Low-carbohydrate diets

Americans spend dollar 33 billion annually on weight loss products and services, and a large portion of this money is spent on low-carbohydrate diets. Because of their higher protein and fat content and lower fiber and carbohydrate content, concerns have been raised about the potential health consequences of low-carbohydrate diets. Published long-term data are lacking. Short-term studies comparing traditional low-fat diets with low-carbohydrate diets found lower triglyceride levels, higher high-density lipoprotein cholesterol levels, similar low-density lipoprotein cholesterol levels, and lower A1C levels in persons on low-carbohydrate diets. These diets induce greater weight loss at three and six months than traditional low-fat diets; however, by one year there is no significant difference in maintained weight loss. Weight loss is directly related to calorie content and the ability to maintain caloric restriction; the proportions of nutrients in the diet are irrelevant. Low-carbohydrate diets had lower dropout rates than low-fat diets in several studies, possibly because of the high protein content and low glycemic index, which can be appetite suppressing. Data indicate that low-carbohydrate diets are a safe, reasonable alternative to low-fat diets for weight loss. Additional studies are needed to investigate the long-term safety and effectiveness of these and other approaches to weight loss.     

Renal Function Following Three Distinct Weight Loss Dietary Strategies During 2 Years of a Randomized Controlled Trial

OBJECTIVE

This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes.

RESEARCH DESIGN AND METHODS

In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m²; mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m²; mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine <176 μmol/L (eGFR ≥30 mL/min/1.73 m²) were randomized to low-fat, Mediterranean, or low-carbohydrate diets. The 2-year compliance was 85%, and the proportion of protein intake significantly increased to 22% of energy only in the low-carbohydrate diet (P < 0.05 vs. low-fat and Mediterranean). We examined changes in urinary microalbumin and eGFR, estimated by Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formulas.

RESULTS

Significant (P < 0.05 within groups) improvements in eGFR were achieved in low-carbohydrate (+5.3% [95% CI 2.1–8.5]), Mediterranean (+5.2% [3.0–7.4]), and low-fat diets (+4.0% [0.9–7.1]) with similar magnitude (P > 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR <60 mL/min/1.73 m² (+7.1%) versus eGFR ≥60 mL/min/1.73 m² (+3.7%). In a multivariable model adjusted for age, sex, diet group, type 2 diabetes, use of ACE inhibitors, 2-year weight loss, and change in protein intake (confounders and univariate predictors), only a decrease in fasting insulin (β = −0.211; P = 0.004) and systolic blood pressure (β = −0.25; P < 0.001) were independently associated with increased eGFR. The urine microalbumin-to-creatinine ratio improved similarly across the diets, particularly among participants with baseline sex-adjusted microalbuminuria, with a mean change of −24.8 (P < 0.05).

CONCLUSIONS

A low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss–induced improvements in insulin sensitivity and blood pressure.In recent years, growing evidence has linked obesity with progression of kidney disease (1,2) as assessed by deteriorating glomerular filtration rate (GFR) or microalbuminuria. Microalbuminuria has been identified as an early marker of chronic kidney disease (CKD) and as a predictor of progression to end-stage kidney disease (3). Moreover, CKD manifesting with microalbuminuria is an independent risk factor for morbidity and mortality from cardiovascular diseases, diabetes, and hypertension (4,5).There is a graded association between the severity of obesity and the magnitude of microalbuminuria (6,7). Surgical weight loss can normalize glomerular hyperfiltration and the albumin excretion rate in severely obese patients (8), and dietary weight loss trials show benefits on albuminuria, proteinuria, and the decline in the estimated GFR (eGFR) in patients with pre-existing CKD. A review and meta-analysis of 13 studies, including 2 randomized trials, reported that nonsurgical weight loss interventions reduce proteinuria and blood pressure and seem to prevent further decline in renal function (9,10). However, most of the studies were relatively small and duration of follow-up short (typically not exceeding 12 months). Different dietary strategies to promote weight loss have not directly been compared in a randomized, long-term study. This is especially pertinent to low-carbohydrate high-protein diets that are debated for potentially adversely affecting kidney function, especially among patients with diabetes (11,12). A recent study among obese individuals showed that a low-carbohydrate high-protein weight loss diet was not associated with harmful effects on GFR and albuminuria compared with a low-fat diet (13).We therefore investigated the long-term effect of low-fat, Mediterranean, and low-carbohydrate dietary intervention strategies on renal function among overweight or obese people with or without type 2 diabetes and pre-existing mild to moderate renal dysfunction in the Dietary Intervention Randomized Controlled Trial (DIRECT) (14).     

