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Results for “Caloric Restriction”

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PubMed1992

Timed bromocriptine administration reduces body fat stores in obese subjects and hyperglycemia in type II diabetics.

Obese postmenopausal female volunteers were given timed daily oral dosages of bromocriptine, and tested for reduction of body fat stores. This dopamine agonist has been shown to reset circadian rhythms that are altered in obese animals and to reduce body fat levels in several animal models. The participants were instructed not to alter their existing exercise and eating behavior during treatment. Skinfold measurements were taken on 33 subjects as indices of body fat. The measurements (e.g., suprailiac) were reduced after six weeks by about 25%, which represents a reduction of 11.7% of the total body fat. These dramatic decreases in body fat, which are equivalent to that produced by severe caloric restriction, were accompanied by more modest reductions of body weight (2.5%), indicating a possible conservation of protein that is usually lost as a consequence of such caloric restriction. The effects of bromocriptine treatment on body fat and hyperglycemia were also examined in non-insulin dependent diabetics being treated with oral hypoglycemics (7 subjects) or insulin (7 subjects). Total body fat was reduced by 10.7% and 5.1% in diabetics on oral hypoglycemics and insulin, respectively, without any significant reductions in body weight. Hyperglycemia was reduced in most of the 15 diabetic subjects treated leading to euglycemia and even cessation of hypoglycemic drugs in 3 of the 7 subjects during 4-8 weeks of bromocriptine treatment. These findings support the hypothesis that obesity and type II diabetes may be treated effectively with bromocriptine when administered at the proper times and dosages.

Body Composition↗

PubMedDate not supplied

Diet and calorie restriction.

Current data suggest that the life spans of commonly held rodent species have decreased and the occurrence of tumors occurs earlier in the lifespan of ad libitum-fed animals. The most likely cause of this change in the life span of barrier-reared genetically defined animals is increased body weight. The effects of caloric restriction on a variety of functional measures and on age-dependent tumors and lesions are the focus of this presentation. Recommendations for caloric restriction, or at least "dietary control," will be discussed.

Animals↗

PubMed1996

Regulation of peroxisome proliferator-activated receptor-alpha mRNA in rat liver.

Chemical-induced peroxisome proliferation in rodent liver is postulated to occur via activation of members of the steroid hormone receptor superfamily, the peroxisome proliferation-activated receptors (PPARs). In the present study, the expression of the predominant liver subtype PPAR alpha was examined and compared to that of acyl-CoA oxidase (ACO), a marker for peroxisome proliferation and a prototype for genes regulated via PPARs. Despite the induction of both mRNA species in vivo by the peroxisome proliferator perfluorodecanoic acid (PFDA), dose response and time course indicate PPAR alpha and ACO are not controlled similarly. Messenger RNA levels for ACO increased rapidly in rat liver and declined over the subsequent 7 days following PFDA administration, while PPAR alpha mRNA increased slower and remained elevated over this period. In addition, PPAR alpha mRNA accumulation in PFDA-treated rats appears to be due primarily to hypophagia as pair feeding and complete caloric restriction result in a large increase in the concentration of this messenger RNA. Nuclear run-on experiments in vivo suggest that, unlike ACO, PFDA as well as caloric restriction results in accumulation of PPAR alpha mRNA which cannot be explained solely by transcriptional activation. These data indicated that PPAR alpha mRNA accumulation has a very small peroxisome proliferator-dependent component and that other factors may be involved. A rat hepatoma cell line was examined to determine the direct effect on peroxisome proliferators on PPAR alpha mRNA. PPAR alpha and ACO mRNA levels were increased rapidly in the rat hepatoma cell line FaO after treatment with PFDA or the prototypical peroxisome proliferator Wy 14,643. In this cell line, PPAR alpha mRNA levels are not affected by glucagon or insulin and in addition to peroxisome proliferators are induced in this cell line by oleic acid and dexamethasone. The latter treatment had the greatest effect on PPAR alpha mRNA accumulation while having a minimal effect on ACO mRNA. Treatment of FaO cells with actinomycin D prior to Wy 14,643 abolished ACO and PPAR alpha mRNA accumulation, demonstrating that there must be a transcriptional component of the peroxisome proliferator response. Therefore, although PPAR alpha is responsive to peroxisome proliferators and direct effects are observed in cell cultures, mRNA accumulation in vivo is predominantly posttranscriptional, and endogenous regulators such as glucocorticoids may play critical roles in the tissue- and developmentally specific expression of this steroid hormone receptor.

