The Ob protein (leptin) and the kidney

The Ob protein (leptin) and the kidney. Mutation of the Ob gene, which encodes for leptin, or mutation of the leptin receptor leads to obesity in mice. Humans, for the most part, have a positive correlation of leptin with body fat mass suggesting possible defects in leptin effector mechanisms that may contribute to obesity. As patients on hemodialysis have difficulty with appetite, we investigated whether leptin is cleared by the kidney and is elevated in hemodialysis patients. In patients with intact renal function there was a net renal uptake of 12% of circulating leptin, whereas in patients with renal insufficiency there was no renal uptake of leptin. In a separate cohort of 36 patients with end-stage renal disease (ESRD), peripheral leptin levels factored for body mass index was increased by fourfold as compared to a group of healthy controls (N = 338). The leptin receptor exists in a long and short form, with the long form primarily expressed in the hypothalamus but also in the lungs and kidneys of the mouse. Further studies are necessary to clarify the role of leptin in regulating appetite in patients with ESRD and the role of leptin in directly affecting kidney function via its receptors

Acute and second-meal effects of almond form in impaired glucose tolerant adults: a randomized crossover trial

<p>Abstract</p> <p>Background</p> <p>Nut consumption may reduce the risk of developing type 2 diabetes. The aim of the current study was to measure the acute and second-meal effects of morning almond consumption and determine the contribution of different nut fractions.</p> <p>Methods</p> <p>Fourteen impaired glucose tolerant (IGT) adults participated in a randomized, 5-arm, crossover design study where whole almonds (WA), almond butter (AB), defatted almond flour (AF), almond oil (AO) or no almonds (vehicle - V) were incorporated into a 75 g available carbohydrate-matched breakfast meal. Postprandial concentrations of blood glucose, insulin, non-esterified free fatty acids (NEFA), glucagon-like peptide-1 (GLP-1) and appetitive sensations were assessed after treatment breakfasts and a standard lunch.</p> <p>Results</p> <p>WA significantly attenuated second-meal and daylong blood glucose incremental area under the curve (AUCI) and provided the greatest daylong feeling of fullness. AB and AO decreased blood glucose AUCI in the morning period and daylong blood glucose AUCI was attenuated with AO. WA and AO elicited a greater second-meal insulin response, particularly in the early postprandial phase, and concurrently suppressed the second-meal NEFA response. GLP-1 concentrations did not vary significantly between treatments.</p> <p>Conclusions</p> <p>Inclusion of almonds in the breakfast meal decreased blood glucose concentrations and increased satiety both acutely and after a second-meal in adults with IGT. The lipid component of almonds is likely responsible for the immediate post-ingestive response, although it cannot explain the differential second-meal response to AB versus WA and AO.</p

Mastication of Nuts under Realistic Eating Conditions: Implications for Energy Balance

The low digestibility and high satiety effects of nuts have been partly attributed to mastication. This work examines chewing forces and the bolus particle size of nuts (walnuts, almonds, pistachios) varying in physical properties under different conditions (with and without water, juice, sweetened yogurt and plain yogurt) along with satiety sensations and gut hormone concentrations following walnut consumption (whole or butter). In a randomized, cross-over design with 50 adults (25 males, 25 females; Body Mass Index (BMI) 24.7 ± 3.4 kg/m²; age: 18⁻52 years old (y/o), the chewing forces and particle size distribution of chewed nuts were measured under different chewing conditions. Appetite sensations were measured at regular intervals for 3 h after nut intake, and plasma samples were collected for the measurement of glucose, insulin and Glucagon-like peptide-1 (GLP-1). The three nuts displayed different particle sizes at swallowing though no differences in chewing forces were observed. Walnuts with yogurt yielded larger particle sizes than the other treatments. Particle size was not correlated with either food palatability or flavor. Fullness sensations were higher after whole nut than nut butter consumption though there were no significant changes in glucose, insulin, or GLP-1 concentrations under any condition. Changing the conditions at swallowing might influence the release of energy from nuts

Hepatocyte growth factor regulates neovascularization in developing fat pads

In this study, we used lentiviral-delivered shRNA to generate a clonal line of 3T3-F442A preadipocytes with stable silencing of hepatocyte growth factor (HGF) expression and examined the long-term consequence of this modification on fat pad development. HGF mRNA expression was reduced 94%, and HGF secretion 79% (P < 0.01), compared with preadipocytes treated with nontargeting shRNA. Fat pads derived from HGF knockdown preadipocytes were significantly smaller (P < 0.01) than control pads beginning at 3 days postinjection (0.022 ± 0.003 vs. 0.037 ± 0.004 g), and further decreased in size at day 7 (0.015 ± 0.004 vs. 0.037 ± 0.003 g) and day 14 (0.008 ± 0.002 vs. 0.045 ± 0.007 g). Expression of the endothelial cell genes TIE1 and PECAM1 increased over time in control fat pads (1.6 ± 0.4 vs. 11.4 ± 1.7 relative units at day 3 and 14, respectively; P < 0.05) but not in HGF knockdown fat pads (1.1 ± 0.5 vs. 5.9 ± 2.2 relative units at day 3 and 14). Contiguous vascular structures were observed in control fat pads but were much less developed in HGF knockdown fat pads. Differentiation of preadipocytes to mature adipocytes was significantly attenuated in HGF knockdown fat pads. Fat pads derived from preadipocytes with knockdown of the HGF receptor c-MET were smaller than control pads at day 3 postinjection (0.034 ± 0.002 vs. 0.049 ± 0.004 g; P < 0.05), and remained the same size through day 14. c-MET knockdown fat pads developed a robust vasculature, and preadipocytes differentiated to mature adipocytes. Overall these data suggest that preadipocyte-secreted HGF is an important regulator of neovascularization in developing fat pads

Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection Versus Insulin Alone in Type 2 Diabetes

Context Glucagon-like peptide-1 (GLP-1) and the clinically available GLP-1 agonists have been shown to exert effects on the heart. It is unclear whether these effects occur at clinically used doses in vivo in humans, possibly contributing to CVD risk reduction. Objective To determine whether liraglutide at clinical dosing augments myocardial glucose uptake alone or in combination with insulin compared to insulin alone in metformin-treated Type 2 diabetes mellitus. Design Comparison of myocardial fuel utilization after 3 months of treatment with insulin detemir, liraglutide, or combination detemir+liraglutide. Setting Academic hospital Participants Type 2 diabetes treated with metformin plus oral agents or basal insulin. Interventions Insulin detemir, liraglutide, or combination added to background metformin Main Outcome Measures Myocardial blood flow, fuel selection and rates of fuel utilization evaluated using positron emission tomography, powered to demonstrate large effects. Results We observed greater myocardial blood flow in the insulin-treated groups (median[25th, 75th percentile]: detemir 0.64[0.50, 0.69], liraglutide 0.52[0.46, 0.58] and detemir+liraglutide 0.75[0.55, 0.77] mL/g/min, p=0.035 comparing 3 groups and p=0.01 comparing detemir groups to liraglutide alone). There were no evident differences between groups in myocardial glucose uptake (detemir 0.040[0.013, 0.049], liraglutide 0.055[0.019, 0.105], detemir+liraglutide 0.037[0.009, 0.046] µmol/g/min, p=0.68 comparing 3 groups). Similarly there were no treatment group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusions These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection

Comparison of β-Cell Function Between Overweight/Obese Adults and Adolescents Across the Spectrum of Glycemia

OBJECTIVE: Type 2 diabetes is a growing health problem among both adults and adolescents. To better understand the differences in the pathogenesis of diabetes between these groups, we examined differences in β-cell function along the spectrum of glucose tolerance. RESEARCH DESIGN AND METHODS: We evaluated 89 adults and 50 adolescents with normal glucose tolerance (NGT), dysglycemia, or type 2 diabetes. Oral glucose tolerance test results were used for C-peptide and insulin/glucose minimal modeling. Model-derived and direct measures of insulin secretion and insulin sensitivity were compared across glycemic stages and between age-groups at each stage. RESULTS: In adolescents with dysglycemia, there was marked insulin resistance (insulin sensitivity index: adolescents, median [interquartile range] 1.8 [1.1-2.4] × 10-4; adults, 5.0 [2.3-9.9]; P = 0.01). The nature of β-cell dysfunction across stages of dysglycemia differed between the groups. We observed higher levels of secretion among adolescents than adults (total insulin secretion: NGT, 143 [103-284] × 10-9/min adolescent vs. 106 [71-127], P = 0.001); adults showed stepwise impairments in static insulin secretion (NGT, 7.5 [4.0-10.3] × 10-9/min; dysglycemia, 5.0 [2.3-9.9]; type 2 diabetes, 0.7 [0.1-2.45]; P = 0.003), whereas adolescents showed diabetes-related impairment in dynamic secretion (NGT, 1,905 [1,630-3,913] × 10-9; dysglycemia, 2,703 [1,323-3,637]; type 2 diabetes, 1,189 [269-1,410]; P = 0.001). CONCLUSIONS: Adults and adolescents differ in the underlying defects leading to dysglycemia, and in the nature of β-cell dysfunction across stages of dysglycemia. These results may suggest different approaches to diabetes prevention in youths versus adults

Retinopathy predicts progression of fasting plasma glucose: An Early Diabetes Intervention Program (EDIP) analysis

