scholarly journals Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport

2020 ◽  
Vol 8 (1) ◽  
pp. e001178 ◽  
Author(s):  
Ele Ferrannini ◽  
Ricardo Pereira-Moreira ◽  
Marta Seghieri ◽  
Eleni Rebelos ◽  
Aglécio L Souza ◽  
...  
Keyword(s):  
Sodium Excretion ◽  
Insulin Infusion ◽  
Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Sodium Glucose Cotransporter ◽  
Urinary Glucose ◽  
Patients With Diabetes ◽  
Sglt2 Inhibition ◽  
Glucose Excretion

IntroductionInsulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.MethodsWe applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination.ResultsDuring saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kgFFM/min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion.ConclusionsAcute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin.

155-LB: The Increase in Endogenous Glucose Production with SGLT2 Inhibition Is Unchanged by Renal Denervation but Highly Correlates to Urinary Glucose Excretion

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 155-LB
Author(s):  
CAROLINA SOLIS-HERRERA ◽  
MARIAM ALATRACH ◽  
CHRISTINA AGYIN ◽  
HENRI HONKA ◽  
RUPAL PATEL ◽  
...  
Keyword(s):  
Renal Denervation ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Urinary Glucose Excretion ◽  
Urinary Glucose ◽  
Sglt2 Inhibition ◽  
Endogenous Glucose ◽  
Glucose Excretion

scholarly journals Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments

2019 ◽  
Vol 14 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Juan Tamargo
Keyword(s):  
Heart Failure ◽  
Glycaemic Control ◽  
Adverse Effects ◽  
Major Cardiovascular Events ◽  
Sodium Glucose Cotransporter ◽  
Urinary Glucose ◽  
Patients With Diabetes ◽  
Near Future ◽  
Glucose Excretion

Heart failure is a common complication in patients with diabetes, and people with both conditions present a worse prognosis. Sodium– glucose cotransporter 2 inhibitors (SGLT2Is) increase urinary glucose excretion, improving glycaemic control. In type 2 diabetes (T2D), some SGLT2Is reduce major cardiovascular events, heart failure hospitalisations and worsening of kidney function independent of glycaemic control. Multiple mechanisms (haemodynamic, metabolic, hormonal and direct cardiac/renal effects) have been proposed to explain these cardiorenal benefits. SGLT2Is are generally well tolerated, but can produce rare serious adverse effects, and the benefit/risk ratio differs between SGLT2Is. This article analyses the mechanisms underlying the cardiorenal benefits and adverse effects of SGLT2Is in patients with T2D and heart failure and outlines some questions to be answered in the near future.

scholarly journals Glucose Production and Glucose Disposal Integrated by an Intrinsic Inverse Coupling in Vivo: hypothesis of inter-organ reflex on glucose regulation

2020 ◽  
Author(s):  
Nan Liu ◽  
Wei Zou ◽  
Ying Xing ◽  
Xi Zhang ◽  
Bin Song ◽  
...  
Keyword(s):  
Insulin Infusion ◽  
Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Glucose Turnover ◽  
Fundamental Parameters ◽  
Homeostasis Regulation ◽  
Insulin Infusion Protocol ◽  
Infusion Protocol

ABSTRACTGlucose production (GP) and glucose disposal (Rd) are two decisive and fundamental parameters in glucose turnover and in glucose homeostasis regulation. In conventional theory, GP and Rd were responsive to regulatory factors respectively and independently of each other. Even though GP and Rd responded in reverse to insulin, GP for suppression and Rd for elevation, these inverse alterations used to be attributed to insulin multiple functions both on hepatic GP, directly or indirectly, and on whole-body glucose Rd. However, in the present study, we found GP and Rd were inversely coupled intrinsically no matter which side was the target of insulin by comparison of Rd and GP data pairs between peripheral vein insulin infusion protocol and portal vein insulin infusion protocol in rats. Furthermore, neither circulating NEFA nor HFD induced resistance broke the GP-Rd inverse coupling, but both of them reduced the responses of both GP and Rd to insulin. In conclusion, we provide the evidence that GP and Rd are two coupled parameters in vivo and they alter in reverse simultaneously, the mechanism under which needs further investigation but we tend to believe an inter-organ neural reflex was involved.

Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats

2013 ◽  
Vol 304 (4) ◽  
pp. E414-E423 ◽  
Author(s):  
Takumi Nagata ◽  
Masanori Fukazawa ◽  
Kiyofumi Honda ◽  
Tatsuo Yata ◽  
Mio Kawai ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Sglt2 Inhibitor ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Sglt2 Inhibition ◽  
Renal Glucose Reabsorption

To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20–50% with phlorizin and by 1–5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg−1·min−1 and increased EGP by 1–2 mg·kg−1·min−1, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg−1·min−1 and increased EGP by about 4 mg·kg−1·min−1; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.

scholarly journals Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia

2014 ◽  
Vol 306 (2) ◽  
pp. F188-F193 ◽  
Author(s):  
Timo Rieg ◽  
Takahiro Masuda ◽  
Maria Gerasimova ◽  
Eric Mayoux ◽  
Kenneth Platt ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Plasma Concentrations ◽  
Sglt2 Inhibitor ◽  
Double Knockout ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Sglt2 Inhibition ◽  
Renal Glucose Reabsorption ◽  
Glucose Excretion ◽  
Free Plasma

In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1−/−) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1−/− vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1−/− vs. WT after 24 h (−33 vs. −11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1−/−. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ∼10-fold and reduced FGR to 44 ± 3% in WT and to −1 ± 3% in Sglt1−/−. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50–60% of filtered glucose is excreted.

scholarly journals Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 394-404 ◽  
Author(s):  
Jonathan P. German ◽  
Joshua P. Thaler ◽  
Brent E. Wisse ◽  
Shinsuke Oh-I ◽  
David A. Sarruf ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Underlying Mechanism ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Uncontrolled Diabetes ◽  
Urinary Glucose ◽  
Hepatic Glucose ◽  
Glucose Excretion ◽  
The Brain

Abstract The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats

1994 ◽  
Vol 77 (2) ◽  
pp. 534-541 ◽  
Author(s):  
J. Gao ◽  
W. M. Sherman ◽  
S. A. McCune ◽  
K. Osei
Keyword(s):  
Heart Failure ◽  
Insulin Sensitivity ◽  
Acute Exercise ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Insulin Responsiveness ◽  
Obese Male

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

scholarly journals Clinical and genetic determinants of urinary glucose excretion in patients with diabetes mellitus

2020 ◽  
Author(s):  
Keisuke Monobe ◽  
Shinsuke Noso ◽  
Naru Babaya ◽  
Yoshihisa Hiromine ◽  
Yasunori Taketomo ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Genetic Determinants ◽  
Urinary Glucose Excretion ◽  
Urinary Glucose ◽  
Patients With Diabetes ◽  
Glucose Excretion

Insulin resistance and regulation of serum amino acid levels in myotonic dystrophy

1986 ◽  
Vol 71 (4) ◽  
pp. 429-436 ◽  
Author(s):  
Richard T. Moxley ◽  
William J. Kingston ◽  
Kenneth L. Minaker ◽  
Alastair J. Corbett ◽  
John W. Rowe
Keyword(s):  
Insulin Resistance ◽  
Amino Acid ◽  
Myotonic Dystrophy ◽  
Insulin Infusion ◽  
Normal Subjects ◽  
Amino Acid Uptake ◽  
Whole Body ◽  
Glucose Disposal ◽  
Acid Uptake ◽  
Amino Acid Levels

1. To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and to determine if these same patients display signs of a whole body decrease in the action of insulin on amino acid uptake and glucose disposal, three separate 120 min studies employing the euglycaemic insulin clamp technique (20, 80 and 200 m-units min−1 m−2) were performed on five ambulatory patients with myotonic dystrophy. The results were compared with findings obtained in identical studies in 21 normal volunteers. 2. Myotonic dystrophy patients showed a slower, less marked decline in the serum concentration of insulin sensitive amino acids (threonine, valine, leucine, isoleucine, tyrosine, phenylalanine) during all three insulin infusions compared with normals. The greatest difference occurred at the low physiological elevations of insulin produced by the 20 m-units min−1 m−2 infusion. 3. Alanine levels fell significantly below baseline in patients with myotonic dystrophy after 60 and 120 min of insulin infusion with all three rates of insulin infusion. Normal subjects had only a minimal, insignificant decline in arterialized alanine concentrations during the three different insulin infusions. 4. Creatinine adjusted rates of whole body glucose disposal were 30–40% lower in the myotonic dystrophy group at all three doses of insulin compared with the normals. This demonstrates that their insulin resistance was not due simply to a reduction in muscle mass. 5. The overall pattern of findings in these studies of patients with myotonic dystrophy indicates that there is a whole body derangement in the regulation of circulating amino acid levels by insulin as well as a marked decrease in the action of this hormone in stimulating glucose uptake by target tissues.

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