Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of...

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Vydáno v:Diabetes (New York, N.Y.) Ročník 65; číslo 5; s. 1190
Hlavní autoři: Ferrannini, Ele, Baldi, Simona, Frascerra, Silvia, Astiarraga, Brenno, Heise, Tim, Bizzotto, Roberto, Mari, Andrea, Pieber, Thomas R, Muscelli, Elza
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.05.2016
Témata:
3-Hydroxybutyric Acid - agonists
3-Hydroxybutyric Acid - blood
3-Hydroxybutyric Acid - metabolism
Algorithms
Benzhydryl Compounds - administration & dosage
Benzhydryl Compounds - adverse effects
Benzhydryl Compounds - therapeutic use
C-Reactive Protein - analysis
Carbohydrate Metabolism - drug effects
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - urine
Energy Metabolism - drug effects
Glucagon - blood
Glucagon - metabolism
Glucagon-Like Peptide 1 - blood
Glucose Intolerance - blood
Glucose Intolerance - drug therapy
Glucose Intolerance - metabolism
Glucose Intolerance - urine
Glucosides - administration & dosage
Glucosides - adverse effects
Glucosides - therapeutic use
Glycosuria - chemically induced
Humans
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - adverse effects
Hypoglycemic Agents - therapeutic use
Insulin - blood
Insulin - metabolism
Insulin Secretion
Lipid Metabolism - drug effects
Lipolysis - drug effects
Membrane Transport Modulators - administration & dosage
Membrane Transport Modulators - adverse effects
Membrane Transport Modulators - therapeutic use
Renal Elimination - drug effects
Sodium-Glucose Transporter 2 - metabolism
Sodium-Glucose Transporter 2 Inhibitors
Time Factors
ISSN:1939-327X, 1939-327X
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Shrnutí:Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [(2)H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating β-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis.
Bibliografie:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ISSN:1939-327X
1939-327X
DOI:10.2337/db15-1356