Effect of large weight reductions on measured and estimated kidney function

BACKGROUND: When patients experience large weight loss, muscle mass may be affected followed by changes in plasma creatinine (pCr). The MDRD and CKD-EPI equations for estimated GFR (eGFR) include pCr. We hypothesised that a large weight loss reduces muscle mass and pCr causing increase in eGFR (creatinine-based equations), whereas measured GFR (mGFR) and cystatin C-based eGFR would be unaffected if adjusted for body surface area. METHODS: Prospective, intervention study including 19 patients. All attended a baseline visit before gastric bypass surgery followed by a visit six months post-surgery. mGFR was assessed during four hours plasma (51)Cr-EDTA clearance. GFR was estimated by four equations (MDRD, CKD-EPI-pCr, CKD-EPI-cysC and CKD-EPI-pCr-cysC). DXA-scans were performed at baseline and six months post-surgery to measure changes in lean limb mass, as a surrogate for muscle mass. RESULTS: Patients were (mean ± SD) 40.0 ± 9.3 years, 14 (74%) were female and 5 (26%) had type 2 diabetes, baseline weight was 128 ± 19 kg, body mass index 41 ± 6 kg/m2 and absolute mGFR 122 ± 24 ml/min. Six months post-surgery weight loss was 27 (95% CI: 23; 30) kg, mGFR decreased by 9 (−17; −2) from 122 ± 24 to 113 ± 21 ml/min (p = 0.024), but corrected for current body surface area (BSA) mGFR was unchanged by 2 (−5; 9) ml/min/1.73 m(2) (p = 0.52). CKD-EPI-pCr increased by 12 (6; 17) and MDRD by 13 (8; 18) (p < 0.001 for both), while CKD-EPI-cysC was unchanged by 2 (−8; 4) ml/min/1.73 m(2) (p = 0.51). Lean limb mass was reduced by 3.5 (−4.4;−2.6; p < 0.001) kg and change in lean limb mass correlated with change in plasma creatinine (R (2) = 0.28, p = 0.032). CONCLUSIONS: Major weight reductions are associated with a reduction in absolute mGFR, which may reflect resolution of glomerular hyperfiltration, while mGFR adjusted for body surface area was unchanged. Estimates of GFR based on creatinine overestimate renal function likely due to changes in muscle mass, whereas cystatin C based estimates are unaffected. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02138565. Date of registration: March 24, 2014

Altered PI3-kinase/Akt signalling in skeletal muscle of young men with low birth weight.

BACKGROUND: Low birth weight (LBW) is associated with increased future risk of insulin resistance and type 2 diabetes mellitus. The underlying molecular mechanisms remain poorly understood. We have previously shown that young LBW men have reduced skeletal muscle expression of PI3K p85alpha regulatory subunit and p110beta catalytic subunit, PKCzeta and GLUT4 in the fasting state. The aim of this study was to determine whether insulin activation of the PI3K/Akt and MAPK signalling pathways is altered in skeletal muscle of young adult men with LBW. METHODS: Vastus lateralis muscle biopsies were obtained from 20 healthy 19-yr old men with BW< or = 10th percentile for gestational age (LBW) and 20 normal birth weight controls (NBW), matched for physical fitness and whole-body glucose disposal, prior to (fasting state) and following a 4-hr hyperinsulinemic euglycemic clamp (insulin stimulated state). Expression and phosphorylation of selected proteins was determined by Western blotting. PRINCIPAL FINDINGS: Insulin stimulated expression of aPKCzeta (p<0.001) and Akt1 (p<0.001) was decreased in muscle of LBW men when compared to insulin stimulated controls. LBW was associated with increased insulin stimulated levels of IRS1 (p<0.05), PI3K p85alpha (p<0.001) and p110beta (p<0.05) subunits, while there was no significant change in these proteins in insulin stimulated control muscle. In addition LBW had reduced insulin stimulated phospho-Akt (Ser 473) (p<0.01), indicative of reduced Akt signalling. Insulin stimulated expression/phosphorylation of all the MAPK proteins studied [p38 MAPK, phospho-p38 MAPK (Thr180/Tyr182), phospho-ERK (Thr 202/Tyr204), JNK1, JNK2 and phospho-JNK (Thr 183/Tyr185)] was not different between groups. CONCLUSIONS: We conclude that altered insulin activation of the PI3K/Akt but not the MAPK pathway precedes and may contribute to development of whole-body insulin resistance and type 2 diabetes in men with LBW

Antidiabetic Actions of Endogenous and Exogenous GLP-1 in Type 1 Diabetic Patients With and Without Residual β-Cell Function

OBJECTIVE—To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual b-cell function. RESEARCH DESIGN AND METHODS—Eight type 1 diabetic patients with (T1D+), eight without (T1D2) residual b-cell func-tion, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured

Chenodeoxycholic acid stimulates glucagon-like peptide-1 secretion in patients after Roux-en-Y gastric bypass

Postprandial secretion of glucagon‐like peptide‐1 (GLP‐1) is enhanced after Roux‐en‐Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP‐1 secretion through activation of TGR5‐receptors. We aimed to evaluate GLP‐1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB‐operated participants. Eleven participants (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo‐controlled, crossover‐study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral intake of CDCA increased plasma concentrations of GLP‐1, C‐peptide, glucagon, peptide YY, neurotensin, total bile acids, and fibroblast growth factor 19 significantly compared with placebo (all P < 0.05 for peak and positive incremental area‐under‐the‐curve (piAUC)). All plasma hormone concentrations were unaffected by UDCA. Neither UDCA nor CDCA changed glucose, cholecystokinin or glucose‐dependent insulinotropic polypeptide (GIP) concentrations. In conclusion, our findings demonstrate that the primary bile acid chenodeoxycholic acid is able to enhance secretion of gut hormones when administered orally in RYGB‐operated patients—even in the absence of nutrients