Determinants of high and low attendance to diet and exercise interventions among overweight and obese older adults. Results from the arthritis, diet, and activity promotion trial

BACKGROUND: Determinants of adherence to lifestyle regimens are ill understood. Attendance to intervention sessions is crucial for patients to acquire knowledge and skills regarding the core elements of an intervention. Therefore, we explored demographic, health-related, and social determinants of high and low attendance to diet and exercise sessions among overweight and obese patients with knee osteoarthritis (> or = 60 years; N = 206). METHODS: The Arthritis, Diet, and Activity Promotion Trial was an 18-month randomized controlled trial on the effectiveness of dietary weight loss and exercise interventions. We conducted chi-square and t-tests, and logistic regression analyses on categories of short- and long-term attendance to intervention sessions. RESULTS: Over the 18-month duration of the study, 60.7% (+/- 28.5) of diet sessions, and 53.2% (+/- 29.0) of exercise sessions were attended. Not being married, low social participation, and single intervention randomization predicted high attendance to diet sessions during months 1-4. Exercising at home, and single intervention randomization predicted high attendance to exercise sessions during months 5-18. High attendance to sessions early in the intervention was a significant determinant of high session attendance thereafter. CONCLUSIONS: Offering people a choice where to exercise, and stimulating early intervention session attendance can be effective in improving long-term attendance to both interventions. Several determinants we found may be amenable to change to enhance intervention adherence of future randomized controlled trials involving dietary weight loss and/or physical exercise.     

Effects of Weight Loss,Weight Cycling,and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program

OBJECTIVE

This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors.

RESEARCH DESIGN AND METHODS

This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years.

RESULTS

Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = −0.57 mg/dL per kg, 95% CI −0.66, −0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0–6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits.

CONCLUSIONS

Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.     

Effects of High-Protein Versus High-Carbohydrate Diets on Markers of β-Cell Function,Oxidative Stress,Lipid Peroxidation,Proinflammatory Cytokines,and Adipokines in Obese,Premenopausal Women Without Diabetes: A randomized controlled trial

OBJECTIVE

To study the effects of high-protein versus high-carbohydrate diets on various metabolic end points (glucoregulation, oxidative stress [dichlorofluorescein], lipid peroxidation [malondialdehyde], proinflammatory cytokines [tumor necrosis factor-α and interleukin-6], adipokines, and resting energy expenditure [REE]) with high protein–low carbohydrate (HP) and high carbohydrate–low protein (HC) diets at baseline and after 6 months of dietary intervention.

RESEARCH DESIGN AND METHODS

We recruited obese, premenopausal women aged 20–50 years with no diabetes or prediabetes who were randomized to HC (55% carbohydrates, 30% fat, and 15% protein) or HP (40% carbohydrates, 30% fat, and 30% protein) diets for 6 months. The diets were provided in prepackaged food, which provided 500 kcal restrictions per day. The above metabolic end points were measured with HP and HC diet at baseline and after 6 months of dietary intervention.

RESULTS

After 6 months of the HP versus HC diet (12 in each group), the following changes were significantly different by Wilcoxon rank sum test for the following parameters: dichlorofluorescein (−0.8 vs. −0.3 µmol/L, P < 0.0001), malondialdehyde (−0.4 vs. −0.2 μmol/L, P = 0.0004), C-reactive protein (−2.1 vs. −0.8 mg/L, P = 0.0003), E-selectin (−8.6 vs. −3.7 ng/mL, P = 0.0007), adiponectin (1,284 vs. 504 ng/mL, P = 0.0011), tumor necrosis factor-α (−1.8 vs. −0.9 pg/mL, P < 0.0001), IL-6 (−1.3 vs. −0.4 pg/mL, P < 0.0001), free fatty acid (−0.12 vs. 0.16 mmol/L, P = 0.0002), REE (259 vs. 26 kcal, P < 0.0001), insulin sensitivity (4 vs. 0.9, P < 0.0001), and β-cell function (7.4 vs. 2.1, P < 0.0001).

