Starvation In Humans Research Articles

Starvation and Its Effects on the Gut

There is growing awareness that intestinal dysfunction determines the clinical outcomes of situations as diverse as undernourished children in urban tropical slums and undernourished surgical patients in intensive care units. As experimental starvation in humans has only rarely been studied, and largely not using current biomedical research tools, we must draw inference from disparate clinical and experimental observations as to the derangements present in the starved gut. There is good evidence of intestinal atrophy and achlorhydria in starvation and severe undernutrition. Historical reports from concentration camps and conflict settings consistently reported a noncontagious phenomenon called "hunger diarrhea," but in settings where starved individuals are isolated from others (prisoners on hunger strike, anorexia nervosa) diarrhea is not a feature. Changes in intestinal permeability and absorption have been infrequently studied in experimental starvation; available data suggest that short-term starvation reduces sugar absorption but not permeability. Severe acute malnutrition in children is associated with severe changes in the intestinal mucosa. Experimental animal models may help explain some observations in humans. Starved rats develop a hypersecretory state and intestinal barrier defects. Starved pigs demonstrate prolongation of rotavirus diarrhea and reproduce some of the absorptive and barrier defects observed in malnourished children. However, there remains much to be learned about the effects of starvation on the gut. Given the high prevalence of undernutrition in hospitals and disadvantaged communities, the lack of attention to the interaction between undernutrition and gastrointestinal damage is surprising and needs to be corrected. Current sophisticated cellular and molecular techniques now provide the opportunity to create fresh understanding of gastrointestinal changes in pure undernutrition, using volunteer studies and samples from anorexia nervosa.

Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans.

In order to determine whether the glucose-alanine cycle regulates rates of hepatic mitochondrial oxidation in humans, we applied positional isotopomer NMR tracer analysis (PINTA) to assess rates of hepatic mitochondrial oxidation and pyruvate carboxylase flux in healthy volunteers following both an overnight (12 hours) and a 60-hour fast. Following the 60-hour fast, rates of endogenous glucose production and mitochondrial oxidation decreased, whereas rates of hepatic pyruvate carboxylase flux remained unchanged. These reductions were associated with reduced rates of alanine turnover, assessed by [3-13C]alanine, in a subgroup of participants under similar fasting conditions. In order to determine whether this reduction in alanine turnover was responsible for the reduced rates of hepatic mitochondrial oxidation, we infused unlabeled alanine into another subgroup of 60-hour fasted subjects to increase rates of alanine turnover, similar to what was measured after a 12-hour fast, and found that this perturbation increased rates of hepatic mitochondrial oxidation. Taken together, these studies demonstrate that 60 hours of starvation induce marked reductions in rates of hepatic mitochondrial oxidation, which in turn can be attributed to reduced rates of glucose-alanine cycling, and reveal a heretofore undescribed role for glucose-alanine in the regulation of hepatic mitochondrial oxidation in humans.

225-OR: Key Role for Glucose-Alanine Cycling in the Regulation of Hepatic Mitochondrial Oxidation during Starvation in Humans

