Contribution of pancreatic α‐cell function to insulin sensitivity and glycemic variability in patients with type 1 diabetes

Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes.

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

10.2337/figshare.17064497 ◽

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 (n = 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.

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358-OR: ß-Cell Function and Insulin Sensitivity with Islet Alone and Islet-after-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation (CIT) Consortium

Diabetes ◽

10.2337/db20-358-or ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 358-OR

Author(s):

MICHAEL R. RICKELS ◽

THOMAS EGGERMAN ◽

LEVENT BAYMAN ◽

JULIE QIDWAI ◽

JOSEPH NAJI ◽

...

Keyword(s):

Type 1 Diabetes ◽

Kidney Transplantation ◽

Insulin Sensitivity ◽

Islet Transplantation ◽

Cell Function ◽

Clinical Islet Transplantation

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

Journal of Diabetes Research ◽

10.1155/2018/5936360 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 1

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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Post-exercise glycemic control in type 1 diabetes is associated with residual ꞵ-cell function

10.2337/figshare.12616118 ◽

2020 ◽

Author(s):

Guy S Taylor ◽

Kieran Smith ◽

Tess E Capper ◽

Jadine H Scragg ◽

Ayat Bashir ◽

...

Keyword(s):

Type 1 Diabetes ◽

Acute Exercise ◽

Cell Function ◽

Glycemic Variability ◽

Free Living ◽

Continuous Glucose Monitor ◽

Post Exercise ◽

C Peptide ◽

The Impact

Objective To investigate the impact of residual ꞵ-cell function on continuous glucose monitor (CGM) outcomes following acute exercise in people with Type 1 diabetes. Research Design and Methods Thirty participants with type 1 diabetes for ≥3 years were recruited. Firstly, participants wore a blinded CGM for 7 days of free-living data capture. Secondly, a 3 hour mixed meal test, assessed stimulated C-peptide and glucagon. Peak C-peptide was used to allocate participants into undetectable (Cpepund <3 pmol/L), low (Cpeplow 3–200 pmol/L) or high C-peptide groups (Cpephigh >200 pmol/L). Finally, participants completed 45 minutes of incline treadmill walking at 60%VO2peak followed by a further 48 hours’ CGM capture. Results CGM parameters were comparable across groups during the free-living observation week. In the 12 (12hr) and 24 hours (24hr) post-exercise periods the Cpephigh group had significantly greater amount of time spent with glucose 3.9-10 mmol/L (12hr: 73.5±27.6%, 24hr: 76.3±19.2%) compared to Cpeplow (12hr: 43.6±26.1%, p=0.027, 24hr: 52.3±25.0%, p=0.067) or Cpepund (40.6±17.0%, p=0.010, 24hr: 51.3±22.3%, p=0.041). Time spent in hyperglycemia (12hr and 24hr glucose >10 and >13.9 mmol/L, p<0.05) and glycemic variability (12hr and 24hr SD, p<0.01) were significantly lower in the Cpephigh group compared to Cpepund and Cpeplow. Change in CGM outcomes from pre to 24hr post-exercise was divergent: Cpepund and Cpeplow experienced worsening (glucose 3.9-10 mmol/L: -9.1% and -16.2% respectively), with Cpephigh experiencing improvement (+12.1%)(p=0.017). Conclusions Residual ꞵ-cell function may partially explain the inter-individual variation in the acute glycemic benefits of exercise in individuals with type 1 diabetes. Quantifying C-peptide could aid in providing personalized and targeted support for exercising patients.