CONCLUSIONS

To our knowledge, this is the first report on the significant advantages of a 6-month hypocaloric HP diet versus hypocaloric HC diet on markers of β-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in normal, obese females without diabetes.Obesity has reached epidemic proportions in the U.S., where more than one-third of U.S. adults (35.7%) are obese (1,2). Obesity is one of the highest risk factors for type 2 diabetes, heart disease, hypertension, and other metabolic diseases in women (3). Many diets have been recommended for weight loss, but there has been controversy regarding whether a low-carbohydrate or high-protein diet is more efficacious (4–7).The use of high-protein diets for weight loss is based on a number of valid observations. Most studies suggest that high protein intake has the potential to suppress hunger and induce satiety (6,8,9). Different reasons have been postulated for this effect. Low glycemic index (GI) of proteins has been proposed as one such factor. A significant negative relationship is seen between protein content of foods and GI (10). Hyperglycemia after high-GI meals is followed 4–6 h later by a tendency for hypoglycemia with an earlier return of a sensation of hunger (11). Proteins also increase the thermic effect of feeding (12), mostly by increasing protein synthesis. Even though weight loss may not be different between isocaloric high-protein and high-carbohydrate diets, the diet composition can alter a number of other variables. Lipids are considered a primary risk factor for cardiovascular disease. The dietary composition can affect the plasma lipid profile and its metabolism. Some studies have evaluated the relationship of macronutrient composition and lipids (13,14) with greater decrease in triglycerides on a low-carbohydrate diet but no change in other lipid parameters (13). It has been shown that protein intake by itself induces insulin release. Protein is a much less potent secretagogue for insulin than is glucose in normal individuals. If they are given together, the insulin response has been found to be synergistic, and the effect on insulin secretion is only additive (15).A hypocaloric high-protein diet may also help maintain lean body mass and positive nitrogen balance in comparison with a hypocaloric high-carbohydrate diet (16).There are few studies comparing moderately high-carbohydrate diets with a variety of diets with different percentages of macronutrients in which cardiovascular risk factors have been evaluated for at least 6 months. Particularly lacking are studies of markers of oxidative stress, proinflammatory cytokines, and activation of the immune system between high-carbohydrate and high-protein diets.Formulation of a diet with adequate lipid for improved taste and thus better adherence should follow the recommended 30% fat (consisting mostly of unsaturated fat) and adequate fiber recommended by the American Diabetes Association and Institute of Medicine (17,18). Some studies have suggested that calorie restriction is the primary factor for successful weight loss rather than macronutrients per se (6,19,20). Studies by Dandona and coworkers have demonstrated that hyperglycemia during glucose challenge (21), as well as elevation of free fatty acids (FFAs) by triglyceride infusion (Liposyn; Abbott Laboratories, Chicago, IL) (22) lead to activation of leukocytes and reactive oxygen species. In addition, dietary restriction with weight loss can modulate these parameters (23). We have also shown that hyperglycemia in vivo (24) and in vitro (25) activates T cells with de novo expression of growth factor receptors, reactive oxygen species, and inflammatory markers. A similar effect is also observed with saturated FFAs (26). Other studies suggest that obesity, type 2 diabetes, and hyperlipidemia are associated with proinflammatory states (27,28).In our study on macronutrients, we investigated the effects of moderately high-protein diet versus moderately high-carbohydrate diet for 6 months in premenopausal women without diabetes with restriction of 500 kcal intake/day based on resting energy expenditure (REE). We hypothesized that a daily 500-kcal reduction in diet will result in similar amount of weight loss in both groups. We further hypothesized that high-protein diet compared with high-carbohydrate diet might provide greater advantage for various metabolic parameters such as β-cell function, cardiovascular risk factors, oxidative stress, and lipid peroxidation and, therefore, would be a more suitable diet for obese, normal females.     

DIETFITS study (diet intervention examining the factors interacting with treatment success) – Study design and methods

Numerous studies have attempted to identify successful dietary strategies for weight loss, and many have focused on Low-Fat vs. Low-Carbohydrate comparisons. Despite relatively small between-group differences in weight loss found in most previous studies, researchers have consistently observed relatively large between-subject differences in weight loss within any given diet group (e.g., ~ 25 kg weight loss to ~ 5 kg weight gain). The primary objective of this study was to identify predisposing individual factors at baseline that help explain differential weight loss achieved by individuals assigned to the same diet, particularly a pre-determined multi-locus genotype pattern and insulin resistance status. Secondary objectives included discovery strategies for further identifying potential genetic risk scores. Exploratory objectives included investigation of an extensive set of physiological, psychosocial, dietary, and behavioral variables as moderating and/or mediating variables and/or secondary outcomes. The target population was generally healthy, free-living adults with BMI 28–40 kg/m² (n = 600). The intervention consisted of a 12-month protocol of 22 one-hour evening instructional sessions led by registered dietitians, with ~ 15–20 participants/class. Key objectives of dietary instruction included focusing on maximizing the dietary quality of both Low-Fat and Low-Carbohydrate diets (i.e., Healthy Low-Fat vs. Healthy Low-Carbohydrate), and maximally differentiating the two diets from one another. Rather than seeking to determine if one dietary approach was better than the other for the general population, this study sought to examine whether greater overall weight loss success could be achieved by matching different people to different diets. Here we present the design and methods of the study.     

