scholarly journals Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes

2016 ◽  
Vol 101 (11) ◽  
pp. 4421-4430 ◽  
Author(s):  
Michael R. Rickels ◽  
Amy J. Peleckis ◽  
Eileen Markmann ◽  
Cornelia Dalton-Bakes ◽  
Stephanie M. Kong ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
University Of Pennsylvania ◽  
Symptom Recognition ◽  
Endogenous Glucose ◽  
The University

Context: Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia episodes and symptom unawareness, but long-term data are lacking. Objective: To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period. Design, Setting, and Participants: Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects. Intervention: All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania. Main Outcome Measures: Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose. Results: Near-normal glycemia (HbA1c ≤ 6.5%; time 70–180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant. Conclusions: In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.

691-P: Exercise Effect on Endogenous Glucose Production in Type 1 Diabetes: A Modeling Analysis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 691-P
Author(s):  
DAVIDE ROMERES ◽  
MICHELE SCHIAVON ◽  
ROBERTO VISENTIN ◽  
ANANDA BASU ◽  
CLAUDIO COBELLI ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Modeling Analysis ◽  
Exercise Effect ◽  
Endogenous Glucose

scholarly journals Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes

2009 ◽  
Vol 94 (9) ◽  
pp. 3297-3305 ◽  
Author(s):  
Burak Salgin ◽  
Maria L. Marcovecchio ◽  
Rachel M. Williams ◽  
Sarah J. Jackson ◽  
Leslie J. Bluck ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Growth Hormone ◽  
Type 1 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Endogenous Glucose

Context: Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D. Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit. Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity. Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis. Growth hormone decreases insulin sensitivity through increases in free fatty acid levels.

scholarly journals Improvement in Insulin Sensitivity After Human Islet Transplantation for Type 1 Diabetes

2013 ◽  
Vol 98 (11) ◽  
pp. E1780-E1785 ◽  
Author(s):  
Michael R. Rickels ◽  
Stephanie M. Kong ◽  
Carissa Fuller ◽  
Cornelia Dalton-Bakes ◽  
Jane F. Ferguson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Islet Transplantation ◽  
Low Dose ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Induce Insulin Resistance ◽  
Endogenous Glucose

Context: Islet transplantation can improve metabolic control for type 1 diabetes (T1D), an effect anticipated to improve insulin sensitivity. However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents. Objective: The objective of the study was to evaluate the effect of islet transplantation on insulin sensitivity in T1D using euglycemic clamps with the isotopic dilution method to distinguish between effects at the liver and skeletal muscle. Design, Setting, and Participants: Twelve T1D subjects underwent evaluation in the Clinical and Translational Research Center before and between 6 and 7 months after the transplant and were compared with normal control subjects. Intervention: The intervention included intrahepatic islet transplantation according to a Clinical Islet Transplantation Consortium protocol under low-dose tacrolimus and sirolimus immunosuppression. Main Outcome Measures: Total body (M/Δinsulin), hepatic (1/endogenous glucose production ·basal insulin) and peripheral [(Rd − endogenous glucose production)/Δinsulin] insulin sensitivity assessed by hyperinsulinemic (1 mU·kg−1·min−1) euglycemic (∼90 mg/dL) clamps with 6,6-2H2-glucose tracer infusion were measured. Results: Glycosylated hemoglobin was reduced in the transplant recipients from 7.0% ± 0.3% to 5.6% ± 0.1% (P < .01). There were increases in total (0.11 ± 0.01 to 0.15 ± 0.02 dL/min·kg per microunit per milliliter), hepatic [2.3 ± 0.1 to 3.7 ± 0.4 × 102 ([milligrams per kilogram per minute]−1·(microunits per milliliter)−1)], and peripheral (0.08 ± 0.01 to 0.12 ± 0.02 dL/min·kg per microunit per milliliter) insulin sensitivity from before to after transplantation (P < .05 for all). All insulin sensitivity measures were less than normal in T1D before (P ≤ .05) and not different from normal after transplantation. Conclusions: Islet transplantation results in improved insulin sensitivity mediated by effects at both the liver and skeletal muscle. Modern dosing of glucocorticoid-free immunosuppression with low-dose tacrolimus and sirolimus does not induce insulin resistance in this population.