Acyl-CoA Oxidase↗

PubMed1992

Effect of macronutrient composition of an energy-restrictive diet on maximal physical performance.

Thirty-six sedentary, mildly obese (30-40% fat), premenopausal women (29-49 yr) were randomly assigned to one of two dietary regimens for an 8-wk double-blind, parallel study of the effect of moderate caloric restriction and macronutrient variation on maximal physical performance. Group 1 (N = 19) consumed 4186 kJ.d-1 (1000 kcal.d-1) with a diet composition of 40% fat, 40% carbohydrate (CHO), and 20% protein. Group 2 (N = 17) also consumed 4186 kJ.d-1 but varied the percent kilojoules to 20% fat, 60% CHO, and 20% protein. Maximal aerobic power was measured using a modified Balke protocol, strength was assessed using isotonic bench and leg press machines and a Cybex 340 isokinetic device during knee flexion and extension, and muscular endurance was taken as the number of sit-ups performed in 1 min. Pre- to post-testing revealed significant (P less than or equal to 0.05) reductions in body weight (group 1, -7.4 kg; group 2, -6.5 kg) within both groups. No significant changes were seen in maximal aerobic power within both groups. Strength measures for both groups showed a trend toward reduction but statistical significance was only evident in right knee extension for group 1 and left knee extension for group 2 (P less than or equal to 0.05). Sit-up number increased nonsignificantly for both groups. Between group differences were not found in any body weight, body composition, or physical performance index. We therefore conclude that in mildly obese women, maximal exercise performance is relatively unimpaired after 8 wk of caloric restriction with either of two diets differing moderately in their macronutrient content.

Adult↗

PubMed1998

Effects of weight cycling on urinary catecholamines: sympathoadrenal role in refeeding hypertension.

OBJECTIVES: We sought to determine whether the sympathetic nervous system plays a role in the hypertensive response to refeeding from a very low-calorie diet (VLCD). DESIGN: Cycles of weight loss and regain were induced in the obese spontaneously hypertensive rat (SHROB) model of genetic obese hypertension. METHODS: A 12-day VLCD (1/6 of baseline calories) was alternated with 4-6 weeks of ad libitum chow refeeding for three cycles. Control SHROB ate chow ad libitum. Urine was collected for 24 h before and after each period of VLCD, and catecholamines were measured radioenzymatically. Tail cuff blood pressures and body weight were measured in parallel with urine collections. Kidneys were collected for assay of alpha2-adrenergic receptor density. RESULTS: VLCD induced rapid weight loss, but all the lost weight was regained during refeeding. Blood pressure fell during caloric restriction, but rose above baseline during refeeding. Urinary excretion of norepinephrine, epinephrine and dopamine changed several fold during weight cycling. Urinary catecholamines paralleled the changes in blood pressure, falling during caloric restriction and rebounding during refeeding. Dopamine showed the greatest decreases during weight loss and rises during weight regain, whereas epinephrine changed the least and norepinephrine was intermediate. Weight cycling elevated blood pressure above the initial baseline throughout the rapid weight gain phase of refeeding. The density of alpha2-adrenergic receptors was decreased in both the renal medulla and cortex of weight cycled SHROB, consistent with receptor down-regulation owing to overstimulation. CONCLUSIONS: The exacerbations of hypertension during weight regain in SHROB coincide with sustained activation of sympathoadrenal activity, as reflected in urinary catecholamine excretion and adrenergic receptor down regulation.

