scholarly journals Relation of cardiac function to insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis in individuals with type 2 diabetes

2021 ◽  
Author(s):  
Natsu Otowa‐Suematsu ◽  
Kazuhiko Sakaguchi ◽  
Akihiro Kaneko ◽  
Jun Ito ◽  
Yasuko Morita ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiac Function ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

scholarly journals New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

2021 ◽  
Author(s):  
Roberto Bizzotto ◽  
Domenico Tricò ◽  
Andrea Natali ◽  
Amalia Gastaldelli ◽  
Elza Muscelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Oral Glucose ◽  
Β Cell ◽  
Euglycemic Clamp ◽  
Glucose Ingestion ◽  
Per Se

<i>Objective</i> Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. <p><i>Research Design and Methods</i> We estimated standardized EIC (EIC<sub>ISR</sub>) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EIC<sub>ISR</sub> association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555).</p> <p><i>Results</i> Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EIC<sub>ISR</sub>, ~4 times more influential than insulin-resistance related hypersecretion. EIC<sub>ISR</sub> independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles.</p> <p><i>Conclusions</i> Based on EIC<sub>ISR</sub>, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC<sub>ISR</sub> with insulin resistance (not with higher BMI <i>per se</i>) and is more relevant than the concomitant hypersecretion; the second reduces EIC<sub>ISR</sub> with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion <i>per se</i> reduces insulin clearance.<br> </p>

scholarly journals Liraglutide, a Glucagon-Like Peptide-1 Analog, Increased Insulin Sensitivity Assessed by Hyperinsulinemic-Euglycemic Clamp Examination in Patients with Uncontrolled Type 2 Diabetes Mellitus

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Hideaki Jinnouchi ◽  
Seigo Sugiyama ◽  
Akira Yoshida ◽  
Kunio Hieshima ◽  
Noboru Kurinami ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Insulin Therapy ◽  
Euglycemic Clamp ◽  
Type 2 Dm ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Aims. Glucagon-like peptide-1 (GLP-1) analog promotes insulin secretion by acting on pancreaticβ-cells. This antihyperglycemic treatment for type 2 diabetes mellitus (DM) has attracted increased clinical attention not only for its antihyperglycemic action but also for its potential extrapancreatic effects. We investigated whether liraglutide, a GLP-1 analog, could enhance insulin sensitivity as assessed by the hyperinsulinemic-euglycemic clamp in type 2 DM patients.Materials. We prospectively enrolled 31 uncontrolled type 2 DM patients who were hospitalized and equally managed by guided diet- and exercise-therapies and then introduced to either liraglutide- or intensive insulin-therapy for 4 weeks. Insulin sensitivity was assessed by the glucose infusion rate (GIR) using hyperinsulinemic-euglycemic clamp before and after the therapies.Results. Values of HbA1c, postprandial plasma glucose, and body mass index (BMI) were significantly decreased by hospitalized intensive insulin-therapy or liraglutide-therapy. GIR was significantly increased by liraglutide-therapy but not by insulin-therapy, indicating that liraglutide-therapy significantly enhanced insulin sensitivity. BMI decreased during liraglutide-therapy but was not significantly correlated with changes in GIR. Multivariate logistic regression analysis demonstrated that liraglutide-therapy significantly correlated with increased insulin sensitivity in uncontrolled DM patients.Conclusions. Liraglutide may exhibit favorable effects on diabetes control for type 2 DM patients by increasing insulin sensitivity as an extrapancreatic action. Clinical trial registration Unique Identifier isUMIN000015201.

Abstract 038: Hyperglycemia Mediated Cardiac Damage in High-Fat Fed E487K Aldehyde Dehydrogenase 2 (ALDH 2*2) Mutant Diabetic Mice: Role for ALDH2 Activation

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Guodong Pan ◽  
Suresh Palaniyandi
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiac Function ◽  
Aldehyde Dehydrogenase ◽  
Diabetic Mice ◽  
High Fat ◽  
Aldehyde Dehydrogenase 2 ◽  
Cardiac Damage

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in the heart, detoxifies reactive aldehydes and protects heart from oxidative stress. East Asians (~700 million) are carriers of E487K point mutation of ALDH2 (ALDH2*2) with intrinsically low ALDH2 activity. ALDH2*2 is associated with increased maternal inheritance of diabetes mellitus (DM), and DM-induced neuropathy and vasculopathy. However the pathophysiology of diabetic cardiac damage.is not studied in ALDH2*2 carriers. DM is a polygenic disease and DM-induced cardiac damage may be multifactorial. However we hypothesis that hyperglycemia-induced oxidative stress mediated 4-hydroxy-2-nonel (4HNE) toxicity contributes to the cardiac damage in ALDH2*2 mutant mice (low intrinsic ALDH2 activity) with type-2 diabetes. We induced type-2 diabetes by feeding high-fat diet and found they developed hyperglycemia (blood glucose (BG) levels increased to 357 ± 100 mg/dl vs 137 ± 7 mg/dl) and insulin resistance as measured by glucose tolerance test (GTT) (BG levels 408 ± 50 mg/dl vs 165 ± 18 mg/dl at 2 hours after GTT). To delineate the role of hyperglycemia, we treated the diabetic mice with a sodium-glucose co-transporter 2 (SGLT2) inhibitor, Empaglifuzin (EMP) (3mg/kg/day) or Vehicle for 8 weeks. EMP reduced BG levels from 502 ± 75 mg/dl to 193 ± 50 mg/dl by enhancing urinary glucose excretion. Surprisingly EMP reversed insulin resistance as maintained similar BG levels before and after 2 hours of GTT; 190 ± 23 mg/dl vs 188 ± 16 mg/dl. EMP also increased ALDH2 activity to 22 ± 8 % from 7 ± 3 % and 4HNE protein adduct levels. Finally EMP improved cardiac function i.e. % fractional shortening (FS) is increased to 70 ± 4 compared to 53 ± 10. Our data suggested hyperglycemia partially contribute to the diabetic cardiac damage via increasing 4HNE protein adducts. Alda-1 (10 mg/kg/day) treatment further augmented ALDH2 activity, reduced 4HNE adducts and improved cardiac function in EMP-treated ALDH2*2 mice. Thus hyperglycemia mediated secondary events in type-2 DM are significant pathomechanism of the cardiac damage. In conclusion, we propose ALDH2 activation may ameliorate diabetic patients from cardiac complications who receive glucose lowering treatments.

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