Effects of a Tailored Text Messaging Intervention Among Diverse Adults With Type 2 Diabetes: Evidence From the 15-Month REACH Randomized Controlled Trial

OBJECTIVEText messaging interventions have high potential for scalability and for reductions in health disparities. However, more rigorous, long-term trials are needed. We examined the long-term efficacy and mechanisms of a tailored text messaging intervention.RESEARCH DESIGN AND METHODSAdults with type 2 diabetes participated in a parallel-groups, 15-month randomized controlled trial and were assigned to receive Rapid Education/Encouragement and Communications for Health (REACH) for 12 months or control. REACH included interactive texts and tailored texts addressing medication adherence and nontailored texts supporting other self-care behaviors. Outcomes included hemoglobin A_1c (HbA_1c), diabetes medication adherence, self-care, and self-efficacy.RESULTSParticipants (N = 506) were approximately half racial/ethnic minorities, and half were underinsured, had annual household incomes <$35,000, and had a high school education or less; 11% were homeless. Average baseline HbA_1c was 8.6% ± 1.8%; 70.0 ± 19.7 mmol/mol) with n = 219 having HbA_1c ≥8.5% (69 mmol/mol). Half were prescribed insulin. Retention was over 90%. Median response rate to interactive texts was 91% (interquartile range 75%, 97%). The treatment effect on HbA_1c at 6 months (−0.31%; 95% CI −0.61%, −0.02%) was greater among those with baseline HbA_1c ≥8.5% (−0.74%; 95% CI −1.26%, −0.23%), and there was no evidence of effect modification by race/ethnicity or socioeconomic disadvantage. REACH improved medication adherence and diet through 12 months and self-efficacy through 6 months. Treatment effects were not significant for any outcome at 15 months. REACH reduced barriers to adherence, but barrier reduction did not mediate outcome improvements.CONCLUSIONSREACH engaged at-risk patients in diabetes self-management and improved short-term HbA_1c. More than texts alone may be needed to sustain the effects.     

Adherence of pilus- Opa+ gonococci to epithelial cells in vitro involves heparan sulfate

Neisseria gonorrhoeae attaches to host epithelial cells via pili and opacity-associated (Opa) outer membrane proteins. Pilus- gonococci (Gc) of strain MS11 adhere to both human and nonhuman cells, but only when particular Opa proteins are expressed; OpaA+ variants adhere best, OpaC+ variants are next best, and the seven other Opa+ variants adhere poorly or not at all. The adherence of OpaA+ Gc to Chinese hamster ovary (CHO) cells is inhibited by heparin or heparan sulfate (HS), but not by chondroitin sulfate. OpaA+ Gc do not adhere to CHO cells devoid of HS proteoglycans; low concentrations of heparin restore OpaA+ Gc adherence to these HS-deficient CHO cells and high concentrations inhibit it. 3H-heparin binding to whole Gc parallels their adherence abilities (OpaA+ > OpaC+ > OpaH+ >> Opas B, D, E, F, G, I = Opa- = 0). Opa proteins separated by SDS-PAGE also bind 3H-heparin. These data suggest that adherence of pilus-, Opa+ Gc involves HS-proteoglycan of eukaryotic cells.     