We examined whether starvation alters rates of hepatic mitochondrial oxidation in humans by applying a novel 13C Positional Isotopomer NMR Tracer Analysis (PINTA) method to assess rates of hepatic mitochondrial oxidation in healthy volunteers (n=15) following an overnight (12h) and a 60h fast. A 3h intravenous infusion of [3-13C] lactate (4.3 μmol/Kg-min), [1,2,3,4,5,6,6-2H7] glucose (0.22 μmol/Kg-min), and [13C4]-β-hydroxybutyrate (BOHB) (0.01 mg/Kg-min) was administered and blood was collected for GC-MS, LC-MS/MS and 13C MRS PINTA analyses. Following the 60h fast rates of endogenous glucose production decreased by 27% (p=0.0002) and rates of hepatic mitochondrial oxidation decreased by 52% (p=0.0014) whereas rates of hepatic pyruvate carboxylase flux remained unchanged. To ascertain whether decreased rates of alanine turnover during starvation play a role in promoting decreased rates of hepatic mitochondrial oxidation we infused [3-13C] alanine in a subgroup (n=5) of subjects and found that 60h of fasting promoted a 28% reduction in alanine turnover (p=0.044 vs. 12h fast). In order to determine whether this reduction in alanine turnover was responsible for the reduced rates of hepatic mitochondrial oxidation we infused unlabeled alanine to a subgroup (n=9) of the 15 subjects in a repeat 60h fasting study to increase rates of alanine turnover to rates measured after 12h of fasting and found that this perturbation increased rates of hepatic mitochondrial oxidation by 63% (p=0.009 vs. 60h fast) to rates similar to the 12h fasting state (60h+ala: 232±21 vs. 12h: 295±44 μmol/min, p=0.303). Conclusion: These studies demonstrate that 60h of starvation in humans induces marked reductions in rates of hepatic mitochondrial oxidation, which in turn can be attributed to reduced rates of glucose-alanine cycling. Disclosure K. Petersen: Advisory Panel; Spouse/Partner; Aegerion Pharmaceuticals, AstraZeneca, AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. Consultant; Spouse/Partner; Gilead Sciences, Inc. Consultant; Self; Merck & Co., Inc. Consultant; Spouse/Partner; Nimbus Discoverey. Consultant; Self; Novo Nordisk A/S. S. Dufour: None. G. Cline: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V. Funding National Institutes of Health

FGF21 and the late adaptive response to starvation in humans.

In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases--markers of tissue breakdown--as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown.

Why does starvation make bones fat?

Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance.

Adaptive responses to starvation in humans: important role for skeletal muscle PDK4

Adaptive responses to starvation in humans: important role for skeletal muscle PDK4

Short‐term fasting‐induced autonomic activation and changes in catecholamine levels are not mediated by changes in leptin levels in healthy humans

In animal models, the adipocyte-secreted hormone leptin increases energy expenditure by increasing sympathetic outflow but its role in humans remains to be elucidated. We evaluated whether inducing hypoleptinaemia (with and without administration of leptin at replacement doses) for 3 days would influence catecholamine levels and sympathetic and parasympathetic activity in healthy humans. We studied six normal-weight subjects in the General Clinical Research Center (GCRC) under three conditions: baseline fed state (control study) and two 72-h fasting studies (to decrease leptin levels), with administration of either placebo or replacement-dose recombinant methionyl human leptin (r-metHuLeptin) in a randomized, double-blind fashion. In each condition, 24-h urinary catecholamine levels, heart rate and heart rate variability (HRV), a standard tool for assessing cardiac autonomic modulation, were measured. Study parameters remained stable during the control condition and the baseline assessment of all three studies. In response to 72-h fasting, which decreased serum leptin levels by 80%, 24-h urinary norepinephrine and dopamine levels and heart rate increased while cardiac vagal modulation decreased (all P < 0.05). Replacement-dose r-metHuLeptin to keep leptin levels within the physiological range during fasting did not alter fasting-associated changes in heart rate, catecholamine levels or cardiac vagal tone. The findings of this controlled, interventional study indicate that changes in heart rate, catecholamine levels and cardiac vagal modulation associated with 72-h fasting are independent of regulation by leptin. Thus, changes in leptin levels within the physiological range do not seem to play a role in regulating autonomic function during short-term starvation in healthy humans.

Dynamics of starvation in humans

A differential equation model describing the dynamics of stored energy in the form of fat mass, lean body mass and ketone body mass during prolonged starvation is developed. The parameters of the model are estimated using available data for 7 days into starvation. A simulation of energy stores for a normal individual with body mass index between 19 and 24 and an obese individual with body mass index over 30 are calculated. The length of time the obese subject can survive during prolonged starvation is estimated using the model.

Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans

This study investigated the molecular alterations underlying the physiological adaptations to starvation and refeeding in human skeletal muscle. Forty-eight hours' starvation reduced whole-body insulin sensitivity by 42% and produced marked changes in expression of key carbohydrate (CHO) regulatory genes and proteins: SREBP1c and hexokinase II (HKII) were downregulated 2.5- and 5-fold, respectively, whereas the pyruvate dehydrogenase kinase 4 (PDK4) was upregulated 4-fold. These responses were not dependent on the phosphorylation status of Akt and FOXO1. On the other hand, starvation and the concomitant increase in circulating free fatty acids did not upregulate the expression of transcription factors and genes involved in fat metabolism. Twenty-four hours' refeeding with a CHO-rich diet completely reversed the changes in PDK4, HKII and SREBP1c expression in human skeletal muscle but failed to fully restore whole-body insulin sensitivity. Thus, during starvation in healthy humans, unlike rodents, regulation of fat metabolism does not require an adaptive response at transcriptional level, but adaptive changes in gene expression are required to switch off oxidative glucose disposal. Lack of effect on key proteins in the insulin-signalling pathway may indicate that changes in intracellular substrate availability/flux may be responsible for these adaptive changes in glucose metabolism. This may represent an important aspect of the molecular basis of the development of insulin resistance in metabolic conditions characterized by energy restriction.

Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans

To elucidate whether the role of leptin in regulating neuroendocrine and immune function during short-term starvation in healthy humans is permissive, i.e., occurs only when circulating leptin levels are below a critical threshold level, we studied seven normal-weight women during a normoleptinemic-fed state and two states of relative hypoleptinemia induced by 72-h fasting during which we administered either placebo or recombinant methionyl human leptin (r-metHuLeptin) in replacement doses. Fasting for 72 h decreased leptin levels by approximately = 80% from a midphysiologic (14.7 +/- 2.6 ng/ml) to a low-physiologic (2.8 +/- 0.3 ng/ml) level. Administration of r-metHuLeptin during fasting fully restored leptin to physiologic levels (28.8 +/- 2.0 ng/ml) and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF-1 hormone levels, hypothalamic-pituitary-adrenal and renin-aldosterone activity. FSH and sex steroid levels were not altered. Short-term reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but r-metHuLeptin did not have major effects on their number or in vitro function. Thus, changes of leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans. Studies involving more severe and/or chronic leptin deficiency are needed to precisely define the lower limit of normal leptin levels for each of leptin's physiologic targets.

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Starvation in humans: Evolutionary background and contemporary implications

Although there is extensive evidence that caloric restriction (CR) extends lifespan in several species the evidence base for humans is weak. We are still at the stage of applying inductive reasoning and of framing hypotheses to be tested. It is known that a genetic background contributes about 25% to the variation in human longevity, but thought unlikely that any genes conferring longer lifespan have been positively selected to do so. It is more likely that any such benefits are unintended consequences arising from other adaptations. If there is an association between CR and longevity in humans it may have been selected by previous exposures to famine. This paper briefly reviews the historical evidence on the extent and frequency of famines in human history. It is concluded that starvation has been one of the major selective pressures on the human genome and has left abundant evidence of adaptive survival traits. Many of these are mediated through effects on reproduction. However, interpretation of the possible links between these energy-sparing mechanisms and any association between CR and ageing is handicapped by an absence of data on the latter and will remain a matter of debate for many years to come.

The role of free fatty acids (FFA) in the regulation of intrahepatic fluxes of glucose and glycogen metabolism during short-term starvation in healthy humans.

s of the Netherlands Society of Gastroenterology and the Netherlands Society of Hepatology: Spring Meeting, 15–16 March 2001

A role for leptin in autoimmunity?