Adrenal Glands↗

PubMed2007

Response of plasma CNP forms to acute anabolic and catabolic interventions in growing lambs.

Using a novel marker of C-type natriuretic peptide (CNP) synthesis [amino-terminal pro-CNP (NT-proCNP)], we have recently shown that plasma NT-proCNP is strongly correlated with skeletal growth and markers of bone formation and is reversibly reduced by glucocorticoids. The effects on CNP of other catabolic or anabolic factors, known to affect skeletal growth, are unknown. Accordingly, we have studied the response of plasma CNP forms to acute catabolic (caloric restriction) and anabolic [growth hormone (GH) stimulation] interventions in lambs and related the findings to circulating IGF-I levels, growth velocity, and markers of bone formation. Lambs fed a reduced caloric intake (25% of normal) for 6 days exhibited reduced live weight, plasma urea, and IGF-I (P < 0.001 for all) compared with control lambs. Basal levels of NT-proCNP (40.1 +/- 0.9 pmol/l) fell promptly to a nadir (28.1 +/- 0.8 pmol/l, P < 0.001) on day 6, returning rapidly to basal levels upon refeeding. Although plasma alkaline phosphatase (ALP) fell (P < 0.001), reductions in metacarpal growth velocity were not significant within the 12-day period of study. In contrast to caloric restriction, long-acting bovine recombinant GH (2.5 mg/kg on days 0 and 6), as expected, increased plasma IGF-I more than twofold above control for 12 days (P < 0.001). Growth velocity did not differ during the 30 days of observation, and, consistent with unchanged growth velocity, plasma NT-proCNP and ALP were also unaffected. In conclusion, CNP synthesis and markers of bone formation are acutely sensitive to catabolism but unaffected by doses of GH that fail to stimulate skeletal growth.

Alkaline Phosphatase↗

PubMed1975

Experimental evidence of dietary factors and hormone-dependent cancers.

Current awareness of the importance of environmental factors such as diet in the etiology of human cancer has stimulated renewed interest in animal models for studying effects of diet on tumorigenesis. Diet can influence cancer in animals by affecting the initiation or subsequent preneoplastic stage of tumorigenesis, but it has less effect on tumor growth. Caloric restriction has a general inhibitory influence on tumorigenesis. Dietary fat, on the other hand, tends to promote tumorigenesis, but only certain types of tumors, such as mammary tumors, are affected. Both caloric restriction and dietary fat appear to act primarily during the preneoplastic state, and their effects on hormone-dependent tumors may be mediated through changes in the hormonal environment. Variations in other dietary factors, such as protein, vitamins, or minerals, above the levels required for normal maintenance seem to have little influence on the genesis or growth of tumors.

Animal Feed↗

PubMed2006

MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance.

Ablation of the hypothalamic peptide, melanin-concentrating hormone (MCH), leads to a lean phenotype and resistance to diet-induced obesity. Observation of MCH(-/-) mice at older ages suggested that these effects persist in mice >1 year old. Leanness secondary to caloric restriction is known to be associated with improved glucose tolerance as well as an overall increase in life span. Because the MCH(-/-) model represents leanness secondary to increased energy expenditure rather than caloric restriction, we were interested in determining whether this model of leanness would be associated with beneficial metabolic effects at older ages. To assess the effects of MCH ablation over a more prolonged period, we monitored male and female MCH(-/-) mice up to 19 months. The lean phenotype of MCH(-/-) mice persisted over the duration of the study. At 19 months, MCH(-/-) male and female mice weighed 23.4 and 30.8% less than their wild-type counterparts, a result of reduced fat mass in MCH(-/-) mice. Aged MCH(-/-) mice exhibited better glucose tolerance and were more insulin sensitive compared with wild-type controls. Aging-associated decreases in locomotor activity were also attenuated in MCH(-/-) mice. We also evaluated two molecules implicated in the pathophysiology of aging, p53 and silent inflammatory regulator 2 (Sir2). We found that expression of the tumor suppressor protein p53 was higher in MCH(-/-) mice at 9 and 19 months of age. In contrast, expression of Sir2 was unchanged. In aggregate, these findings suggest that MCH ablation improves the long-term outcome for several indicators of the aging process.

