Acute Caloric Restriction Research Articles

The Impact of Acute Nutritional Interventions on the Plasma Proteome.

Humans respond profoundly to changes in diet, while nutrition and environment have a great impact on population health. It is therefore important to deeply characterize the human nutritional responses. Endocrine parameters and the metabolome of human plasma are rapidly responding to acute nutritional interventions such as caloric restriction or a glucose challenge. It is less well understood whether the plasma proteome would be equally dynamic, and whether it could be a source of corresponding biomarkers. We used high-throughput mass spectrometry to determine changes in the plasma proteome of i) 10 healthy, young, male individuals in response to 2 days of acute caloric restriction followed by refeeding; ii) 200 individuals of the Ely epidemiological study before and after a glucose tolerance test at 4 time points (0, 30, 60, 120 minutes); and iii) 200 random individuals from the Generation Scotland study. We compared the proteomic changes detected with metabolome data and endocrine parameters. Both caloric restriction and the glucose challenge substantially impacted the plasma proteome. Proteins responded across individuals or in an individual-specific manner. We identified nutrient-responsive plasma proteins that correlate with changes in the metabolome, as well as with endocrine parameters. In particular, our study highlights the role of apolipoprotein C1 (APOC1), a small, understudied apolipoprotein that was affected by caloric restriction and dominated the response to glucose consumption and differed in abundance between individuals with and without type 2 diabetes. Our study identifies APOC1 as a dominant nutritional responder in humans and highlights the interdependency of acute nutritional response proteins and the endocrine system.

Partial Body Mass Recovery After Caloric Restriction Abolishes Improved Glucose Tolerance in Obese, Insulin Resistant Rats.

Caloric restriction, among other behavioral interventions, has demonstrated benefits on improving glycemic control in obesity-associated diabetic subjects. However, an acute and severe intervention without proper maintenance could reverse the initial benefits, with additional metabolic derangements. To assess the effects of an acute caloric restriction in a metabolic syndrome model, a cohort of 15-week old Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were calorie restricted (CR: 50% × 10 days) with or without a 10-day body mass (BM) recovery period, along with their respective ad libitum controls. An oral glucose tolerance test (oGTT) was performed after CR and BM recovery. Both strains had higher rates of mass gain during recovery vs. ad lib controls; however, the regain was partial (ca. 50% of ad lib controls) over the measurement period. Retroperitoneal and epididymal adipose masses decreased 30% (8.8 g, P < 0.001) in OLETF; however, this loss only accounted for 11.5% of the total BM loss. CR decreased blood glucose AUC 16% in LETO and 19% in OLETF, without significant decreases in insulin. Following CR, hepatic expression of the gluconeogenic enzyme, PEPCK, was reduced 55% in OLETF compared to LETO, and plasma triglycerides (TG) decreased 86%. Acute CR induced improvements in glucose tolerance and TG suggestive of improvements in metabolism; however, partial recovery of BM following CR abolished the improvement in glucose tolerance. The present study highlights the importance of proper maintenance of BM after CR as only partial recovery of the lost BM reversed benefits of the initial mass loss.

Abstract 061: Systolic Blood Pressure is Maintained Despite Varying Degrees of Acute Caloric Restriction and Sodium-Glucose Cotransporter-2 Inhibition in Obese, Insulin Resistant Rats