Leptin was first described as a hormone-like cytokine involved in the control of food intake. It is proposed to act as a ‘fat-o-stat’, being made by fat cells to limit food intake and promote fat breakdown. The discovery of leptin led to the hope that it might be used to treat obesity in humans because genetically obese ob/ob mice, when treated with leptin, lose weight. In humans, however, a lack of responsiveness to leptin, rather than a deficiency of leptin, might be responsible for certain types of obesity. In addition to its effects on food intake and fat metabolism, leptin has also been shown to activate CD4+ T cells via the long isoform of the leptin receptor. Structurally, leptin belongs to the helical cytokine family and its receptors belong to the hematopoeitic cytokine receptor superfamily. It therefore came as no surprise that leptin would have effects on immunity. Decreased levels of leptin during starvation or malnutrition in humans leads to immunosuppression, and chronic leptin deficiency has been shown to decrease T-helper 1 (Th1) cell responses and increase Th2 cell function.A recent report by Matarese et al. 1xRequirement for Leptin in the induction and progression of autoimmune encephalomyelitis. Matarese, G. et al. J. Immunol. 2001; 166: 5909–5961PubMedSee all References1 now indicates that leptin could be important for autoimmunity. The role of leptin in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), has been studied. Naturally, leptin-deficient mice (C57BL/6J-ob/ob) were studied for their responses to an immunodominant peptide from an oligodendrocyte glycoprotein that induces EAE in wild-type mice. The leptin-deficient mice showed no neurological impairment, either after immunization with the peptide or following the adoptive transfer of pathogenic T cells. However, chronic leptin administration in these mice made them susceptible to both treatments. When wild-type mice were treated with leptin, their disease was severely exacerbated. These effects of leptin were attributed to a pronounced Th1-type response.Therefore, it appears that leptin is required for the induction and propagation of autoimmune-mediated demyelination. This effect on the expansion and maintenance of pathogenic Th1 cells indicates that inhibition of leptin might be well worth pursuing as an immunomodulatory therapy for MS.

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

The function of the thyroid gland is to produce the thyroid hormones T3 and T4, which regulate gene transcription throughout the body (1). In medical practice, the thyroid becomes an issue when its size or shape becomes abnormal or when it produces too much or too little hormone. Thus, we typically think of the thyroid with reference to the clinical states of goiter, or hyper- or hypothyroidism. But what is the physiology of the thyroid when the gland and the entire hypothalamic-pituitary-thyroid axis are intact? As first year medical students ask each year, Why exactly do we have a thyroid, at all?

Brain metabolism during short-term starvation in humans.

During prolonged starvation, brain energy requirements are covered in part by the metabolism of ketone bodies. It is unknown whether short-term starvation of a few days' duration may lead to reduced brain glucose metabolism due to the change toward ketone body consumption. In the present study we measured the cerebral metabolism of glucose and ketone bodies in nine healthy volunteers before and after 3.5 days of starvation. Regional glucose metabolism was measured by dynamic positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. The mean value of K1* in gray and white matter increased by 12% (p < 0.05), whereas k2* and k3* were unchanged compared with control values. Regional glucose metabolism in cortical gray matter was reduced by 26% from 0.294 +/- 0.054 to 0.217 +/- 0.040 mumol g-1 min-1 (p < 0.001). White matter glucose metabolism decreased by 27% (p < 0.02). The decrease was uniform in gray and white matter with regional decreases ranging from 24 to 30%. A determination using Fick's principle confirmed the reduction in glucose metabolism yielding a decrease of 24% from 0.307 +/- 0.050 to 0.233 +/- 0.073 mumol g-1 min-1 (p < 0.05), whereas CBF did not change (0.57 +/- 0.07 vs. 0.57 +/- 0.06 ml g-1 min-1). The global net uptake of beta-hydroxybutyrate increased 13-fold from 0.012 +/- 0.024 to 0.155 +/- 0.140 mumol g-1 min-1 (p < 0.05). Net uptake of acetoacetate and net efflux of lactate and pyruvate did not change significantly during starvation. The present study shows that the human brain adapts to the changes in energy supply as early as 3 days following initiation of starvation, at which time ketone bodies account for approximately one-fourth of the cerebral energy requirements.

