is on the advisory boards of AstraZeneca, Novo Nordisk, Janssen Pharmaceuticals, Intarcia Therapeutics, and Boehringer Ingelheim; has received research support from Bristol-Myers Squibb, Boehringer Ingelheim, and AstraZeneca; and is on the speakers bureaus of Novo Nordisk and AstraZeneca. Author Contributions. to 10 1.1 U/mL; 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 15 to 112 9 mg/dL; = 0.01) and fasting plasma insulin (14 3 to 11 2 U/mL; = 0.02) decreased, and plasma glucagon increased (all 0.05 vs. placebo). EGP was unchanged from baseline (2.21 0.19 vs. 1.96 0.14 mg/kg/min) in T2D ( 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 0.10 to 1 1.78 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (= 0.824; 0.001) was observed. CONCLUSIONS Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG. Introduction In individuals with type 2 diabetes (T2D), an increased basal rate of endogenous glucose production (EGP) and impaired suppression of EGP following a meal are characteristic pathophysiologic abnormalities that contribute to fasting and postprandial hyperglycemia, respectively (1C9). Thus, understanding the factors that regulate EGP is key to understanding the maintenance of normal glucose homeostasis and development of hyperglycemia in patients with T2D. SodiumCglucose cotransporter 2 inhibitors (SGLT2i) lower the plasma glucose directly by inducing glucosuria and indirectly by ameliorating glucotoxicity, resulting in improved insulin sensitivity and -cell function (10C12). We (10,12) and others (13) have demonstrated that the glucosuria produced by SGLT2i stimulates EGP and that the increase in EGP offsets by 50% the amount of glucose lost in the urine. This observation suggests the presence of a renohepatic axis that is activated to prevent an excessive decline in plasma glucose concentration and resultant hypoglycemia. In contrast, the increase in EGP in individuals with T2D is paradoxical in that it occurs while the plasma glucose concentration is within the hyperglycemic range and, as stated above, quantitatively offsets by 50% the amount of glucose lost in the urine (10), thereby attenuating the glucose-lowering effect of SGLT2i. Elucidating the mechanisms that mediate the rise in EGP in response to SGLT2i-induced D-Ribose glucosuria will provide D-Ribose a better understanding of glucose homeostasis and may allow the development of strategies to prevent the increase in EGP and enhance the efficacy of SGLT2i. The rise in EGP following SGLT2i is associated with an increase in plasma glucagon concentration and progressive decline in plasma insulin concentration (10,13). Although SGLT2 transporter receptors have been demonstrated on -cells (14), there are no SGLT2 transporters on -cells (14). Moreover, the rise in plasma glucagon occurs well after the initial rise in EGP (10). The rapid onset (30C60 min) of rise in EGP following SGLT2i ingestion suggests the presence of a neural arc in which activation of the renal sympathetic nerves sends a signal to the brain, which in turn leads to value= 3) or treated with metformin with or without dipeptidyl peptidase 4 inhibitor (= 3). Subjects with evidence of proliferative diabetic retinopathy, estimated glomerular filtration rate 45 mL/min/1.73 m2 (calculated by MDRD), or albumin-to-creatinine ratio 300 mg/g were excluded. Individuals taking a -blocker or any medication known to affect sympathetic/parasympathetic activity were excluded. Recruitment was done at the Texas Diabetes Institute in collaboration with the Transplant Clinic at UT Health San Antonio. After screening, eligible subjects received two measurements of EGP on separate days. Subjects reported to the Texas Diabetes Institute at 6:00 a.m. after a 10-h overnight fast. At 6:00 a.m. a catheter was placed into an anticubital vein, and subjects received an infusion of [3-3H]glucose (prime = 25 Ci fasting plasma glucose [FPG]/100; continuous = 0.25 Ci/min) for 3 h (6:00C9:00 a.m.). After the 3-h.In subjects with normal glucose tolerance, a combined epinephrine/insulin infusion has been shown to increase EGP fivefold compared insulin infusion alone (22). 0.19 vs. 1.96 0.14 mg/kg/min) in T2D ( 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 0.10 to 1 1.78 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (= 0.824; 0.001) was observed. CONCLUSIONS Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG. Introduction In individuals with type 2 diabetes (T2D), an increased basal rate of endogenous glucose production (EGP) and impaired suppression of EGP following a meal are characteristic pathophysiologic abnormalities that contribute to fasting and postprandial hyperglycemia, respectively (1C9). Thus, understanding the factors that regulate EGP is key to understanding the maintenance of normal glucose homeostasis and development of hyperglycemia in patients with T2D. SodiumCglucose cotransporter 2 inhibitors (SGLT2i) lower the plasma glucose directly by inducing glucosuria and indirectly by ameliorating glucotoxicity, resulting in improved insulin sensitivity and -cell function (10C12). We (10,12) CSF3R and others (13) have demonstrated that the glucosuria produced by SGLT2i stimulates EGP and that the increase in EGP offsets by 50% the amount of glucose lost in the urine. This observation suggests the presence of a renohepatic axis that is activated to prevent an excessive decline in plasma glucose concentration and resultant hypoglycemia. In contrast, the increase in EGP in individuals with T2D is paradoxical in that it occurs while the plasma glucose concentration is within the hyperglycemic range and, as stated above, quantitatively offsets by 50% the amount of glucose lost in the urine (10), thereby attenuating the glucose-lowering effect of SGLT2i. Elucidating the mechanisms that mediate the rise in EGP in response to SGLT2i-induced glucosuria will provide a better understanding of glucose homeostasis and may allow the development of strategies to prevent the increase in EGP and enhance the efficacy of SGLT2i. The rise in EGP following SGLT2i is associated with an increase in plasma glucagon concentration and progressive decline D-Ribose in plasma insulin concentration (10,13). Although SGLT2 transporter receptors have been demonstrated on -cells (14), there are no SGLT2 transporters on -cells (14). Moreover, the rise in plasma glucagon occurs well after the initial rise in EGP (10). The rapid onset (30C60 min) of rise in EGP following SGLT2i ingestion suggests the presence of a neural arc in which activation of the renal sympathetic nerves sends a signal to the brain, which in turn leads to value= 3) or treated with metformin with or without dipeptidyl peptidase 4 inhibitor (= 3). Subjects with evidence of proliferative diabetic retinopathy, estimated glomerular filtration rate 45 mL/min/1.73 m2 (calculated by MDRD), or albumin-to-creatinine ratio 300 mg/g were excluded. Individuals taking a -blocker or any medication known to affect sympathetic/parasympathetic activity were excluded. Recruitment was done at the Texas Diabetes Institute in collaboration with the Transplant Clinic at UT Health San Antonio. After screening, eligible subjects received two measurements of EGP on separate days. Subjects reported to the Texas Diabetes Institute at 6:00 a.m. after a 10-h overnight fast. At 6:00 a.m. a catheter was placed into an anticubital vein, and subjects received an infusion of [3-3H]glucose (prime = 25 Ci fasting.
is on the advisory boards of AstraZeneca, Novo Nordisk, Janssen Pharmaceuticals, Intarcia Therapeutics, and Boehringer Ingelheim; has received research support from Bristol-Myers Squibb, Boehringer Ingelheim, and AstraZeneca; and is on the speakers bureaus of Novo Nordisk and AstraZeneca
