scholarly journals Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin

2016 ◽  
Vol 101 (4) ◽  
pp. 1798-1806 ◽  
Author(s):  
Anna Vanderheiden ◽  
Lindsay B. Harrison ◽  
Jeremy T. Warshauer ◽  
Beverley Adams-Huet ◽  
Xilong Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Treatment ◽  
Glycosylated Hemoglobin ◽  
Challenge Test ◽  
Glucagon Secretion ◽  
Mechanisms Of Action ◽  
High Dose ◽  
C Peptide

Abstract Context: The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied. Objective: To evaluate changes in β-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin. Design: A single-center, randomized, double-blind, placebo-controlled trial. Setting: University of Texas Southwestern and Parkland Memorial Hospital clinics. Patients: Seventy-one patients with long-standing (median, 17 years) T2D requiring high-dose insulin treatment (>1.5 U/kg/d; average, 2.2 ± 0.9 U/kg/d). Intervention: Patients were randomized to liraglutide 1.8 mg/d or matching placebo for 6 months. Main Outcome Measures: We measured changes in insulin and glucagon secretion using a 4-hour mixed-meal challenge test. Magnetic resonance-based techniques were used to estimate sc and visceral fat in the abdomen and ectopic fat in the liver and pancreas. Results: Glycosylated hemoglobin improved significantly with liraglutide treatment, with an end-of-trial estimated treatment difference between groups of −0.9% (95% confidence interval, −1.5, −0.4%) (P = .002). Insulin secretion improved in the liraglutide group vs placebo, as measured by the area under the curve of C-peptide (P = .002) and the area under the curves ratio of C-peptide to glucose (P = .003). Insulin sensitivity (Matsuda index) and glucagon secretion did not change significantly between groups. Liver fat and sc fat decreased in the liraglutide group vs placebo (P = .0006 and P = .01, respectively), whereas neither visceral nor pancreatic fat changed significantly. Conclusions: Treatment with liraglutide significantly improved insulin secretion, even in patients with long-standing T2D requiring high-dose insulin treatment. Liraglutide also decreased liver and sc fat, but it did not alter glucagon secretion.

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

2007 ◽  
Vol 292 (6) ◽  
pp. E1775-E1781 ◽  
Author(s):  
Kenneth Cusi ◽  
Sangeeta Kashyap ◽  
Amalia Gastaldelli ◽  
Mandeep Bajaj ◽  
Eugenio Cersosimo
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Family History ◽  
Second Phase ◽  
Β Cell ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
History Of ◽  
Plasma Ffa

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

scholarly journals Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes

2009 ◽  
Vol 94 (1) ◽  
pp. 81-88 ◽  
Author(s):  
David A. D'Alessio ◽  
Amanda M. Denney ◽  
Linda M. Hermiller ◽  
Ronald L. Prigeon ◽  
Julie M. Martin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Cell Function ◽  
Glycosylated Hemoglobin ◽  
Fasting Blood Glucose ◽  
Dipeptidyl Peptidase ◽  
Islet Function ◽  
C Peptide ◽  
Dipeptidyl Peptidase 4

Abstract Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. Objective: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. Design: We conducted a randomized, double-blind, placebo-controlled trial. Setting: The study was performed in General Clinical Research Centers at two University Hospitals. Subjects: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2–7.5%. Intervention: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. Results: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P &lt; 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023). Conclusion: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

scholarly journals The association of anthropometric parameters with markers of insulin and leptin secretion and resistance in type 2 diabetes mellitus

2020 ◽  
Vol 28 (3) ◽  
pp. 299-314
Author(s):  
Simona Cernea ◽  
Emőke Both ◽  
Adriana Fodor
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Diabetes Duration ◽  
Leptin Resistance ◽  
Anthropometric Parameters ◽  
C Peptide