Acute, same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus

2006 ◽  
Vol 290 (6) ◽  
pp. E1331-E1338 ◽  
Author(s):  
Darleen A. Sandoval ◽  
Deanna L. Aftab Guy ◽  
M. Antoinette Richardson ◽  
Andrew C. Ertl ◽  
Stephen N. Davis
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Muscle Sympathetic Nerve Activity ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Moderate Intensity ◽  
Endogenous Glucose ◽  
Exercise Induced

Exercise-induced hypoglycemia can occur within hours after exercise in type 1 diabetes mellitus (T1DM) patients. This study tested the hypothesis that an acute exercise bout causes (within hours) blunted autonomic and metabolic responses to subsequent hypoglycemia in patients with T1DM. Twelve T1DM patients (3 W/9 M) were studied during a single-step, 2-h hyperinsulinemic (572 ± 4 pmol/l) hypoglycemic (2.8 ± 0.1 mmol/l) clamp 2 h after either a hyperinsulinemic euglycemic (AM EUG) or hypoglycemic clamp (AM HYPO) or after sitting in a chair with basal insulin infusion (AM CON) or 90 min of moderate-intensity exercise (50% V̇o2 max, AM EX). Both AM HYPO and AM EX significantly blunted epinephrine responses and muscle sympathetic nerve activity responses to subsequent hypoglycemia compared with both control groups. Endogenous glucose production was significantly lower and the exogenous glucose infusion rate needed to maintain the hypoglycemic level was significantly greater during subsequent hypoglycemia in AM EX vs. CON. Rate of glucose disposal (Rd) was significantly reduced following AM HYPO. In summary, within 2.5 h, both moderate-intensity AM EX and AM HYPO blunted key autonomic counterregulatory responses. Despite this, glucose Rdwas reduced during afternoon hypoglycemia following morning hypoglycemia, indicating posthypoglycemic insulin resistance. After morning exercise, endogenous glucose production was blunted, but glucose Rdwas maintained during afternoon hypoglycemia, thereby indicating reduced metabolic defenses against hypoglycemia. These data suggest that exercise-induced counterregulatory failure can occur very rapidly, increasing the risk for hypoglycemia in T1DM within hours.

Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

2005 ◽  
Vol 289 (2) ◽  
pp. E258-E265 ◽  
Author(s):  
Deanna Aftab Guy ◽  
Darleen Sandoval ◽  
M. A. Richardson ◽  
Donna Tate ◽  
Stephen N. Davis
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Blood Pressure Response ◽  
Severe Hypoglycemia ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Target Organ ◽  
Epinephrine Infusion ◽  
Glucose Levels

Severe hypoglycemia occurs in intensively treated patients with type 1 diabetes mellitus (T1DM) due in part to deficient epinephrine counterregulatory responses. Previously, we have found that T1DM patients demonstrated a spectrum of altered responses to epinephrine at a variety of target organs compared with nondiabetic healthy subjects. What is not known is whether intensive glycemic control further modifies target organ responses in individuals with T1DM. Therefore, the aim of this study is to assess whether there is tissue specific (liver, muscle, adipose tissue, pancreas and cardiovascular) resistance to epinephrine in intensively controlled (IC) T1DM compared with those with conventional control (CC). Eight IC patients (age 33 ± 4 yr, BMI 24 ± 2 kg/m2, Hb A1C6.7 ± 0.1%), and 11 CC patients (age 35 ± 3 yr, BMI 25 ± 1 kg/m2, Hb A1C9.6 ± 0.1%) underwent two separate randomized, single-blind, 2-h hyperinsulinemic euglycemic clamp studies with (EPI) and without (NO EPI) epinephrine infusion. Epinephrine levels during EPI were similar in all groups (5,197 ± 344 pmol/l). Glucose (5.3 ± 0.1 mmol/l) and insulin levels (515 ± 44 pmol/l) were similar in all groups during the glucose clamps. Endogenous glucose production (EGP) and glucose uptake (Rd) were determined using [3-H3]glucose. Muscle biopsy was performed at the end of each study. IC had a significantly reduced EGP and Rdresponses to EPI compared with CC. Glucagon responses to EPI were similarly blunted in both IC and CC. Free fatty acid and glycerol response to EPI was greater in CC compared with IC. There was a significantly greater systolic blood pressure response to EPI in CC. We conclude that, despite similar epinephrine, insulin, and glucose levels, intensively treated T1DM patients had reduced cardiovascular, skeletal muscle, hepatic, and adipose target organ responses to EPI compared with conventionally treated T1DM patients.