A 5-10% reduction of body mass by caloric restriction (CR) has been effective in normalizing SBP in hypertensive patients. Moreover, SGLT2 inhibitors lowered SBP in spontaneous hypertensive rats and are considered a therapeutic alternative to patients with T2DM concomitant with hypertension. However, these potential benefits have not been fully addressed in a model of metabolic syndrome, which is characterized by multiple factors. Lean LETO and obese, insulin resistant OLETF rats from 2 independent studies were divided in the following groups (n=7): 1) ad lib LETO, 2) ad lib OLETF, 3) LETO 50% CR (10 d at 15 wks of age), 4) OLETF 50% CR, 5) LETO 30% CR (14 d at 12 wks of age), 6) OLETF 30% CR, 7) OLETF SGLT2i (Luseoglifozin 10 mg/kg/day x 4 wks at 10 wks of age), and 8) OLETF SGLT2i + 30% CR. SBP was measured weekly by tail-cuff plethysmography.SBP increased 19% (23 mmHg, P =0.002) consistently in OLETF compared to LETO (124 mmHg), but neither the CR-induced reduction in body mass nor the supplementation of SGLT2i modified the strain-associated increase in SBP (Fig. 1). Mean body mass in OLETF decreased by 18% with 50% CR (409 to 334 g) but decreased only 7% (34 g) with 30% CR and 8% (38 g) with SGLT2i and CR (454 g control). Serum Na + remained unaltered by 50% CR. Urinary Na+ excretion also was unchanged in 30% CR. While the CR treatments induced profound changes in body mass (and adiposity, not shown), they were not sufficient to alter Na+ balance and SBP. Furthermore, the addition of SGLT2i did not reduce SBP suggesting that in the OLETF model of metabolic syndrome factors beyond adiposity and impaired glucose regulation contribute to the maintenance of elevated arterial pressure.

Acute Caloric Restriction Improves Adipokine Profile with Concomitant Increase in Glucose Reabsorption and Decreased Gluconeogenesis in Obese, Insulin‐Resistant Rats

The adipokine leptin has an important role in regulating body mass, and high concentrations lead to a resistance in target organs (e.g. β‐cells). Adiponectin, on the other hand, is considered antidiabetic and is inversely correlated to adipose tissue mass, which is reduced via caloric restriction (CR). SGLT2 transporter expression in the kidney is increased in diabetic conditions, leading to a higher glucose reabsorption and maintained hyperglycemia. During conditions of caloric restriction, increased hepatic PEPCK‐C expression contributes to an increase in hepatic gluconeogenesis via production of G3P. Our goal was to assess the effect of acute CR on adipokine profile and glucose metabolism in an obese, insulin resistant, animal model.Twenty‐eight lean LETO and 28 obese, insulin resistant OLETF rats were separated in two ad libidum food control groups (n=14 each), two CR groups, and two partial recovery (PR) groups (n=7 each). All groups were fed ad libidum for 4 weeks. After that time CR and PR groups were fed half the mean food intake of the ad libidum LETO group for 10 days, after which CR were dissected. The PR groups were fed ad libidum for 7 days and dissected.Blood was collected during dissection after 12 h fasting, and serum was preserved for measuring adipokines. Both leptin and adiponectin were measured by commercially available ELISA kits. SGLT2 and PEPCK‐C expression were measured by Western Blot from the kidney cortex and liver, using Ponceau stain as a loading control.Mean serum leptin was higher in OLETF (P=0.038) than LETO, but decreased 3‐fold after CR and recovered below threshold levels after PR (8.6 ± 1.2 in PR vs 15.4 ± 4.5 ng/ml Control). Serum adiponectin remained unchanged in both strains after CR, but increased after PR (2.3 ± 0.2 To 3.7 ± 0.2, P&lt;0.001 in LETO and 3.3 ± 0.2 to 3.9 ± 0.1 μg/ml, P=0.05 in OLETF). Baseline leptin‐adiponectin ratio was 3‐fold higher in OLETF vs LETO. However, the ratio decreased 2‐fold in LETO and 3‐fold in OLETF (P&lt;0.001) after CR (Fig. 1)Mean SGLT2 expression in the kidney increased after CR in both strains (21%, in LETO and 40%, in OLETF), and that increase was maintained in OLETF, but not for LETO, after PR (Fig. 2). Changes in PEPCK‐C expression in LETO were not detectable; however, expression in OLETF was higher than LETO (P&lt;0.001) and decreased after CR (222% to 178%) and even further after PR (to 124%) (Fig. 3). Nonetheless, mean expression for PR control in OLETF is half of CR control, suggesting a high variability within the strain.In conclusion, an acute caloric restriction improves adipokine profile in both strains even after PR, suggesting a protective effect by increased expression of adiponectin with reduced fat mass. Moreover, glucose reabsorption in the kidney may be enhanced in lieu of increased gluconeogenesis and contributing to the hyperglycemia associated with the development of T2D.Support or Funding InformationThis research was funded by a doctoral fellowship from UC MEXUS‐CONACYT and an MHIRT Fellowship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute Caloric Restriction Leads to Loss of Hypoglycemic Counter-Regulation in Mice following Short-Term Refeeding