AbstractAim: We evaluated the association between anthropometric parameters and markers of insulin and leptin secretion/resistance in patients with type 2 diabetes mellitus (T2DM).Material and methods: This post-hoc data analysis from a cross-sectional study included 176 T2DM patients. Laboratory tests (serum leptin, soluble form of leptin receptor (sObR), C peptide, glycemic and lipid parameters) and anthropometric parameters were obtained, adiposity indexes (including body adiposity index (BAI), visceral adiposity index (VAI)), indicators of insulin resistance, β-cell function, and leptin resistance (Free Leptin Index, FLI) were calculated.Results: The body mass index (BMI), diabetes duration, VAI and leptin correlated independently with HOMA-IR, while BMI, diabetes duration and HbA1c with HOMA-B. The total body fat mass (TBFM), C peptide, diabetes duration, BMI and BAI correlated with leptin concentrations, while the first three with FLI. VAI was an indicator of insulin resistance (β=0.166, p=0.003), while BAI of leptin secretion (β=0.260, p=0.010). TBFM strongly associated with leptin resistance and secretion (β=0.037, r=0.688, p<0.0001, and β=0.521, r=0.667, p<0.0001), and BMI correlated weakly with insulin secretion and resistance. While insulin and leptin secretion increased progressively with BMI, leptin and insulin resistance became significant only in case of obesity. The sObR was significantly associated with C peptide concentrations (β=-0.032; p=0.044), but not with HOMA-B or -IR. A strong positive correlation between the C peptide/leptin ratio and non-fat mass /TBFM ratio was noted (r=0.62 [0.52, 0.71], p<0.0001).Conclusions: Parameters of peripheral adiposity correlated better with markers of leptin system, and those of visceral adiposity with markers of insulin secretion/resistance. The sObR correlated independently and negatively with C peptide.

scholarly journals Decrement of postprandial insulin secretion determines the progressive nature of type-2 diabetes

2006 ◽  
Vol 155 (4) ◽  
pp. 615-622 ◽  
Author(s):  
Wan Sub Shim ◽  
Soo Kyung Kim ◽  
Hae Jin Kim ◽  
Eun Seok Kang ◽  
Chul Woo Ahn ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Diabetic Patients ◽  
Β Cell ◽  
Type 2 Diabetic Patients ◽  
C Peptide ◽  
Duration Of Diabetes ◽  
Type 2 Diabetic ◽  
Postprandial Insulin

Objective: Type-2 diabetes is a progressive disease. However, little is known about whether decreased fasting or postprandial pancreatic β-cell responsiveness is more prominent with increased duration of diabetes. The aim of this study was to evaluate the relationship between insulin secretion both during fasting and 2 h postprandial, and the duration of diabetes in type-2 diabetic patients. Design: Cross-sectional clinical investigation. Methods: We conducted a meal tolerance test in 1466 type-2 diabetic patients and calculated fasting (M0) and postprandial (M1) β-cell responsiveness. Results: The fasting C-peptide, postprandial C-peptide, M0, and M1 values were lower, but HbA1c values were higher, in patients with diabetes duration > 10 years than those in other groups. There was no difference in the HbA1c levels according to the tertiles of their fasting C-peptide level. However, in a group of patients with highest postprandial C-peptide tertile, the HbA1c values were significantly lower than those in other groups. After adjustment of age, sex, and body mass index (BMI), the duration of diabetes was found to be negatively correlated with fasting C-peptide (γ = −0.102), postprandial C-peptide (γ = −0.356), M0 (γ = −0.263), and M1 (γ = −0.315; P < 0.01 respectively). After adjustment of age, sex, and BMI, HbA1c was found to be negatively correlated with postprandial C-peptide (γ = −0.264), M0 (γ = −0.379), and M1 (γ = −0.522), however, positively correlated with fasting C-peptide (γ = 0.105; P < 0.01 respectively). In stepwise multiple regression analysis, M0, M1, and homeostasis model assessment for insulin resistance (HOMA-IR) emerged as predictors of HbAlc after adjustment for age, sex, and BMI (R2 = 0.272, 0.080, and 0.056 respectively). Conclusions: With increasing duration of diabetes, the decrease of postprandial insulin secretion is becoming more prominent, and postprandial β-cell responsiveness may be a more important determinant for glycemic control than fasting β-cell responsiveness.

scholarly journals A Plant-Based Meal Stimulates Incretin and Insulin Secretion More Than an Energy- and Macronutrient-Matched Standard Meal in Type 2 Diabetes: A Randomized Crossover Study

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 486 ◽  
Author(s):  
Hana Kahleova ◽  
Andrea Tura ◽  
Marta Klementova ◽  
Lenka Thieme ◽  
Martin Haluzik ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Repeated Measures ◽  
Beta Cell Function ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
C Peptide

Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals (p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p < 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p < 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p < 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p < 0.001) and a decrease in GIP (by −9.4%; 95% CI −17.3 to −0.7%; p = 0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Our results showed an increase in postprandial incretin and insulin secretion, after consumption of a V-meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D.

scholarly journals Postprandial serum C-peptide to plasma glucose ratio as a predictor of subsequent insulin treatment in patients with type 2 diabetes

