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Introduction Low carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However, whether the improvements in glycemic control and insulin sensitivity are secondary to the weight loss or result from a direct effect of hyperketonemia is controversial.Research design and methods 29 overweight obese subjects were randomized to one of three dietary interventions for 10 days: (1) Weight-maintaining standard diet; (2) Weight-maintaining ketogenic diet; (3) Weight-maintaining ketogenic diet plus supplementation with the ketone ester of beta-hydroxybutyrate (β-OH-B), 8 g every 8 hours. At baseline, all subjects had oral glucose tolerance test, 2-step euglycemic insulin clamp (20 mU/m2.min and 60 mU/m2.min) with titrated glucose and indirect calorimetry.Results Body weight, fat content, and per cent body fat (DEXA) remained constant over the 10-day dietary intervention period in all three groups. Plasma β-OH-B concentration increased twofold, while carbohydrate oxidation decreased, and lipid oxidation increased demonstrating the expected shifts in substrate metabolism with institution of the ketogenic diet. Glucose tolerance either decreased slightly or remained unchanged in the two ketogenic diet groups. Whole body (muscle), liver, and adipose tissue sensitivity to insulin remained unchanged in all 3 groups, as did the plasma lipid profile and blood pressure.Conclusion In the absence of weight loss, a low carbohydrate ketogenic diet has no beneficial effect on glucose tolerance, insulin sensitivity, or other metabolic parameters.

Acute and chronic sodium–glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP). However, the organ—liver versus kidney—responsible for the increase in EGP has not been identified. In this study, 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) received [3-3H]glucose infusion (to measure total EGP) combined with arterial and renal vein catheterization and para -aminohippuric acid infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 h after dapagliflozin (DAPA) and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 min, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in NGT or T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P < 0.05 vs. placebo). The increase in renal glucose uptake was entirely explained by the increase in glucosuria. A single dose of DAPA significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis. Article Highlights: Sodium–glucose cotransporter 2 (SGLT2) inhibitors increase endogenous glucose production (EGP) but the organ—liver versus kidney—responsible for the increase in EGP is unknown. Total EGP ([3-3H]glucose), net renal arteriovenous balance (renal vein catheterization), and renal glucose production were measured in 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) before and 4 h after dapagliflozin and placebo administration. Dapagliflozin increased EGP in both T2D and NGT subjects. All of the increase in EGP was derived from an increase in hepatic glucose output. These results establish the existence of a novel renal-hepatic axis. [ABSTRACT FROM AUTHOR]

Context This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria. Objective To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. Our hypothesis was that increased EGP in response to SGLT2i-induced glycosuria persists for a long period and is not abolished by GLP-1 RA stimulation of insulin secretion and glucagon suppression. Methods Seventy-five patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) (intravenous 3-(3H)-glucose oral (1-14C)-glucose): (1) before/after 1 of dapagliflozin (DAPA); exenatide (EXE), or both, DAPA/EXE (acute study), and (2) after 1 and 4 months of therapy with each drug. Results In the acute study, during the OGTT plasma glucose (PG) elevation was lower in EXE (Δ = 42 ± 1 mg/dL) than DAPA (Δ = 72 ± 3), and lower in DAPA/EXE (Δ = 11 ± 3) than EXE and DAPA. EGP decrease was lower in DAPA (Δ = −0.65 ± 0.03 mg/kg/min) than EXE (Δ = −0.96 ± 0.07); in DAPA/EXE (Δ = −0.84 ± 0.05) it was lower than EXE, higher than DAPA. At 1 month, similar PG elevations (EXE, Δ = 26 ± 1 mg/dL; DAPA, Δ = 62 ± 2, DAPA/EXE, Δ = 27 ± 1) and EGP decreases (DAPA, Δ = −0.60 ± 0.05 mg/kg/min; EXE, Δ = −0.77 ± 0.04; DAPA/EXE, Δ = −0.72 ± 0.03) were observed. At 4 months, PG elevations (EXE, Δ = 55 ± 2 mg/dL; DAPA, Δ = 65 ± 6; DAPA/EXE, Δ = 46 ± 2) and lower EGP decrease in DAPA (Δ = −0.66 ± 0.04 mg/kg/min) vs EXE (Δ = −0.84 ± 0.05) were also comparable; in DAPA/EXE (Δ = −0.65 ± 0.03) it was equal to DAPA and lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs EXE mg/kg/min. Conclusion Our findings provide strong evidence for the emergence of a new long-lasting, glucose-independent, insulin/glucagon-independent, glucoregulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in patients with T2D. SGLT2i plus GLP-1 receptor agonist combination therapy is accompanied by superior glycemic control vs monotherapy. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions To investigate the effect of sodium‐glucose co‐transporter 2 inhibitor [SGLT‐2i] therapy on renal haemodynamics in T2D patients with glomerular hyperfiltration.Sixty T2D patients with elevated [HYPER] and normal [NORMO] GFR were randomized to dapagliflozin 10 mg/day [DAPA/HYPER, n = 15; DAPA/NORMO, n = 15] or to metformin/glipizide [CONTROL/HYPER, n = 15; CONTROL/NORMO, n = 15] to reach similar glycaemic control after 4 months. GFR was measured with Iohexol and hyperfiltration was empirically defined as >125 mL/min/1.73 m2. GFR, renal plasma flow [RPF], mean arterial pressure [MAP], filtration fraction [FF], and renal vascular resistance [RVR] were determined before/after therapy.HbA1c decreased similarly in all 4 groups. GFR declined by ~18% in DAPA/HYPER and by ~7% in DAPA/NORMO and did not change in CONTROLS (p < 0.05 vs. DAPA). RPF remained unchanged in all four groups. Thus, FF (%) declined from 0.23 ± 0.01 to 0.18 ± 0.01 in DAPA/HYPER and from 0.17 ± 0.01 to 0.15 ± 0.01 in DAPA/NORMO and remained unchanged in CONTROLS (p < 0.05 vs. DAPA). MAP (mmHg) decreased from 95.4 ± 1.4 to 88.1 ± 1.3 in DAPA/HYPER and from 95.6 ± 1.3 to 91.8 ± 0.8 in DAPA/NORMO and remained unchanged in CONTROLS (p < 0.05 vs. DAPA). RVR [mmHg/L/min] declined in DAPA/HYPER (92.7 ± 7.8 to 80.4 ± 6.1) and DAPA/NORMO (90.1 ± 3.0 to 81.4 ± 2.1) but not in CONTROLS (p < 0.05 vs. DAPA).Despite comparable glycaemic control, dapagliflozin treatment, but not metformin and /or glipizide, reduced glomerular hyperfiltration in T2D patients and decreased both filtration fraction and renal vascular resistance. These findings suggest that a post‐glomerular vasodilatory action of SGLT2 inhibitors contributes to their renal protective effect in T2D. [ABSTRACT FROM AUTHOR]