Background: Hypoglycemia-associated autonomic failure (HAAF) is a maladaptive failure in glucose counter-regulation known to be caused by recurrent exposure to insulin-induced hypoglycemia. Fasting or caloric restriction is the only natural physiological process which induces prolonged moderate-to-severe hypoglycemia similar to the antecedent of HAAF. In this study we tested the hypothesis that exposure to fasting-induced hypoglycemia can cause HAAF-like symptoms in mice. Methods: Two groups of mice were used, an ad libitum (ad lib) fed group (n=6) and a caloric restriction (CR) group (n=6). CR mice were placed on 60% caloric restriction for 6 consecutive days. Ad lib mice were housed in an identical manner but fed ad libitum during this same period. Following 6 days of restriction, CR mice were given ad lib access to food for 16 h. After the 16 h period of refeeding, both CR and ad lib mice began a 6 h fast which was immediately followed by a hypoglycemic insulin tolerance test (ITT). ITTs consisted of a variable dose of insulin (1.4-1.75 U/kg, IP) which produced similar levels of hypoglycemia in each group (∼45 mg/dL). Results: As expected, mice exposed to 6 days of 60% CR lost ≈30% of their initial body weight, and experienced a gradual fall in blood glucose to an average minimum of 67.9 mg/dL. CR mice displayed a significantly reduced fasting glucose level relative to ad lib mice (102.7 and 171.0 mg/dL respectively, p = 0.0002) as well as reduced serum glucagon levels in response to the ITT (6.0 and 30.4 pg/mL respectively, p = 0.0182). Conclusions: Our results demonstrate that exposure to fasting-induced hypoglycemia produces HAAF-like symptoms in mice following refeeding. These results suggest that HAAF may be a result of an adaptive response to fasting which is inappropriately elicited during exposure to insulin-induced hypoglycemia. Further characterization of the effects of CR on the induction of deficits in glucose counterregulation warrants further investigation. Disclosure D. McDougal: None.

A Metabolomic Signature of Acute Caloric Restriction.

Context:The experimental paradigm of acute caloric restriction (CR) followed by refeeding (RF) can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss.Objective:Metabolomics, the measurement of hundreds of small molecule metabolites, their precursors, derivatives, and degradation products, has emerged as a useful tool for the study of physiology and disease and was used here to study the metabolic response to acute CR.Participants, Design, and Setting:We used four ultra high-performance liquid chromatography-tandem mass spectrometry methods to characterize changes in carbohydrates, lipids, amino acids, and steroids in eight normal weight men at baseline, after 48 hours of CR (10% of energy requirements) and after 48 hours of ad libitum RF in a tightly controlled environment.Results:We identified a distinct metabolomic signature associated with acute CR characterized by the expected switch from carbohydrate to fat utilization with increased lipolysis and β-fatty acid oxidation. We found an increase in ω-fatty acid oxidation and levels of endocannabinoids, which are known to promote food intake. These changes were reversed with RF. Several plasmalogen phosphatidylethanolamines (endogenous antioxidants) significantly decreased with CR (all P ≤ 0.0007). Additionally, acute CR was associated with an increase in the branched chain amino acids (all P ≤ 1.4 × 10−7) and dehydroepiandrosterone sulfate (P = 0.0006).Conclusions:We identified a distinct metabolomic signature associated with acute CR. Further studies are needed to characterize the mechanisms that mediate these changes and their potential contribution to the adaptive response to dietary restriction.

