  
Robert R. Henry ◽  
Julio Rosenstock ◽  
Steven Edelman ◽  
Sunder Mudaliar ◽  
Alexandros-Georgios Chalamandaris ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Pilot Study ◽  
Sglt2 Inhibitor ◽  
Double Blind ◽  
Double Blind Placebo

scholarly journals Phase II multicentre, double-blind, randomised trial of ustekinumab in adolescents with new-onset type 1 diabetes (USTEK1D): trial protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. e049595
Author(s):  
John W Gregory ◽  
Kymberley Carter ◽  
Wai Yee Cheung ◽  
Gail Holland ◽  
Jane Bowen-Morris ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Research Ethics ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Double Blind ◽  
C Peptide ◽  
New Onset

IntroductionMost individuals newly diagnosed with type 1 diabetes (T1D) have 10%–20% of beta-cell function remaining at the time of diagnosis. Preservation of residual beta-cell function at diagnosis may improve glycaemic control and reduce longer-term complications.Immunotherapy has the potential to preserve endogenous beta-cell function and thereby improve metabolic control even in poorly compliant individuals. We propose to test ustekinumab (STELARA), a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta-cells in the pancreas at the time of diagnosis.Methods and analysisThis is a double-blind phase II study to assess the safety and efficacy of ustekinumab in 72 children and adolescents aged 12–18 with new-onset T1D.Participants should have evidence of residual functioning beta-cells (serum C-peptide level >0.2nmol/L in the mixed-meal tolerance test (MMTT) and be positive for at least one islet autoantibody (GAD, IA-2, ZnT8) to be eligible.Participants will be given ustekinumab/placebo subcutaneously at weeks 0, 4 and 12, 20, 28, 36 and 44 in a dose depending on the body weight and will be followed for 12 months after dose 1.MMTTs will be used to measure the efficacy of ustekinumab for preserving C-peptide area under the curve at week 52 compared with placebo. Secondary objectives include further investigations into the efficacy and safety of ustekinumab, patient and parent questionnaires, alternative methods for measuring insulin production and exploratory mechanistic work.Ethics and disseminationThis trial received research ethics approval from the Wales Research Ethics Committee 3 in September 2018 and began recruiting in December 2018.The results will be disseminated using highly accessed, peer-reviewed medical journals and presented at conferences.Trial registration numberISRCTN14274380.

scholarly journals Vildagliptin Reduces Glucagon during Hyperglycemia and Sustains Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes

2012 ◽  
Vol 97 (10) ◽  
pp. 3799-3806 ◽  
Author(s):  
Johan Farngren ◽  
Margaretha Persson ◽  
Anja Schweizer ◽  
James E. Foley ◽  
Bo Ahrén
Keyword(s):  
Type 1 Diabetes ◽  
Treatment Period ◽  
Cell Function ◽  
Glycosylated Hemoglobin ◽  
Glucagon Secretion ◽  
Double Blind ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitor ◽  
Respective Treatment

Abstract Context: The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes. Objective: The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D). Patients and Methods: The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D [21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%)]. Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter. Main Outcome Measure: The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165–195 of the test) was measured. Results: During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curveglucagon 2.4 ± 0.2 vs. 2.6 ± 0.2 nmol/liter × minutes, P = 0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5 ± 1.0 pmol/liter with vildagliptin vs. 1.7 ± 0.8 pmol/liter with placebo, P = NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo [between group difference was −3.4 ± 1.0 mmol/mol (−0.32 ± 0.09%; P = 0.002)] from baseline of 57.9 mmol/mol (7.5%). Conclusions: Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D.

scholarly journals Effects ofLactobacillus rhamnosusGG andBifidobacterium lactisBb12 on beta-cell function in children with newly diagnosed type 1 diabetes: protocol of a randomised controlled trial

BMJ Open ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. e017178 ◽  
Author(s):  
Lidia Groele ◽  
Hania Szajewska ◽  
Agnieszka Szypowska
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Controlled Trial ◽  
Lactobacillus Rhamnosus ◽  
Newly Diagnosed ◽  
Double Blind

IntroductionRecent evidence has demonstrated that, among other factors, dysbiosis (imbalances in the composition and function of the gut microbiota) may be relevant in the development of type 1 diabetes (T1D). Thus, gut microbiota may be a target for improving outcomes in subjects with T1D. The aim of the study is to examine the effects ofLactobacillus rhamnosusGG andBifidobacterium lactisBb12 on beta-cell function in children with newly diagnosed T1D.Methods and analysisA total of 96 children aged 8 to 17 years with newly diagnosed T1D, confirmed by clinical history and the presence of at least one positive autoantibody, will be enrolled in a double-blind, randomised, placebo-controlled trial in which they will receiveL. rhamnosusGG andB. lactisBb12 at a dose of 109colony-forming units or an identically appearing placebo, orally, once daily, for 6 months. The follow-up will be for 12 months. The primary outcome measures will be the area under the curve of the C-peptide level during 2-hour responses to a mixed meal.Ethics and disseminationThe Bioethics Committee approved the study protocol. The findings of this trial will be submitted to a peer-reviewed paediatric journal. Abstracts will be submitted to relevant national and international conferences.Trial registration numberNCT03032354; Pre-results.

scholarly journals Integration of Routine Parameters of Glycemic Variability in a Simple Screening Method for Partial Remission in Children with Type 1 Diabetes

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Nina Nielens ◽  
Olivier Pollé ◽  
Annie Robert ◽  
Philippe A. Lysy
Keyword(s):  
Type 1 Diabetes ◽  
Partial Remission ◽  
Cell Function ◽  
Screening Method ◽  
Glycemic Variability ◽  
Clinical Feature ◽  
Alternative Formula ◽  
Definition Of ◽  
Glycemic Target

Although different criteria were used to define partial remission in type 1 diabetes, the IDAA1C formula has prevailed as it correlates with stimulated C-peptide levels. Our retrospective study evaluated clinical variables associated with the occurrence of IDAA1C-defined partial remission in a series of 239 pediatric patients. Diabetic ketoacidosis and age at diagnosis, but no other clinical feature, influenced the occurrence of remission. We then evaluated whether parameters of glycemic variability used in clinical routine may reliably define partial remission, as these would alleviate confounding factors related to insulin treatment. Using multiple linear regression, we observed that HbA1C levels and percentage of normoglycemia were efficient and sufficient to predict partial remission. These parameters were entered into a formula, called glycemic target-adjusted HbA1C (GTAA1C), that corresponded to HbA1C(%) − (3 × % of normoglycemic values(70–180 mg/dL)). With a threshold of 4.5, this alternative formula predicted partial remission with a sensitivity and a specificity of 72.3% and 92%, respectively, and yielded strong correlation with IDAA1C levels and BETA-2 score, which is a correlate of β-cell function after islet transplantation. We propose GTAA1C, based on routine and objective markers of glycemic variability, as a valid alternative for definition of partial remission in type 1 diabetes.

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