Context: Increased mesenteric visceral fat is associated with the metabolic syndrome, insulin resistance, and type 2 diabetes., Methods: Using Targeted Cell Separation and Extraction Technology (TC-SET), we examined the effect of removal of intra-abdominal fat, specifically small bowel mesenteric fat, on glycemic control and insulin sensitivity in 7 obese, poorly controlled type 2 diabetic individuals (HbA1c = 8.9±0.2%; FPG = 211±12 mg/dl)., Results: At month 6, both HbA1c and FPG significantly declined to 7.7% (p=0.01) and 140 mg/dl (p<0.01). At month 12, both the FPG (172 mg/dl, P=0.02) and HbA1c (8.1%, P=0.10) tended to increase. Time-in-range (CGM) increased from 22% to 74% (month 6, p<0.001) and 50% (month 12, p<0.05). Suppression of endogenous (hepatic) glucose production increased from 29% to 45% (p<0.05) and to 43% (p<0.01) at months 6 and 12, respectively; whole body (muscle) insulin-mediated glucose disposal did not change significantly at months 6 and 12. Body weight (106.8 to 103.3 kg) and percent body fat (33.3 to 31.6%) both decreased slightly (p<0.05) at month 12. Hepatic fat content (1H-MRS) decreased significantly (23.9±3.7 to 19.1±3.4%, P<0.005) at month 12. Insulin secretion and disposition index during OGTT increased more than 2-fold at month 6 (both p<0.05), and these improvements persisted at 12 months., Conclusion: Mesenteric visceral lipectomy shows potential as a novel, minimally invasive approach to improve glycemic control in suboptimally controlled type 2 diabetes patients, but further controlled studies are needed to confirm these findings and better understand the potential benefits of MVL., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Introduction: Low carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However, whether the improvements in glycemic control and insulin sensitivity are secondary to the weight loss or result from a direct effect of hyperketonemia is controversial., Research Design and Methods: 29 overweight obese subjects were randomized to one of three dietary interventions for 10 days: (1) Weight-maintaining standard diet; (2) Weight-maintaining ketogenic diet; (3) Weight-maintaining ketogenic diet plus supplementation with the ketone ester of beta-hydroxybutyrate (β-OH-B), 8 g every 8 hours. At baseline, all subjects had oral glucose tolerance test, 2-step euglycemic insulin clamp (20 mU/m 2 .min and 60 mU/m 2 .min) with titrated glucose and indirect calorimetry., Results: Body weight, fat content, and per cent body fat (DEXA) remained constant over the 10-day dietary intervention period in all three groups. Plasma β-OH-B concentration increased twofold, while carbohydrate oxidation decreased, and lipid oxidation increased demonstrating the expected shifts in substrate metabolism with institution of the ketogenic diet. Glucose tolerance either decreased slightly or remained unchanged in the two ketogenic diet groups. Whole body (muscle), liver, and adipose tissue sensitivity to insulin remained unchanged in all 3 groups, as did the plasma lipid profile and blood pressure., Conclusion: In the absence of weight loss, a low carbohydrate ketogenic diet has no beneficial effect on glucose tolerance, insulin sensitivity, or other metabolic parameters., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The aim of this study was to examine the relationship between whole-body insulin-mediated glucose disposal and the fasting plasma glucose concentration in nondiabetic individuals., Research Design and Methods: Two hundred fifty-three nondiabetic subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance received a 75-g oral glucose tolerance test and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-hour plasma glucose concentrations in each group., Results: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2-hour plasma glucose (PG; r = 0.40, P < .0001) but not with the fasting PG. When IFG and NGT individuals were stratified based on their 2-hour PG concentration, the increase in 2-hour PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals., Conclusion: The present results indicate the following: 1) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; 2) the large variability in TGD in IFG and NGT individuals is related to the 2-hour PG concentration; and 3) after adjustment for the 2-hour proglucagon concentration, IFG subjects have comparable TGD with NGT individuals.