Glucose Tolerance and Triglyceridemia Improves During Acute Caloric Restriction Without Changes in SBP in Obese, Insulin Resistant Rats

Glucose Tolerance and Triglyceridemia Improves During Acute Caloric Restriction Without Changes in SBP in Obese, Insulin Resistant Rats

Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity.

Bile acid (BA) synthesis is regulated by BA signalling in the liver and by fibroblast growth factor 19 (FGF19), synthesized and released from the intestine. In morbid obesity, faecal excretion and hepatic synthesis of BAs and cholesterol are strongly induced and caloric restriction reduces their faecal excretion considerably. We hypothesized that the high intestinal food mass in morbidly obese subjects promotes faecal excretion of BAs and cholesterol, thereby creating a shortage of both BAs and cholesterol in the liver. Ten morbidly obese women (BMI 42±2.6kgm-2 ) were monitored on days 0, 3, 7, 14 and 28 after beginning a low-calorie diet (800-1100kcalday-1 ). Serum was collected and liver size and fat content determined. Synthesis of BAs and cholesterol was evaluated from serum markers, and the serum levels of lipoproteins, BAs, proprotein convertase subtilisin/kexin type 9 (PCSK9), insulin, glucose and FGF19 were monitored. Fifty-four nonobese women (BMI <25kgm-2 ) served as controls. At baseline, synthesis of both BAs and cholesterol and serum levels of BAs and PCSK9 were elevated in the obese group compared to controls. Already after 3days on a low-calorie diet, BA and cholesterol synthesis and serum BA and PCSK9 levels normalized, whereas LDL cholesterol increased. FGF19 and triglyceride levels were unchanged, and liver volume was reduced by 10%. The results suggest that hepatic BAs and cholesterol are deficient in morbid obesity. Caloric restriction rapidly counteracts these deficiencies, normalizing BA and cholesterol synthesis and circulating PCSK9 levels, indicating that overproduction of cholesterol in enlarged peripheral tissues cannot explain this phenotype. We propose that excessive food intake promotes faecal loss of BAs and cholesterol contributing to their hepatic deficiencies.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Increased bile acid and cholesterol syntheses and PCSK9 in morbid obesity are rapidly normalized following acute caloric restriction

Increased Bile Acid And Cholesterol Syntheses And PCSK9 In Morbid Obesity Are Rapidly Normalized Following Acute Caloric Restriction

Energy depletion by diet or aerobic exercise alone: impact of energy deficit modality on appetite parameters

Millions of Americans attempt to lose weight each year, and it is unclear whether the modality of acute, tightly controlled energy depletions can differently affect appetite parameters and olfaction. The objectives were to examine how the modality of an acute 3-d isocaloric 25% energy depletion by dieting alone or by aerobic exercise alone differently affects appetite and appetite-related hormones, ad libitum feeding, food reward (snack points), and olfaction. Ten male participants with a mean ± SD age of 23.7 ± 5.1 y and an initial mean ± SD body weight of 83.2 ± 11.5 kg participated in this randomized crossover design. Baseline measurement [day 1 of the control condition (CON1)] was performed and repeated 3 d later [day 4 of the control condition (CON4)], after which randomization was applied to the order of the 2 experimental conditions: 25% daily needs energy deficits induced by diet only (DIET) and by exercise only (EX) and tested before [day 1 of DIET (DIET1) and day 1 of EX (EX1)] and after 3 d [day 4 of DIET (DIET4) and day 4 of EX (EX4)] of the intervention. Body weight, leptin and ghrelin concentrations, relative-reinforcing value of food, and olfaction were measured at days 1 and 4. Body composition (dual-energy X-ray absorptiometry), ad libitum energy intake (EI; buffet), and palatability (visual analog scale) were measured only at day 4. Relative to CON4, EI (P= 0.001), palatability (P= 0.01), and odor threshold (P= 0.05) were higher at DIET4; relative to CON4, palatability (P= 0.03) was higher at EX4. Compared with EX4, EI was higher for DIET4 (P= 0.006). Relative to CON4, snack points earned were higher at DIET4 (P= 0.03) and EX4 (P= 0.001); more snack points were earned at EX4 relative to DIET4 (P= 0.001). Compared with the control condition, DIET represented a greater acute challenge to appetite regulation than EX, as demonstrated by greater appetite and ad libitum EI. This study confirms that compared with depletions by exercise alone, acute caloric restriction results in rapid changes in appetite that result in compensatory eating, which may initially dissuade potential success in weight-loss efforts. This trial was registered at clinicaltrials.gov as NCT02653378.