Several Carcinoembryonic Antigens (CD66) Serve as Receptors for Gonococcal Opacity Proteins

Neisseria gonorrhoeae (GC) is a human pathogen that adheres to and invades genital surfaces. Although pili are required for the initial adherence, the interaction of GC with epithelial cells is also promoted by a family of outer membrane proteins, the opacity (Opa) proteins such as OpaA protein from strain MS11. Studies have demonstrated that the interaction of the OpaA GC with epithelial cells involves binding to heparan sulfate attached to syndecan receptors. However, other Opa proteins interact with CEA gene family member 1 (CGM1) or biliary glycoprotein (BGP), members of the CD66 antigen family. In this study, we demonstrate that, in addition, the 180-kD carcinoembryonic antigen (CEA) is a receptor for Opa proteins. This conclusion was based on the following observations. First, transfected HeLa cells expressing CEA (HeLaCEA) and the CEA-expressing colon cancer cell line (LS 174T) bound and subsequently engulfed the Opa⁺ bacteria. These interactions were inhibited by anti-CEA antibody, but could not be inhibited by addition of heparin. Furthermore, OpaI E. coli directly bound purified CEA. We also compared the adherence and invasion by Opa⁺ bacteria of CD66 transfected HeLa cells: HeLa-BGPa, HeLa-CGM6, HeLa-NCA, HeLa-CGM1a, HeLa-CEA, and HeLa-Neo serving as negative control. Using OpaI as the prototype, the relative ability of the transfected HeLa cell lines to support adherence was (CEA = BGPa >CGM1a >NCA >>CGM6 = Neo). The ability to mediate invasion of the transfectant cells was (CGM1a >CEA >BGPa >NCA >CGM6 = Neo). Among the Opa proteins tested, OpaC proved to be bifunctional, able to mediate adherence to both syndecan receptors and to CD66 antigens.     

Diet, behavior modification, and exercise: a review of obesity treatments from a long-term perspective.

Reviewed herein are the long-term weight loss outcomes of three fairly recent major modifications of standard dietary therapy for obesity. Appraised separately and in combination, these therapeutic approaches are very low calorie diets (VLCD), behavior modification, and exercise. The weight loss results from VLCD are impressive for only the first 6 to 10 months. Adding behavioral procedures to VLCD increases the weight loss for the first year or two, but not in 3 to 5 years. Adding exercise further increases the weight loss at 1 to 2 years, and those who continue regular exercise achieve the best weight loss results 1 to 6 years later.     

Intracellular ionic consequences of dietary salt loading in essential hypertension. Relation to blood pressure and effects of calcium channel blockade.

To study the ionic basis of salt sensitivity in hypertension, 19F-, 13P-, and 23Na-nuclear magnetic resonance techniques were used to measure cytosolic free calcium (Cai), pH (pHi), free magnesium (Mgi), and sodium (Nai) in erythrocytes of essential hypertensive subjects (n = 19). Individuals were studied for 2 mo each on low- (UNaV < 50 meq/d) and high- (UNaV > 200 meq/d) salt diets, with the concomitant administration of nifedipine (10 mg t.i.d.) or placebo tablets for 1 mo of each diet. Salt loading elevated Cai and Nai while suppressing Mgi and pHi; these changes occurred predominantly in salt-sensitive subjects (n = 9). Nifedipine blunted the pressor response to salt loading > 50% (delta diastolic BP [high-low salt vs placebo] = 5 +/- 2 vs 14 +/- 2 mmHg, P < 0.05) and reversed salt-induced ionic changes, lowering Cai and elevating Mgi and pHi. Regardless of the definition of salt sensitivity, continuous relationships were observed between the pressure response to salt loading, the levels of Cai (r = 0.726, P < 0.001), Nai (r = 0.747, P < 0.001), and pHi (r = -0.754, P < 0.001), and the salt-induced change in Mgi (r = -0.757, P < 0.001). Altogether, these results emphasize the reciprocal and coordinate nature of intracellular ionic changes in response to dietary salt loading and calcium channel blockade in essential hypertension. They suggest that salt sensitivity is mediated by cellular calcium accumulation from the extracellular space, in association with magnesium depletion and acidification. Lastly, interpretation of intracellular ion measurements in the future will require concurrent assessment of dietary salt intake.     

Effect of different levels of protein intake on renal deterioration and nutritional state in experimental renal disease

We examined the effects of various levels of dietary protein on the course of adriamycin-induced nephropathy in rats fed with high (30%), intermediately low (10%) or strictly low (5%) protein diets for 24 weeks. In the rats fed on the 30% protein diets, there were massive proteinuria, progressive increases in serum creatinine and focal glomerular sclerosis associated with severe tubulo-interstitial changes. With the 5% dietary protein, proteinuria was decreased, the levels of serum creatinine were preserved within normal ranges and renal histological changes diminished. Weight loss and hypoproteinaemia were more marked. With intermediate protein restriction (10% protein), renal function and plasma protein were preserved but body weight did not increase normally. Aggregated human immunoglobulin G, which had been intravenously injected at weeks 12 and 24, accumulated in the glomeruli more densely in rats fed on the 30% protein diet than in those fed on the 10% or 5% protein diets. We tentatively conclude that functional and histological deterioration of focal glomerular sclerosis can be prevented by appropriate restriction of dietary protein; however, severe protein restriction does aggravate nutritional states.     

Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection.

Short-term alterations in dietary carbohydrate (CHO) energy are known to alter whole-body fuel selection in humans, but the metabolic mechanisms remain unknown. We used stable isotope-mass spectrometric methods with indirect calorimetry in normal subjects to quantify the metabolic response to six dietary phases (5 d each), ranging from 50% surplus CHO (+50% CHO) to 50% deficient CHO (-50% CHO), and 50% surplus fat (+50% fat). Fasting hepatic glucose production (HGP) varied by > 40% from deficient to surplus CHO diets (1.78 +/- 0.08 vs 2.43 +/- 0.09 mg/kg per min, P < 0.01). Increased HGP on surplus CHO occurred despite significantly higher serum insulin concentrations. Lipolysis correlated inversely with CHO intake as did the proportion of whole-body lipolytic flux oxidized. Fractional de novo hepatic lipogenesis (DNL) increased more than 10-fold on surplus CHO and was unmeasurable on deficient CHO diets; thus, the preceding 5-d CHO intake could be inferred from DNL. Nevertheless, absolute hepatic DNL accounted for < 5g fatty acids synthesized per day even on +50% CHO. Whole-body CHO oxidation increased sixfold and fat oxidation decreased > 90% on surplus CHO diets. CHO oxidation was highly correlated with HGP (r2= 0.60). HGP could account for 85% of fasting CHO oxidation on +25% CHO and 67% on +50% CHO diets. Some oxidation of intracellular CHO stores was therefore also occurring. +50% fat diet had no effects on HGP, DNL, or fuel selection. We conclude that altered CHO intake alters HGP specifically and in a dose-dependent manner, that HGP may mediate the effects of CHO on whole-body fuel selection both by providing substrate and by altering serum insulin concentrations, that altered lipolysis and tissue oxidation efficiency contribute to changes in fat oxidation, and that surplus CHO is not substantially converted by the liver to fat as it spares fat oxidation, but that fractional DNL may nevertheless be a qualitative marker of recent CHO intake.     

Low Carbohydrate–Diet Scores and Long-term Risk of Type 2 Diabetes Among Women With a History of Gestational Diabetes Mellitus: A Prospective Cohort Study

OBJECTIVE

Low-carbohydrate diets (LCDs) may improve short-term glycemic control in patients with gestational diabetes mellitus (GDM), but the long-term effect on progression from GDM to type 2 diabetes mellitus (T2DM) is unknown. We aimed to examine the long-term risk of T2DM in association with a low-carbohydrate dietary pattern among women with a history of GDM.

RESEARCH DESIGN AND METHODS

Overall, 4,502 women with a history of GDM from the Nurses'' Health Study II (NHSII) cohort, as part of the Diabetes & Women’s Health (DWH) study, were followed up from 1991 to 2011. Overall, animal, or vegetable LCD scores, which represent adherence to different low-carbohydrate dietary patterns, were calculated using diet intake information assessed every 4 years since 1991 by validated food-frequency questionnaires. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs.

RESULTS

We documented 722 incident cases of T2DM during 68,897 person-years of observation. The multivariable-adjusted HRs (95% CIs) of T2DM, comparing the highest with lowest quintiles, were 1.36 (1.04–1.78) for overall LCD score (P = 0.003 for trend), 1.40 (1.06–1.84) for animal LCD score (P = 0.004 for trend), and 1.19 (0.91–1.55) for vegetable LCD score (P = 0.50 for trend).

CONCLUSIONS

Among women with a history of GDM, a low-carbohydrate dietary pattern, particularly with high protein and fat intake mainly from animal-source foods, is associated with higher T2DM risk, whereas a low-carbohydrate dietary pattern with high protein and fat intake from plant-source foods is not significantly associated with risk of T2DM.     

Standard operating procedures for antibiotic therapy and the occurrence of acute kidney injury: a prospective,clinical, non-interventional,observational study

Introduction

Acute kidney injury (AKI) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of AKI.