Aging↗

PubMed1999

Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes.

Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.

Aging↗

PubMedDate not supplied

"Population" characteristics of birthweight in an animal model of alcohol-related developmental effects.

A retrospective analysis of a large database of maternal and litter variables in rats collected over several years evaluated the robustness of fetal alcohol effects on birthweight. Pregnant rats were fed a liquid diet in which 35% of the calories were derived from alcohol. Control dams were pairfed an isocaloric liquid diet or were fed lab chow ad lib. Alcohol exposure produced large, highly significant, and reliable decreases in birthweight of male and female pups. Multiple regression analyses indicated that alcohol exposure per se, much more than restricted caloric intake alone, caused these effects. Litters of pairfed dams weighed less than chowfed controls but the effects were less consistent, varying with season and requiring more litters to discriminate the effects of restricted caloric intake. Power analyses indicated that 7 to 12 litters per group are needed for detecting a statistically significant reduction in birthweight due to prenatal alcohol exposure, even with single pups selected at random from each litter. Alcohol-exposed pups also weighed consistently and significantly less than both the chowfed and pairfed pups, whereas differences between chowfed and pairfed groups were much smaller and inconsistent. The results imply that decreased birthweight is a consistent characteristic of prenatal alcohol exposure.

Animals↗

PubMed1998

The evolution of aging: a new approach to an old problem of biology.

Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development. The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population turnover, which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging systems (ASs). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective defenses to predation that allow exceptionally long lifespans to evolve are shells, extreme intelligence, isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging systems. Aging organisms should have one dominant, aging system that co-opts vestiges of earlier-evolved systems as well as vestiges of prior systems. In human evolution, aging systems chronologically emerged as follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression (AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy (AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible aging systems. The life-extending/rejuvenating effects of caloric restriction support the idea of aging reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome. Methylated cytosines (5mC) inhibit gene transcription, and deoxyribonucleic acid (DNA) cleavage by restriction enzymes. Cleavage inhibition prevents apoptosis, which requires DNA fragmentation. Free radicals catalyze the demethylation of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA methyltransferases. Hormones act as either surrogate free radicals by stimulating the cyclic adenosine monophosphate (cAMP) pathway or as surrogate antioxidants through cyclic guanosine monophosphate (cGMP) pathway stimulation. Access to DNA containing 5mC inhibited developmental and aging genes and restriction sites is allowed by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase generates free radicals during strand separation; hormones either amplify or counteract this effect. Caloric restriction slows or reverses the aging process by increasing melatonin levels, which suppresses reproductive and free radical hormones, while increasing antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA, which increases bioavailable cGMP. The rapid aging diseases of progeria, the three diseases: (xeroderma pigmentosum (XP), Cockayne syndrome(CS), and ataxia telangiectasia (AT)), and Werner's syndrome are related to or caused by defects in three separate DNA helicases. The rapid aging diseases caused by mitochondrial malfunctions mirror those seen in XP, CS, and AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective aging systems. Follicle-stimulating hormone (FSH) demethylates the genes of AS#4, luteinizing hormone (LH) of AS#5, and estrogen of AS#6 while cortisol may act cooperatively with FSH and LH, and 5-alpha dihydrotestosterone (DHT) with FSH in these role. The Werner's DNA helicase links timing of the age of puberty, menopause, and maximum lifespan in one mechanism. Telomerase is under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of AS#5 and AS#6. The Hayflick limit is reached primarily through loss of cytosine methylation of genes that inhibit replication. Men suffer the diseases of AS#4 at a higher rate than women who suffer from AS#5 more often. Adult mammal cloning suggests aging-related cellular demethylation, and thus aging, is reversible. This theory suggests that the protective effect of smoking and ibuprofen for Alzheimer's disease is caused through LH suppression.