Body mass loss correlates with cognitive performance in primates under acute caloric restriction conditions.

Brain functions are known to consume high levels of energy, thus, the integrity of cognitive performance can be drastically impacted by acute caloric restriction. In this study, we tested the impact of a 40% caloric restriction on the cognitive abilities of the grey mouse lemur (Microcebus murinus).Twenty-three male mouse lemurs were divided into two groups: 13 control animals (CTL) that were fed with 105kJ/day and 10calorie restricted (CR) animals that received 40% less food (63kJ/day) than the CTL animals. The animals were fed according to their group for 19days. Before treatment, we assessed baseline associative learning capacities, resting metabolic rates and locomotor performance of both animal groups. After treatment, we tested the same functions as well as long-term memory.Our results showed that CR animals had lower learning performance following caloric restriction. The effects of caloric restriction on memory recall varied and depended on the metabolism of the individual animal. Body mass loss was linked to memory test performance in the CR group, and lower performance was observed in individuals losing the most weight. While CR was observed to negatively impact learning, locomotor capacities were preserved in CR animals, and there were higher resting metabolic rates in the CR group. Our data reinforce the strong link between energy allocation and brain function, and suggest that in the context of food shortage, learning capacities could be a limiting parameter in the adaptation to a changing environment.

Modulation of the sleep–wake cycle by changes in energy balance

BackgroundThe rise in obesity has been paralleled by a decline in sleep duration according to results of epidemiological studies over the past 30 years. The potential mechanisms linking energy balance and the sleep–wake cycle are not well understood. We aimed to directly assess the effects of manipulating energy balance on the sleep–wake cycle. MethodsThe study included 12 healthy normal weight men. All assessments were done at baseline, after 2 days of caloric restriction to about 200 calories per day, and after 2 days of free feeding to restore energy balance. We measured energy balance with indirect calorimetry; the sleep–wake cycle (total sleep time [TST] and time spent in various stages of sleep [%TST]); the apnoea–hypopnoea index, a marker of hypoventilation, with polysomnography; and serum leptin, insulin, and orexin concentrations. Data are given as mean (SD). FindingsThe energy deficit induced by acute caloric restriction was fully compensated for after 2 days of free feeding when energy balance was restored. Caloric restriction significantly increased the duration of deep (stage 4) sleep (from 16·8 %TST [1·8] at baseline to 21·7 [1·8] during caloric restriction, p=0·03), which was entirely reversed to 16·1 (1·9) upon free feeding (p=0·01). The apnoea–hypopnoea index was increased from 1·5 (0·5) at baseline to 2·2 (0·7) during caloric restriction and returned to baseline values upon free feeding (1·1 [0·2], p=0·05). Caloric restriction was associated with a significant fall in leptin (from 3·35 ng/mL [2·06] to 0·70 [0·52], p=0·002) and insulin concentrations (from 45·6 pmol/L [19·7] to 16·1 [9·2], p=0·005); the change in orexin concentrations from baseline to caloric restriction correlated positively with duration of stage 4 sleep in caloric restriction (Pearson r=0·71, p=0·03). Changes in energy balance also led to changes in sympathetic tone and the pulsatile secretion of thyroid stimulating hormone and growth hormone. InterpretationWe have demonstrated that changes in energy homoeostasis directly and reversibly impact on the sleep–wake cycle. These findings provide a mechanistic framework for investigating the association between sleep duration and obesity risk. FundingWellcome Trust, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, Bernard Wolfe Health Neuroscience Fund, Swiss National Science Foundation, European Society of Endocrinology, German Research Foundation, European Union Seventh Framework programme NeuroFAST consortium.