Methods

This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charité – Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). AKI was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of AKI was compared between groups with exact Chi²-test and multivariate logistic regression analysis (two-sided P <0.05).

Results

LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). AKI occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop AKI compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039).

Conclusion

Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of AKI.

Trial registration

Current Controlled Trials ISRCTN54598675. Registered 17 August 2007.     

Low dietary adherence after a positive food challenge in food allergic adults

BackgroundAfter a positive food challenge (FC), patients receive dietary advice regarding avoidance of the culprit food. We examined the frequency and variables associated with dietary adherence after a positive FC in adults.MethodsIn this prospective daily practice study, adults with a positive FC were included. After every FC, dietary advice was given consisting of three options: (1) strict avoidance, (2) avoidance but products with precautionary allergen labelling (PAL) allowed and (3) (small) amounts allowed. Questionnaires about dietary adherence and associated variables were completed prior to and 6 months after the FC(s).Results41 patients (with 58 positive FCs) were included. Overall, patients adhered to the advised diet after 31% of the FCs. After 33 FCs, the advice was strict avoidance, whereof 82% followed a less strict diet. After 16 FCs, the advice was avoidance but products with PAL allowed, whereof 19% followed a less strict and 25% a stricter diet. In 9 FCs with the least strict advice, “(small) amounts allowed’’, 67% followed a stricter diet. Three variables were associated with adherence: misremembering dietary advice, impaired health‐related quality of life (HRQL) on domain “Emotional impact’’ and the need for dietary change after the FC.ConclusionAfter one third of the positive FCs, patients adhered to the dietary advice. Variables associated with adherence were misremembering dietary advice, impaired HRQL on domain “Emotional impact’’ and the need for dietary change after the FC. It seems important that healthcare professionals should more frequently apply adherence‐enhancing strategies to improve dietary adherence.     

Two patterns of adipokine and other biomarker dynamics in a long-term weight loss intervention

OBJECTIVE

Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain.

RESEARCH DESIGN AND METHODS

We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss.

RESULTS

We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0–6) going in the opposite direction to that in the weight maintenance/regain phase (months 7–24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B.

CONCLUSIONS

hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.Long-term dietary intervention typically induces a rapid weight decline that stabilizes by 6 months. This weight loss phase is followed by weight stabilization or partial to full weight regain despite continued dieting (1). Although it is clear that weight cycling as a result of repeated attempts to lose weight greatly diminishes the beneficial effects of healthier dietary habits (2), whether continued long-term dieting can indeed improve cardiovascular and metabolic risk even beyond weight loss and despite weight regain has remained unclear. Furthermore, it is not well established whether certain biomarkers primarily reflect weight changes or correspond to the continued dieting in long-term dietary intervention.Here we sought to identify adipokines and other biomarkers that may reflect continued beneficial effects of dieting, despite partial weight regain, using new analyses from the Dietary Intervention Randomized Controlled Trial (DIRECT) (3). This 2-year weight loss trial was characterized by high retention rates (95% after 1 year and 85% after 2 years) and a high level of proven adherence (4) to the three distinct dietary strategies: low-fat, Mediterranean, and low-carbohydrate diets (3). Although the three interventions were different, in all three groups, the participants similarly increased the consumption of vegetables and decreased intake of snacks, sugared beverages, and processed foods, suggesting a common denominator of healthful dietary patterns across all groups compared with baseline (5). Diet intervention in the DIRECT study resulted in two segments: a rapid weight loss phase during the first 6 months and a partial regain/plateau phase during the subsequent 18 months of intervention (3,6).To determine the correspondence between weight change dynamics and the change among biomarkers, we used both a nonbiased mathematical modeling approach and qualitative analysis, assessing traditional biomarkers (HDL cholesterol [HDL-C], triglycerides [TGs], insulin, high-sensitivity C-reactive protein [hsCRP], high molecular weight [HMW] adiponectin, and leptin) and more recently discovered adipokines, including chemerin (7), monocyte chemoattractant protein 1 (MCP-1) (8), progranulin (9), fetuin-A (10), retinol-binding protein 4 (RBP4) (11–13), and vaspin (14).     