Enhanced thermogenic response to epinephrine after 48-h starvation in humans

The effects of 48-h starvation on the physiological responses to a 30-min infusion of epinephrine at 25 ng.min-1.kg body wt-1 were studied in 11 normal-weight healthy young subjects. Starvation led to considerable alterations in basal metabolism including a significant (mean 3.6%) increase in resting metabolic rate. During the infusions, plasma epinephrine concentration rose less in the starved state (+1.47 nmol/l) than in the normally fed state (+1.73 nmol/l) (SE 0.06 nmol/l; P less than 0.05). The maximum increments (mean +/- SE) in heart rate induced by epinephrine were 11.9 +/- 1.3 beats/min in the normally fed state and 20.1 +/- 2.0 beats/min in the starved state (P less than 0.001); the corresponding mean increments in blood glycerol concentration were 0.07 and 0.14 mmol/l (SE 0.01 mmol/l; P less than 0.01). The increase in the metabolic rate above base line during the final 10 min of the epinephrine infusion was 0.58 +/- 0.18 kJ/min in the normally fed state and 0.78 +/- 0.14 kJ/min in the starved state (P less than 0.01). The chronotropic, lipolytic, and thermogenic effects of infused epinephrine were therefore enhanced by prior starvation, despite the lower plasma epinephrine levels.

D2-dopaminergic blockade does not influence post-exercise ketosis in non-athletes.

Metoclopramide has previously been shown to inhibit the ketosis of starvation in rats and humans. The effect of D2-dopaminergic blockade on post-exercise ketosis was, therefore, studied in 6 carbohydrate-starved non-athletic persons who had just completed a 9-km walk in mountainous terrain. There were nine control subjects who went on the walk, but who did not ingest metoclopramide. Metoclopramide (0.15 mg.kg-1 body mass) caused a highly significant rise in the plasma prolactin concentration, but did not influence blood concentrations of 3-hydroxybutyrate, free fatty acid, glucose, insulin or glucagon. Unlike ketosis in starvation, therefore, neither prolactin, nor the D2-dopaminergic system play a part in the genesis of post-exercise ketosis.

Antilipolytic effects of N6-phenylisopropyladenosine and prostaglandin E2 in fat-cells of obese volunteers before and during energy restriction

The antilipolytic effects of N6-phenylisopropyladenosine and of prostaglandin E2 were studied with adipocytes of obese volunteers before and after 4 weeks of severe energy restriction [1250 kJ (300 cal)/day] in the presence and absence of adenosine deaminase (1.6 micrograms/ml, corresponding to 320 m-units/ml). The studies were undertaken to define more clearly the role that local modulators might play in adaptation of lipid mobilization to starvation in humans. Starvation was associated with an approx. 3-fold increase in non-stimulated lipolysis. Removal of endogenous adenosine resulted in a similar increase in basal glycerol release under both conditions, averaging 2 and 2.2 mumol/180 min per 10(6) cells respectively. The sensitivity of the cells to N6-phenylisopropyladenosine and to prostaglandin E2 was not changed by starvation in the presence of adenosine deaminase. These results are discussed in terms of the possible role that local regulators might play during dietary adaption in human fat-cells in vitro.

Some hormonal influences on glucose and ketone body metabolism in normal human subjects.

Control of glucose and ketone body metabolism is integrated by a variety of hormones. Insulin is the major anabolic hormone, and its actions are antagonized by rapidly acting catabolic hormones, such as glucagon and the catecholamines, and by others such as cortisol, growth hormone and the thyroid hormones, which generally have more delayed effects. In the normal human subject, the effects of catabolic hormones to raise blood glucose are limited by a compensatory increase in insulin secretion, and these effects are enhanced in insulin deficiency. Hyperketonaemic actions of the catabolic hormones may result from increased supply of non-esterified fatty acids from lipolysis, although glucagon has a major direct action to increase ketogenesis at the liver. As expected, these actions are also restricted in normal humans by the compensatory rise in insulin secretion. Hyperketonaemia does, however, occur with adrenaline (epinephrine) and noradrenaline (norepinephrine), even in the presence of mildly elevated insulin concentrations. These catecholamines may assume particular importance in mobilization of lipid fuels in milder forms of stress, when insulin secretion is normal or mildly increased. In severe stress, when there is catecholamine-induced suppression in insulin secretion, lipolytic and hyperketonaemic effects of all the catabolic hormones may be manifest. Starvation in humans also results in diminished insulin secretion and increased catabolic hormone secretion. The relative importance of individual hormones in lipid mobilization during starvation is uncertain, although glucagon, growth hormone, noradrenaline and, possibly, dopamine may all play a part.