A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes

Type 2 diabetes (T2D) is generally thought to result from the combination of 2 metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic β-cells to compensate for the increased demand. We build on a mathematical model pioneered by Topp and colleagues to elucidate how compensation succeeds or fails. Their model added a layer of slow negative feedback to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law governing β-cell mass. We add to that model regulation of 2 aspects of β-cell function on intermediate time scales. The model quantifies the relative contributions of insulin action and insulin secretion defects to T2D and explains why prevention is easier than cure. The latter is a consequence of a threshold separating the normoglycemic and diabetic states (bistability), which also underlies the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept gives new insight into "Starling's Law of the Pancreas," whereby insulin secretion is higher for prediabetics and early diabetics than for normal individuals.

Substrate Utilization At Rest And Following A Meal After Acute Caloric Restriction

Carbohydrates (CHO) and fat are the predominant substrates oxidized for energy by humans. At rest, when energy demands are low, there is typically a small preference given to fat over CHO oxidation. However, following a meal or during exercise, both times of increased energy demand, many factors influence the type of fuels utilized. A non-invasive and validated technique for estimating substrate utilization is the respiratory exchange ratio (RER; VCO2/VO2). PURPOSE: Determine substrate utilization at rest following a standardized meal after 24hrs of controlled feeding and exercise. METHODS: Ten healthy men (22.8±2.7yrs) performed three trials in random order each consisting of 24hr controlled feeding (57/22/21% CHO/fat/protein) to provide three levels of energy availability: an energy balance trial, and a moderate and mild caloric restriction trials (45, 25 & 35kcal/kg/FFM, respectively). At the end of each 24hr period of controlled feeding, participants ran on a treadmill to expend 10kcal/kg/FFM (684.6±43.3kcal) at 60%VO2max. They returned the next morning for baseline measurements, a mixed-meal challenge (50/39/11% CHO/fat/protein), and subsequent measurements over the next three hours. The RER data was collected in 5min increments interspersed by 10min of no data collection. Data are reported as mean±stdev; repeated measures ANOVAs were utilized with significance accepted as p<0.05. RESULTS: While there were no significant interactions among trials, the collapsed data revealed a main effect for time where RER was higher at 120-125, 135-140, and 165-170min after the meal challenge compared to fasting RER. Moreover, the unique finding gleaned from this investigation was that in the collapsed data among trials, the RER was significantly lower for the 25kcal/kg/FFM trial compared to the 35 and 45kcal/kg/FFM trials (0.84±0.02 vs. 0.86±0.03 and 0.87±0.03, respectively). CONCLUSION: The contribution of CHO and fat oxidation for energy demands is influenced by many factors, but in this group of men, a novel finding was that moderate caloric restriction had an effect on substrate utilization. Funded in part by the MWACSM Student Research Grant, Joseph Allen Butts Award, and the OU-College of Health Sciences and Professions Student Research Grant

Acute caloric restriction improves glomerular filtration rate in patients with morbid obesity and type 2 diabetes