2011 ◽  
Vol 58 (4) ◽  
pp. 315-322 ◽  
Author(s):  
Yoshifumi Saisho ◽  
Kinsei Kou ◽  
Kumiko Tanaka ◽  
Takayuki Abe ◽  
Hideaki Kurosawa ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Glucose ◽  
Insulin Treatment ◽  
C Peptide ◽  
Glucose Ratio

Potentiation of the early-phase insulin response by a prior meal contributes to the second-meal phenomenon in type 2 diabetes

2011 ◽  
Vol 301 (5) ◽  
pp. E984-E990 ◽  
Author(s):  
Seung-Hwan Lee ◽  
Andrea Tura ◽  
Andrea Mari ◽  
Seung-Hyun Ko ◽  
Hyuk-Sang Kwon ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Early Phase ◽  
Cell Function ◽  
Insulin Response ◽  
Free Fatty Acid Level ◽  
Diabetic Patients ◽  
Insulinogenic Index ◽  
C Peptide

Improved glucose tolerance following a sequential meal is known as the second-meal phenomenon. We aimed to investigate its extent and underlying mechanisms in patients with type 2 diabetes. Metabolic responses after lunch in 12 diabetic patients were compared on two separate days: one with (Day BL) and another without (Day FL) breakfast. The responses of hormones were calculated by the incremental area under the curve (iAUC) values for 180 min after each meal. Indexes of early-phase insulin secretion were assessed, and β-cell function was estimated by mathematical modeling. [iAUCglucose(180–360 min)] was significantly lower on Day BL than on Day FL (181 ± 43 vs. 472 ± 29 mmol·liter−1·min, P = 0.0005). The magnitude of the The second-meal phenomenon [iAUCglucose(180–360 min) on Day BL/Day FL] was 35 ± 9%. The peak levels of insulin and C-peptide were attained 45 min earlier after the second meal than after the first meal. iAUCglucose(180–360 min) correlated negatively with iAUCinsulin(180–210 min) ( r = −0.443, P = 0.0300), insulinogenic index ( r = −0.769, P < 0.0001), acute C-peptide response ( r = −0.596, P = 0.0021), and potentiation factor [i.e., potentiation effect on insulin secretion] ratio (180–360)/(0–20) ( r = −0.559, P = 0.0045), while correlated positively with free fatty acid level before lunch ( r = 0.679, P = 0.0003). The second-meal phenomenon was evident in patients with type 2 diabetes. Potentiation of the early-phase insulin response by a prior meal contributes to this phenomenon in type 2 diabetes.

scholarly journals Assessment of pulsatile insulin secretion derived from peripheral plasma C-peptide concentrations by nonparametric stochastic deconvolution

2019 ◽  
Vol 316 (5) ◽  
pp. E687-E694 ◽  
Author(s):  
Marcello C. Laurenti ◽  
Adrian Vella ◽  
Ron T. Varghese ◽  
James C. Andrews ◽  
Anu Sharma ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Hepatic Vein ◽  
A Priori ◽  
Simulated Data ◽  
Systemic Circulation ◽  
C Peptide ◽  
Pulsatile Insulin Secretion ◽  
Do So

The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.

scholarly journals Short Course of Insulin Treatment versus Metformin in Newly Diagnosed Patients with Type 2 Diabetes

2018 ◽  
Vol 7 (9) ◽  
pp. 235 ◽  
Author(s):  
Marta Seghieri ◽  
Eleni Rebelos ◽  
Andrea Mari ◽  
Luigi Sciangula ◽  
Carlo Giorda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Basal Insulin ◽  
Insulin Treatment ◽  
Oral Glucose ◽  
Newly Diagnosed ◽  
Insulin Group ◽  
Short Course

The ß-cell dysfunction of type 2 diabetes is partly reversible. The optimal time window to induce glycemic remission is uncertain; short courses of insulin treatment have been tested as a strategy to induce remission. In a pilot study in 38 newly-diagnosed patients, we assessed the time-course of insulin sensitivity and ß-cell function (by repeat oral glucose tolerance tests) following a 6-week basal insulin treatment compared to metformin monotherapy in equipoised glycemic control. At 6 weeks, insulin secretion and sensitivity were increased in both groups whilst ß-cell glucose sensitivity was unchanged. From this time onwards, in the insulin group glycemia started to rise at 3 months, and was no longer different from baseline at 1 year. The initial improvement in insulin secretion and sensitivity dissipated. In the metformin group, fasting plasma glucose and HbA1c levels reached a nadir at 8 months, at which time insulin secretion, glucose and insulin sensitivity were significantly better than at baseline and higher than in the insulin group. A short course of basal insulin in newly-diagnosed patients does not appear to offer clinical advantage over recommended initiation with metformin.

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