scholarly journals Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

2015 ◽  
Vol 309 (5) ◽  
pp. E474-E486 ◽  
Author(s):  
Ling Hinshaw ◽  
Ashwini Mallad ◽  
Chiara Dalla Man ◽  
Rita Basu ◽  
Claudio Cobelli ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Silico ◽  
Artificial Pancreas ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Action Model ◽  
The Difference ◽  
Hormone Control

Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia.

scholarly journals Hormone-independent activation of EGP during hypoglycemia is absent in type 1 diabetes mellitus

2000 ◽  
Vol 278 (3) ◽  
pp. E421-E429 ◽  
Author(s):  
Michèle Mevorach ◽  
Jonathan Kaplan ◽  
Chee Jen Chang ◽  
Luciano Rossetti ◽  
Harry Shamoon
Keyword(s):  
Diabetes Mellitus ◽  
Growth Hormone ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Endogenous Glucose Production ◽  
Experimental Protocol ◽  
Lower Plasma ◽  
The Face ◽  
Endogenous Glucose

It has been suggested that insulin-induced suppression of endogenous glucose production (EGP) may be counteracted independently of increased epinephrine (Epi) or glucagon during moderate hypoglycemia. We examined EGP in nondiabetic ( n = 12) and type 1 diabetic (DM1, n = 8) subjects while lowering plasma glucose (PG) from clamped euglycemia (5.6 mmol/l) to values just above the threshold for Epi and glucagon secretion (3.9 mmol/l). Individualized doses of insulin were infused to maintain euglycemia during pancreatic clamps by use of somatostatin (250 μg/h), glucagon (1.0 ng ⋅ kg− 1 ⋅ min− 1), and growth hormone (GH) (3.0 ng ⋅ kg− 1 ⋅ min− 1) infusions without need for exogenons glucose. Then, to achieve physiological hyperinsulinemia (HIns), insulin infusions were fixed at 20% above the rate previously determined for each subject. In nondiabetic subjects, PG was reduced from 5.4 ± 0.1 mmol/l to 3.9 ± 0.1 mmol/l in the experimental protocol, whereas it was held constant (5.3 ± 0.2 mmol/l and 5.5 mmol/l) in control studies. In the latter, EGP (estimated by [3-3H]glucose) fell to values 40% of basal ( P < 0.01). In contrast, in the experimental protocol, at comparable HIns but with PG at 3.9 ± 0.1 mmol/l, EGP was activated to values about twofold higher than in the euglycemic control ( P < 0.01). In DM1 subjects, EGP failed to increase in the face of HIns and PG = 3.9 ± 0.1 mmol/l. The decrease from basal EGP in DM1 subjects (4.4 ± 1.0 μmol ⋅ kg− 1 ⋅ min− 1) was nearly twofold that in nondiabetics (2.5 ± 0.8 μmol ⋅ kg− 1 ⋅ min− 1, P < 0.02). When PG was lowered further to frank hypoglycemia (∼3.1 mmol/l), the failure of EGP activation in DM1 subjects was even more profound but associated with a 50% lower plasma Epi response ( P < 0.02) compared with nondiabetics. We conclude that glucagon- or epinephrine-independent activation of EGP may accompany other counterregulatory mechanisms during mild hypoglycemia in humans and is impaired or absent in DM1.

scholarly journals Potent Induction Immunotherapy Promotes Long-Term Insulin Independence After Islet Transplantation in Type 1 Diabetes

2012 ◽  
Vol 12 (6) ◽  
pp. 1576-1583 ◽  
Author(s):  
M. D. Bellin ◽  
F. B. Barton ◽  
A. Heitman ◽  
J. V. Harmon ◽  
R. Kandaswamy ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Insulin Independence

scholarly journals Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

2020 ◽  
Author(s):  
Paola Lucidi ◽  
Paola Candeloro ◽  
Patrizia Cioli ◽  
Anna Marinelli Andreoli ◽  
Chiara Pascucci ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Steady State ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucagon Suppression ◽  
Bolus Insulin ◽  
Design And Methods ◽  
Single Blind ◽  
Randomized Crossover Study

<b>OBJECTIVE</b> <p><b> </b></p> <p>To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM).</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m<sup>2</sup>], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg<sup>-1</sup>) and <a>Deg-100 </a>(0.26±0.06 U.Kg<sup>-1</sup>), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin.</p> <p><b>RESULTS</b></p> <p>At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR<sub>(0-24h)</sub>] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92).</p> <p><b>CONCLUSIONS</b></p> <p>In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.</p>

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