AimThe role of caloric restriction in the improvement of renal function following bariatric surgery is still unclear; with some evidence showing that calorie restriction can reduce proteinuria. However, data on the impact of caloric restriction on renal function are still lacking. MethodsRenal function, as measured by glomerular filtration rate (GFR), was evaluated in 14 patients with type 2 diabetes mellitus, morbid obesity and stage 2 chronic kidney disease before and after a 7-day very low-calory diet (VLCD). ResultsAfter the VLCD, both GFR and overall glucose disposal (M value) significantly increased from 72.6±3.8mL/min/1.73m−2 BSA to 86.9±6.1mL/min/1.73m−2 BSA (P=0.026) and from 979±107μmol/min1/m2 BSA to 1205±94μmol/min1/m2 BSA (P=0.008), respectively. A significant correlation was observed between the increase in GFR and the rise in M value (r=0.625, P=0.017). ConclusionOur observation of improved renal function following acute caloric restriction before weight loss became relevant suggesting that calory restriction per se is able to affect renal function.

Acute hypophosphatasemia

The temporal evolution of a low serum alkaline phosphatase value may relate to its cause. Precipitous lowering of serum alkaline phosphatase below the lower range of normal is uncommon and may indicate severe physiologic stress and increased short-term mortality. The differential diagnosis of a low serum alkaline phosphatase (ALP) value (hypophosphatasemia) is wide ranging, anecdotal, and unfamiliar. The temporal evolution of hypophosphatasemia may relate to its cause. The purpose of this study is to report conditions and circumstances associated with precipitous lowering of serum ALP below the lower range of normal. Marshfield Clinic IRB approved use of their electronic medical record to search for subjects with at least two serum ALP values ≤ 40 U/L (normal 40-125 U/L). When the temporal evolution of the qualifying ALP values indicated a precipitous lowering from usually normal serum ALP values, the subject was deemed to have acute hypophosphatasemia. Thirty years of laboratory data and 10 years of clinical narrative were analyzed. Associated diagnoses, clinical circumstances, and short-term mortality were recorded. A total of 458,767 subjects had 2,584,051 serum ALP values, and 5,190 (1.1 %) subjects had at least two serum values ≤ 40 U/L. A detailed review of 1,276 subjects selected on the basis of their lowest ALP value and age identified 190 subjects with acute hypophosphatasemia. Acute hypophosphatasemia was recorded during periods of major trauma/surgery, multisystem failure, acute anemia, blood product transfusions (often massive), apheresis, hypomagnesemia, and acute caloric restriction. Twenty-eight subjects (15 %) died within 35 days of their nadir serum ALP. Acute hypophosphatasemia is associated with profound illness or physiologic stress and followed by increased short-term mortality. The temporal evolution of hypophosphatasemia may relate to its cause.

Liquid meal composition, postprandial satiety hormones, and perceived appetite and satiety in obese women during acute caloric restriction

The purpose of this study was to compare postprandial satiety regulating hormone responses (pancreatic polypeptide (PP) and peptide tyrosine tyrosine (PYY)) and visual analog scale- (VAS) assessed perceived appetite and satiety between liquid high-protein (HP) and high-carbohydrate (HC) meals in obese women during acute (24-h) caloric restriction. Eleven obese premenopausal women completed two conditions in random order in which they consumed 1500 calories as six 250-calorie HP meals or six 250-calorie HC meals over a 12-h period. Blood samples were taken at baseline and every 20 min thereafter and analyzed for PP and PYY concentrations. At these same points, perceived hunger and fullness were assessed with a VAS. The incremental area under the curve (iAUC) was used to compare postprandial responses. The 12-h PP and PYY iAUC were greater (P≤0.05) during the HP condition (PP: 4727±1306 pg/ml×12 h, PYY: 1373±357 pg/ml×12 h) compared with the HC condition (PP: 2300±528 pg/ml×12 h, PYY: 754±246 pg/ml×12 h). Perceived hunger and fullness were not different between conditions (P>0.05). The greatest changes in PYY and perceived fullness occurred after the morning meals during both conditions. These data suggest that in obese women during acute caloric restriction before weight loss, i) liquid HP meals, compared with HC meals, result in greater postprandial PP and PYY concentrations, an effect not associated with differential appetite or satiety responses, and ii) meal-induced changes in PYY and satiety are greatest during the morning period, regardless of dietary macronutrient composition.