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Early impairment of insulin sensitivity, β-cell responsiveness, and insulin clearance in youth with Stage 1 type 1 diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab344 ◽

2021 ◽

Author(s):

Alfonso Galderisi ◽

Antoinette Moran ◽

Carmella Evans-Molina ◽

Mariangela Martino ◽

Nicola Santoro ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Plasma Insulin ◽

Cell Function ◽

Insulin Clearance ◽

Fasting Insulin ◽

Β Cell ◽

Stage 1

Abstract Background Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). The metabolic phenotypes of beta-cell function and insulin sensitivity and clearance were explored in normoglycemic youth with Stage 1 T1D and compared to healthy non-related peers during a 3-h oral glucose tolerance test (OGTT). Methods Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-h 9-point OGTT with measurement of glucose, C-peptide and insulin. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI= φtotal x SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while post-load clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-h OGTT (ISRAUC/IAUC). Subjects with impaired fasting glucose, impaired glucose tolerance or any OGTT glucose concentration ≥200mg/dL were excluded. Results Cases (10.5y [8, 15]) exhibited reduced DI (p<0.001) due to a simultaneous reduction in both φtotal (p<0.001) and SI (p=0.008) compared to controls (11.5y [10.4, 14.9]). CL0 and CL180 were lower in cases than controls (p=0.005 and p=0.019). Conclusion Pre-symptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.

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

10.2337/figshare.17064497.v1 ◽

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 (n = 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.

Download Full-text

Post-exercise glycemic control in type 1 diabetes is associated with residual ꞵ-cell function

10.2337/figshare.12616118.v1 ◽

2020 ◽

Author(s):

Guy S Taylor ◽

Kieran Smith ◽

Tess E Capper ◽

Jadine H Scragg ◽

Ayat Bashir ◽

...

Keyword(s):

Type 1 Diabetes ◽

Acute Exercise ◽

Cell Function ◽

Glycemic Variability ◽

Free Living ◽

Continuous Glucose Monitor ◽

Post Exercise ◽

C Peptide ◽

The Impact

Objective To investigate the impact of residual ꞵ-cell function on continuous glucose monitor (CGM) outcomes following acute exercise in people with Type 1 diabetes. Research Design and Methods Thirty participants with type 1 diabetes for ≥3 years were recruited. Firstly, participants wore a blinded CGM for 7 days of free-living data capture. Secondly, a 3 hour mixed meal test, assessed stimulated C-peptide and glucagon. Peak C-peptide was used to allocate participants into undetectable (Cpepund <3 pmol/L), low (Cpeplow 3–200 pmol/L) or high C-peptide groups (Cpephigh >200 pmol/L). Finally, participants completed 45 minutes of incline treadmill walking at 60%VO2peak followed by a further 48 hours’ CGM capture. Results CGM parameters were comparable across groups during the free-living observation week. In the 12 (12hr) and 24 hours (24hr) post-exercise periods the Cpephigh group had significantly greater amount of time spent with glucose 3.9-10 mmol/L (12hr: 73.5±27.6%, 24hr: 76.3±19.2%) compared to Cpeplow (12hr: 43.6±26.1%, p=0.027, 24hr: 52.3±25.0%, p=0.067) or Cpepund (40.6±17.0%, p=0.010, 24hr: 51.3±22.3%, p=0.041). Time spent in hyperglycemia (12hr and 24hr glucose >10 and >13.9 mmol/L, p<0.05) and glycemic variability (12hr and 24hr SD, p<0.01) were significantly lower in the Cpephigh group compared to Cpepund and Cpeplow. Change in CGM outcomes from pre to 24hr post-exercise was divergent: Cpepund and Cpeplow experienced worsening (glucose 3.9-10 mmol/L: -9.1% and -16.2% respectively), with Cpephigh experiencing improvement (+12.1%)(p=0.017). Conclusions Residual ꞵ-cell function may partially explain the inter-individual variation in the acute glycemic benefits of exercise in individuals with type 1 diabetes. Quantifying C-peptide could aid in providing personalized and targeted support for exercising patients.

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Abstract #797385: Glycemic Variability Measures and Impact on Patients with Type 1 Diabetes in Research and Practice

Endocrine Practice ◽

10.1016/s1530-891x(20)39462-3 ◽

2020 ◽

Vol 26 ◽

pp. 94-95

Author(s):

Jeff Frimpter

Keyword(s):

Type 1 Diabetes ◽

Glycemic Variability ◽

Research And Practice

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