Aging↗

PubMed2000

Thyroid hormone metabolism in obesity.

Serum thyroid hormone concentrations and their metabolic fate are within the normal range limits in obese subjects. Also serum TSH concentrations and its response to TRH are normal, suggesting that tissue availability of thyroid hormones is normally preserved in these subjects. In contrast, during caloric restriction serum T3 concentrations decrease as a consequence of its reduced production rate from peripheral deiodination of T4. Opposite, serum rT3 concentrations markedly increase as a result of its decreased metabolic clearance rate. During caloric overfeeding serum T3 concentration increase whereas serum rT3 concentrations decrease. In this condition the production rate of T3 increases. During caloric restriction and overfeeding serum T4 concentrations and its production and degradation are not modified.

Energy Intake↗

PubMed1999

Visceral adipose tissue: a critical review of intervention strategies.

OBJECTIVE: To review the published literature regarding the effect of caloric restriction, pharmacologic intervention, and exercise to promote the loss of visceral adipose tissue (VAT) DESIGN: A review was conducted of published studies which measured VAT using computed tomography or magnetic resonance imaging before and after caloric restriction, pharmacologic therapy, or exercise. STUDIES REVIEWED: 23 separate studies were reviewed. Men represented 38% and women 63% of the 599 volunteers. There were 17 black volunteers and 30 patients with NIDDM included in these studies. MEASUREMENTS: Data regarding the baseline and change in VAT, body fat, and body weight were collected. RESULTS: Most interventions demonstrated a preferential loss of VAT regardless of the intervention applied. When expressed as percent change in VAT/percent change in body fat, a ratio can be calculated which we call the Selectivity Index (SI). When this index is applied to the literature reviewed, two observations can be made. First, the Selectivity Index is higher when baseline body fat is higher. Second, there is a direct relationship between the Selectivity Index and the baseline visceral fat ratio. These two observations suggest that individuals with greater visceral fat mass, either through an increase in the body weight or the propensity to store fat in the visceral depot, lose more visceral fat when adjusted to the loss of body fat. CONCLUSION: In conclusion, the Selectivity Index is useful to compare the ability of an intervention to specifically target the loss of AT. This simple index can serve as a benchmark for comparing intervention studies to each other.

Adipose Tissue↗

PubMed2006

Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans.

OBJECTIVE: Oxidative stress may be the unifying mechanism underlying the development of comorbidities in obesity. Evidence suggests that a clustering of sources of oxidative stress exists in obesity: hyperglycemia, hyperleptinemia, increased tissue lipid levels, inadequate antioxidant defenses, increased rates of free radical formation, enzymatic sources within the endothelium, and chronic inflammation. METHOD: This review provides a summary of the available evidence on systemic oxidative stress in humans and specific metabolic pathways by which obesity may elevate systemic oxidant stress. The authors suggest possible methods of reducing oxidative stress such as antioxidant supplementation, caloric restriction and/or physical activity and surgical intervention to combat free radicals and reduce adipose tissue. RESULTS: Obesity is associated with oxidative stress and can be reduced with weight loss (regardless of exercise or surgery induced weight loss), caloric restriction or antioxidant rich diets. CONCLUSION: Oxidative stress levels are elevated in human obesity, and these levels are modifiable with various lifestyle modifications and surgical interventions.

Antioxidants↗

PubMed1981

The "metabolically-obese," normal-weight individual.