Acute effects of different diet compositions on skeletal muscle insulin signalling in obese individuals during caloric restriction

ObjectiveThe cellular effects of restricting fat versus carbohydrate during a low-calorie diet are unclear. The aim of this study was to examine acute effects of energy and macronutrient restriction on skeletal muscle insulin signalling in obesity. Materials/MethodsEighteen obese individuals without diabetes underwent euglycemic–hyperinsulinemic clamp and skeletal muscle biopsy after: (a) 5days of eucaloric diet (30% fat, 50% carbohydrate), and (b) 5days of a 30% calorie-restricted diet, either low fat/high carbohydrate (LF/HC: 20% fat, 60% carbohydrate) or high-fat/low carbohydrate (HF/LC: 50% fat, 30% carbohydrate). ResultsWeight, body composition, and insulin sensitivity were similar between groups after eucaloric diet. Weight loss was similar between groups after hypocaloric diet, 1.3±1.3kg (p<0.0001 compared with eucaloric). Whole-body insulin sensitivity was unchanged after calorie restriction and similar between groups. However, ex vivo skeletal muscle insulin signalling differed depending on macronutrient composition of calorie-restricted diet. Skeletal muscle of the LF/HC group had increased insulin-stimulated tyrosine phosphorylation of IRS-1, decreased insulin-stimulated Ser307 phosphorylation of IRS-1, and increased IRS-1-associated phosphatidylinositol (PI)3-kinase activity. Conversely, insulin stimulation of tyrosine phosphorylated IRS-1 was absent and serine 307 phosphorylation of IRS-1 was increased on HF/LC, with blunting of IRS-1-associated PI3-kinase activity. ConclusionAcute caloric restriction with an LF/HC diet alters skeletal muscle insulin signalling in a way that improves insulin sensitivity, while acute caloric restriction with an HF/LC diet induces changes compatible with insulin resistance. In both cases, ex vivo changes in skeletal muscle insulin signalling appear prior to changes in whole body insulin sensitivity.

Effects of acute caloric restriction compared to caloric balance on the temporal response of the IGF-I system

ObjectiveInsulin-like growth factor-I (IGF-I) is a key regulator of metabolism during altered energy states. The IGF-I system components respond to prolonged caloric restriction but it is not clear if this system responds similarly to acute caloric restriction. The purpose of this study was to characterize the IGF-I system response to acute caloric restriction with a secondary purpose of determining if two isocaloric diets with different ratios of carbohydrate to fat alter the IGF-I system under conditions of caloric balance. Materials/MethodsA double-blind, placebo-controlled crossover design was used in which 27 subjects underwent three, 48-h experimental treatments: 1) caloric restriction 2) carbohydrate and 3) carbohydrate/fat. Blood was sampled periodically (6 time points total) for IGF-I (total and free), IGFBPs1–4, insulin and glucose. ANOVAs were used with significance set at P<0.05. ResultsTotal IGF-I decreased 7% during CR (P=0.051) and remained stable during CHO and CHO/F. Free IGF-I decreased 43% during CR (P<0.05) and remained stable during CHO and CHO/F. IGFBP-1 increased by 445% during CR (P<0.05) compared to CHO and CHO/F with no changes for IGFBP-2, IGFBP-3 and IGFBP-4. There was no change in glucose or insulin during CR over the course of the study. Insulin and glucose increased (P<0.05) after a meal in both the CHO and CHO/F groups with no difference between these two groups. ConclusionOur findings indicate that free IGF-I decreases and IGFBP-1 increases during caloric restriction, but they are not altered with diets differing in carbohydrate and fat content. Changes in free IGF-I and IGFBP-1 are sensitive to caloric restriction, and their measurement may be valuable in monitoring the physiological response to refeeding in those consuming suboptimal calories.