Changes in Plant-Based Diet Indices and Subsequent Risk of Type 2 Diabetes in Women and Men: Three U.S. Prospective Cohorts

OBJECTIVEWe evaluated the associations between changes in plant-based diets and subsequent risk of type 2 diabetes.RESEARCH DESIGN AND METHODSWe prospectively followed 76,530 women in the Nurses’ Health Study (NHS) (1986–2012), 81,569 women in NHS II (1991–2017), and 34,468 men in the Health Professionals Follow-up Study (1986–2016). Adherence to plant-based diets was assessed every 4 years with the overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs). We pooled results of the three cohorts using meta-analysis.RESULTSWe documented 12,627 cases of type 2 diabetes during 2,955,350 person-years of follow-up. After adjustment for initial BMI and initial and 4-year changes in alcohol intake, smoking, physical activity, and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest decrease (>10%) in PDI and hPDI over 4 years had a 12–23% higher diabetes risk in the subsequent 4 years (pooled HR, PDI 1.12 [95% CI 1.05, 1.20], hPDI 1.23 [1.16, 1.31]). Each 10% increment in PDI and hPDI over 4 years was associated with a 7–9% lower risk (PDI 0.93 [0.91, 0.95], hPDI 0.91 [0.87, 0.95]). Changes in uPDI were not associated with diabetes risk. Weight changes accounted for 6.0–35.6% of the associations between changes in PDI and hPDI and diabetes risk.CONCLUSIONSImproving adherence to overall and healthful plant-based diets was associated with a lower risk of type 2 diabetes, whereas decreased adherence to such diets was associated with a higher risk.     

The relationship between headache-attributed disability and lost productivity: 2. Empirical evidence from population-based studies in nine disparate countries

BackgroundHeadache disorders are disabling, with major consequences for productivity, yet the literature is silent on the relationship between headache-attributed disability and lost productivity, often erroneously regarding the two as synonymous. We evaluated the relationship empirically, having earlier found that investment in structured headache services would be cost saving, not merely cost-effective, if reductions in headache-attributed disability led to > 20% pro rata recovery of lost productivity.MethodsWe used individual participant data from Global Campaign population-based studies conducted in China, Ethiopia, India, Nepal, Pakistan and Russia, and from Eurolight in Lithuania, Luxembourg and Spain. We assessed relationships in migraine and probable medication-overuse headache (pMOH), the most disabling common headache disorders. Available symptom data included headache frequency, usual duration and usual intensity. We used frequency and duration to estimate proportion of time in ictal state (pTIS). Disability, in the sense used by the Global Burden of Disease study, was measured as the product of pTIS and disability weight for the ictal state. Impairment was measured as pTIS * intensity. Lost productivity was measured as lost days (absence or < 50% productivity) from paid work and corresponding losses from household work over the preceding 3 months. We used Spearman correlation and linear regression analyses.ResultsFor migraine, in a linear model, we found positive associations with lost paid worktime, significant (p < 0.05) in many countries and highly significant (p < 0.001) in some despite low values of R² (0–0.16) due to high variance. With lost household worktime and total lost productivity (paid + household), associations were highly significant in almost all countries, although still with low R² (0.04–0.22). Applying the regression equations for each country to the population mean migraine-attributed disability, we found pro rata recoveries of lost productivity in the range 16–56% (> 20% in all countries but Pakistan). Analysing impairment rather than disability increased variability. For pMOH, with smaller numbers, associations were generally weaker, occasionally negative and mostly not significant.ConclusionRelief of disability through effective treatment of migraine is expected, in most countries, to recover > 20% pro rata of lost productivity, above the threshold for investment in structured headache services to be cost saving.     

Longitudinal study of bone loss in chronic spinal cord injury patients

[Purpose] This prospective longitudinal study evaluated the changes in bone metabolism markers and bone mineral density of spinal cord injury patients over 3 years. We also assessed the relationships among the bone mineral density, bone metabolism, and clinical data of spinal cord injury patients. [Subjects and Methods] We assessed the clinical data (i.e., immobilization due to surgery, neurological status, neurological level, and extent of lesion) in 20 spinal cord injury patients. Bone mineral density, and hormonal and biochemical markers of the patients were measured at 0, 6, 12, and 36 months. [Results] Femoral neck T score decreased significantly at 36 months (p < 0.05). Among the hormonal markers, parathyroid hormone and vitamin D were significantly elevated, while bone turnover markers (i.e., deoxypyridinoline and osteocalcin) were significantly decreased at 12 and 36 months (p < 0.05). [Conclusion] Bone mineral density of the femoral neck decreases significantly during the long-term follow-up of patients with spinal cord injury due to osteoporosis. This could be due to changes in hormonal and bone turnover markers.Key words: Bone loss, Spinal cord injury, Bone mineral density