A great many disorders including maturity-onset (type II) diabetes, hypertension, and hypertriglyceridemia are frequently associated with adult-onset obesity and improve with caloric restriction. It is the premise of this brief review that there are patients with these disorders who are not obese according to standard weight tables or other readily-available criteria; but who would also respond favorably to caloric restriction. It is proposed that such individuals might be characterized by hyperinsulinism and possibly an increase in fat cell size compared to patients of similar age, height, and weight and/or to themselves at an earlier time. The possibility is also discussed that inactivity is a contributing factor in some of these individuals and that for them, the appropriate therapy might be exercise.

Adipose Tissue↗

PubMed1995

Implications of increased intercellular variability of lipofuscin content with age in dentate gyrus granule cells in the mouse.

The purpose of this study was to further characterize lipofuscin (LF) accumulation with aging in brain cells, with a specific focus on the amount of intercellular variability of lipofuscin content within an apparently a homogenous population of dentate gyrus granule cells in the hippocampus of mice, as a function of age and caloric restriction (CR). Three age groups of CR and control mice including groups at maximum lifespan were studied. This study demonstrated that the intercellular variability of lipofuscin content was significantly greater in older mice and was significantly less in mice calorically restricted. Increased variability of metabolic function among cells with age, as measured by increased intercellular variability of lipofuscin content, may represent a definitive mechanism underlying the overall decreased efficiency of tissue and organ functioning that occurs with age. That this is so, is supported by the fact that CR, which has been shown to maintain the "youthful" state of many physiological functions, has been shown in this study to maintain the "youthful" state of low intercellular variability of lipofuscin content within a population of cells. LF accumulation may be a marker for the intrusion of entropy into cell metabolism.

Aging↗

PubMed1990

Treatment of obesity.

Decreases in resting metabolic rate and thermic effect of exercise during and after caloric restriction contribute to a reduced rate of weight reduction and subsequent difficulty in weight maintenance. Increasing exercise increases the thermic effect of exercise and prevents a decrease in resting metabolic rate, thereby, improving the rate of weight loss. A combined program of caloric restriction, exercise, and behavior therapy (including relapse prevention training and social support systems) is the most successful approach to long term weight reduction efforts. Pharmacologic treatment is currently limited, but there are three areas of development: agents which reduce energy intake, inhibitors of lipid synthesis, and thermogenesis enhancers. Evidence for improving efficiency of weight loss prevention and prevention of weight regain during repeated cycles of dieting (yo-yo phenomenon) exists in rat studies but not in a preliminary human investigation.

Basal Metabolism↗

PubMed2000

Glucose-induced insulin secretion from islets of fasted rats: modulation by alternate fuel and neurohumoral agonists.

Islets from fed and 24-h-fasted rats were studied immediately after collagenase isolation. (1) After a 24-h fast, the insulin secretory responses to 8 mM glucose measured during perifusion were reduced by more than 90% from islets of fasted donors. (2) Increasing glucose to 11 or 27.5 mM resulted in enhanced insulin secretion from islets of fasted animals. (3) Fasting did not reduce islet insulin content. (4) Responses to 8 or 27.5 mM glucose were not affected if fatty acid-free albumin was used during the perifusion. (5) Inclusion of alpha-ketoisocaproate (5 mM), monomethyl succinate (10 mM) or carbachol (10 microM) significantly amplified insulin release from fasted islets in the simultaneous presence of 8 mM glucose. (6) Phospholipase C activation by glucose, carbachol or their combination was not adversely affected by fasting. (7) The response to the protein kinase C activator, phorbol 12-myristate 13-acetate (500 nM), was reduced by about 60% after fasting. (8) Extending the fast to 48 h resulted in a severe decline in response to 11 mM glucose; however, the further addition of 10 microM carbachol still enhanced release from these islets. The results confirm that caloric restriction impairs islet sensitivity to glucose stimulation and that protein kinase C may be involved in the reduction of glucose-induced insulin release from these islets. The activation of phospholipase C by cholinergic stimulation may contribute to the maintenance of insulin secretion from calorically restricted animals. These results also demonstrate that free fatty acids are not essential for glucose to evoke secretion from isolated islets of fasted donors.

Analysis of Variance↗