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Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration.

ABSTRACT: Diabetic nephropathy is characterized at its onset by glomerular hyperfiltration. Prospective studies in humans measuring filtration rates with weight gain are lacking. We investigated renal filtration following weight gain induced by overfeeding.Eight weeks of overfeeding (40% above energy requirements, 44% fat, 15% protein and 41% carbohydrate) as well as a 6-month follow-up after the overfeeding intervention.Thirty-five participants (age: 26.7 ±5.3 years; body mass index: 25.5 ± 2.2 kg m(-2) ; 29 m/6f).Creatinine clearance rate (Ccr) from 24-h urine collection, estimated glomerular filtration rate (eGFR) from the modification of diet in renal disease (MDRD), insulin sensitivity/glucose disposal rate (GDR) by a euglycemic-hyperinsulinemic clamp, components from basic metabolic panels and serum lipid panels.Both eGFR and Ccr increased with overfeeding (P = 0.04) and serum lipids (all P < 0.05), along with a decrease in insulin sensitivity (P = 0.003). Fasting glucose concentration was not affected (P = 0.98), but the per cent change in Ccr correlated positively with the change in GDR with overfeeding (r = 0.39, P = 0.02). Six months following overfeeding, serum glucose was maintained, and no evidence of urinary glucose was observed at any time-point.These data suggest that renal hyperfiltration may act as a mechanism to preserve insulin sensitivity through maintenance of systemic glucose homoeostasis with caloric excess.

SUBMITTER: Covington JD

PROVIDER: S-EPMC4560986 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration.

Covington J D JD Bray G A GA Redman L M LM Johannsen D L DL Ravussin E E

Journal of internal medicine 20150615 4

<h4>Objective</h4>Diabetic nephropathy is characterized at its onset by glomerular hyperfiltration. Prospective studies in humans measuring filtration rates with weight gain are lacking. We investigated renal filtration following weight gain induced by overfeeding.<h4>Design</h4>Eight weeks of overfeeding (40% above energy requirements, 44% fat, 15% protein and 41% carbohydrate) as well as a 6-month follow-up after the overfeeding intervention.<h4>Subjects</h4>Thirty-five participants (age: 26.7 ...[more]

PMID: 25903638

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Project description:BACKGROUND:High glomerular filtration rate (GFR) is often used as a surrogate for single-nephron hyperfiltration. Our objective was to determine the definition for high GFR that best reflects clinical and structural characteristics of hyperfiltration. METHODS:We studied living kidney donors at the Mayo Clinic and Cleveland Clinic. Potential donors underwent evaluations that included measured GFR (mGFR) by iothalamate clearance and estimated GFR (eGFR) by the serum creatinine-based Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI) equation. High GFR was defined by the 95th percentile for each method (mGFR or eGFR) using either overall or age-specific thresholds. High mGFR was defined as both corrected and uncorrected for body surface area. The association of high GFR by each definition with clinical characteristics and radiologic findings (kidney volume) was assessed. In the subset that donated, the association of high GFR with kidney biopsy findings (nephron number and glomerular volume) and single-nephron GFR was assessed. RESULTS:We studied 3317 potential donors, including 2125 actual donors. The overall 95th percentile for corrected mGFR was 134?mL/min/1.73 m2 and for eGFR was 118?mL/min/1.73 m2. The age-based threshold for uncorrected mGFR was 198?mL/min - 0.943×Age, for corrected mGFR it was 164?mL/min/1.73 m2 - 0.730×Age and for eGFR it was 146?mL/min/1.73 m2 - 0.813×Age. High age-based uncorrected mGFR had the strongest associations with higher single-nephron GFR, larger glomerular volume, larger kidney volume, male gender, higher body mass index and higher 24-h urine albumin, but also had the strongest association with high nephron number. A high age-height-gender-based uncorrected mGFR definition performed almost as well but had a weaker association with nephron number and did not associate with male gender. CONCLUSIONS:High age-based uncorrected mGFR showed the most consistent associations reflective of hyperfiltration. However, high age-based uncorrected mGFR has limited clinical utility because it does not distinguish between hyperfiltration and high nephron number.

Project description:ObjectiveFibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake.MethodsA diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order.ResultsAfter CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml-1, p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n-7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration.ConclusionExcess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.

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Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration.

Publications

Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration.

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