Background Retinopathy is increasingly recognized in prediabetic populations, and may herald increased risk of metabolic worsening. The Early Diabetes Intervention Program (EDIP) evaluated worsening of glycemia in screen-detected Type 2 diabetes, following participants for up to 5 years. Here we have evaluated whether the presence of retinopathy at the time of detection of diabetes was associated with accelerated progression of glycemia. Methods We prospectively studied 194 participants from EDIP with available baseline retinal photographs. Retinopathy was determined at baseline using 7-field fundus photography and defined as an Early Treatment of Diabetic Retinopathy Study Scale grading score of ≥ 20. Results At baseline, 12% of participants had classical retinal lesions indicating retinopathy. In univariate Cox proportional hazard analysis, the presence of retinopathy at baseline was associated with a doubled risk of progression of fasting plasma glucose (HR 2.02; 95% CI 1.05–3.89). The retinopathy effect was robust to individual adjustment for age and glucose, the most potent determinants of progression in EDIP. Conclusion Retinopathy was associated with increased risk of progression of fasting plasma glucose among adults with screen-detected, early diabetes. Early detection of retinopathy may help individualize more aggressive therapy to prevent progressive metabolic worsening in early diabetes

Almond consumption decreases android fat mass percentage in adults with high android subcutaneous adiposity but does not change HbA1c in a randomised controlled trial

The purpose of this study was to determine if the mixed evidence of almond consumption on HbA1c stems from testing people with different body fat distributions (BFD) associated with different risks of glucose intolerance. A 6-month randomised controlled trial in 134 adults was conducted. Participants were randomly assigned to the almond (A) or control (C) group based on their BFD. Those in the almond group consumed 1·5 oz of almonds with their breakfast and as their afternoon snack daily. Those in the control group continued their habitual breakfast and afternoon snack routines. Body weight and composition were measured and blood samples were collected for determination of HbA1c, glycaemia and lipaemia at 0 and 6 months. Appetite ratings, energy intake and diet quality were collected at 0, 2, 4 and 6 months. Participants consuming almonds ingested 816 (sem 364) kJ/d more than participants in the control group (P = 0·03), but this did not result in any differences in body weight (A: –0·3 (sem 0·4), C: –0·4 (sem 0·4); P > 0·3). Participants in the almond, high android subcutaneous adipose tissue (SAT) group had a greater reduction in android fat mass percentage (A: –1·0 (sem 0·6), C: 1·1 (sem 0·6); P = 0·04), preserved android lean mass percentage (A: 0·9 (sem 0·6), C: –1 (sem 0·6); P = 0·04) and tended to decrease android visceral adipose tissue mass (A: –13 (sem 53) g, C: 127 (sem 53) g; P = 0·08) compared with those in the control, high SAT group. There were no differences in HbA1c between groups (A: 5·4 (sem 0·04), C: 5·5 (sem 0·04); P > 0·05). Thus, BFD may not explain the mixed evidence on almond consumption and HbA1c. Long-term almond consumption has limited ability to improve cardiometabolic health in those who are overweight and obese but otherwise healthy

Inquiry into the short- and long-term effects of Roux-en-Y gastric bypass on the glomerular filtration rate

Bariatric surgery is known to attenuate glomerular hyperfiltration over the long term and thereby protect the kidney from mechanical damage. Whether this effect is directly related to weight loss or is independent of weight as are some of its other beneficial metabolic effects is not known. We explored this question in a preliminary study that directly measured glomerular filtration rate (GFR) before, immediately after, and again many months after Roux-en-Y gastric bypass after large weight loss had occurred. We simultaneously measured stimulated circulating glucagon-like peptide-1, which is upregulated after Roux-en-Y gastric bypass and is a putative mediator of GFR after bariatric surgery. We found no weight-independent effect of Roux-en-Y gastric bypass on GFR nor an association between circulating GLP-1 levels and GFR. These findings, if confirmed in larger studies, will help steer future enquiries in this area

Correlation between Ventromedial Prefrontal Cortex Activation to Food Aromas and Cue-driven Eating: An fMRI Study

Food aromas are signals associated with both food's availability and pleasure. Previous research from this laboratory has shown that food aromas under fasting conditions evoke robust activation of medial prefrontal brain regions thought to reflect reward value (Bragulat, et al. 2010). In the current study, eighteen women (eleven normal-weight and seven obese) underwent a two-day imaging study (one after being fed, one while fasting). All were imaged on a 3T Siemens Trio-Tim scanner while sniffing two food (F; pasta and beef) odors, one non-food (NF; Douglas fir) odor, and an odorless control (CO). Prior to imaging, participants rated hunger and perceived odor qualities, and completed the Dutch Eating Behavior Questionnaire (DEBQ) to assess “Externality” (the extent to which eating is driven by external food cues). Across all participants, both food and non-food odors (compared to CO) elicited large blood oxygenation level dependent (BOLD) responses in olfactory and reward-related areas, including the medial prefrontal and anterior cingulate cortex, bilateral orbitofrontal cortex, and bilateral piriform cortex, amygdala, and hippocampus. However, food odors produced greater activation of medial prefrontal cortex, left lateral orbitofrontal cortex and inferior insula than non-food odors. Moreover, there was a significant correlation between the [F > CO] BOLD response in ventromedial prefrontal cortex and “Externality” sub-scale scores of the DEBQ, but only under the fed condition; no such correlation was present with the [NF > CO] response. This suggests that in those with high Externality, ventromedial prefrontal cortex may inappropriately valuate external food cues in the absence of internal hunger