Non-fasting Levels Research Articles

Postprandial lipemia and cardiovascular disease: impact of age and gender on nonfasting triacylglycerol levels

case–control studies have further qualitatively established nonfasting TAG as a CVD risk factor [16,17], with information on the quantitative relationship limited to a small number of studies [6,8,9,18,19]. In the Copenhagen Heart Study, nonfasting TAG levels of more than or equal to 5, 4–4.99, 3–3.99, 2–2.99 and 1–1.99 mmol/l versus less than 1 mmol/l were shown to predict a 16.8-, 5.1-, 3.9-, 4.4and 2.2-fold increase in risk of myocardial infarction in females, respectively, with equivalent values in males of 4.6-, 3.3-, 3.6-, 2.3and 1.6-fold, respectively [8]. This greater ‘penetrance’ in females is consistent with an earlier meta-ana lysis that considered fasting TAG data [4].

Abstract A46: Pharmacodynamic biomarkers for OSI-906, an insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in cancer patients with advanced solid tumors

Abstract Background: OSI-906 is a potent small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), a receptor tyrosine kinase that is overexpressed in several human cancer types and implicated in resistance to chemotherapy. Disruption of the growth hormone-IGF1 signaling axis can affect levels of biomarkers such as IGF1, growth hormone (GH) and insulin and can affect glucose homeostasis, making these potentially useful markers for demonstrating the activity of IGF-1R inhibitors in solid tissues. Methods: Two phase I dose escalation trials were initiated in cancer patients with advanced solid tumors who received OSI-906 on either continuous or intermittent dosing schedules. Pharmacodynamic (PD) and pharmacokinetic (PK) assessments were included as secondary objectives of these studies. Circulating biomarkers, including total IGF1, IGFBP3 and non-fasting GH and insulin levels, were measured at various times during the dosing cycle (21 days for continuous dosing; 14 days for intermittent dosing) and changes were correlated with plasma concentrations of OSI-906. Results: To date, patients have been treated with up to 450 mg QD and 200 mg BID on the continuous dosing schedule and up to 750 mg QD on the intermittent dosing schedule. Maximum tolerated dose (MTD) was determined to be 400 mg QD and 150 mg BID for continuous dosing and 600 mg QD for intermittent dosing. Preliminary analysis of the PK data suggests that the exposure of OSI-906 increased with dose. Median plasma concentrations of OSI-906 at MTD exceeded the predicted concentration required for efficacy based on the preclinical models (1 µM). Total IGF1 concentrations in plasma were increased relative to predose levels at doses ≥ 450 mg QD on the intermittent dosing schedule and ≥ 150 mg QD or 40 mg BID on the continuous dosing schedule. Elevations in non-fasting plasma insulin levels were also observed in patients with plasma concentrations of OSI-906 exceeding 5000 ng/mL. PK/PD relationships were observed for IGF1 and insulin. OSI-906 did not affect plasma IGFBP3 levels in most patients. Analysis of additional biomarkers, including GH, is ongoing. Conclusions: At or below MTD, plasma concentrations of OSI-906 could be achieved that exceed concentrations required for anti-tumor efficacy based on the preclinical models. The pharmacodynamic data indicate that pharmacologically-relevant concentrations of OSI-906 were achieved in tissues involved in regulating the GH-IGF1 signaling axis. Together, these PK and PD data indicate that the current recommended dosing regimens may provide sufficient exposure for activity against solid tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A46.

Nonfasting Hyperlipidemia and Cardiovascular Disease

Most humans are in the nonfasting or postprandial state in the majority of a 24 hour cycle; however, lipids, lipoproteins, and apolipoproteins are usually measured in the fasting state. Recent studies demonstrate that these values at most change minimally in response to normal food intake, changes that are clinically unimportant. Also, elevated levels of nonfasting triglycerides as a marker of elevated remnant lipoprotein cholesterol associate strongly with increased risk of myocardial infarction, ischemic stroke, and early death. The mechanism behind these findings likely involves entrance of remnant lipoproteins into the arterial intima with subsequent retention leading to atherogenesis, while low HDL cholesterol levels may be an innocent bystander. Finally, nonfasting levels of total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, HDL cholesterol, apolipoprotein A1, total cholesterol/HDL cholesterol, and apolipoprotein B/apolipoprotein A1 all associate with increased risk of cardiovascular disease. These new data open the possibility that nonfasting rather than fasting lipid profiles can be used for cardiovascular risk prediction. If implemented, this would simplify blood sampling for lipid measurements for millions of patients worldwide. Furthermore, the results also highlight the need for randomized double-blind trials of new and established drugs to reduce nonfasting triglycerides and remnant lipoprotein cholesterol, with the ultimate aim of reducing risk of cardiovascular disease and early death.

Fasting and Nonfasting Lipid Levels

Lipid profiles are usually measured after fasting. We tested the hypotheses that these levels change only minimally in response to normal food intake and that nonfasting levels predict cardiovascular events. We cross-sectionally studied 33 391 individuals 20 to 95 years of age from the Copenhagen General Population Study. We also studied 9319 individuals 20 to 93 years of age from the Copenhagen City Heart Study, 1166 of whom developed cardiovascular events during 14 years of follow-up. Compared with fasting levels, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and albumin levels were reduced up to 3 to 5 hours after the last meal; triglycerides levels were increased up to 6 hours after the last meal; and non-HDL cholesterol level, apolipoprotein A1 level, apolipoprotein B level, ratio of total cholesterol to HDL cholesterol, and ratio of apolipoprotein B to apolipoprotein A1 did not change in response to normal food intake. The maximum changes after normal food and fluid intake from fasting levels were -0.2 mmol/L for total cholesterol, -0.2 mmol/L for low-density lipoprotein cholesterol, -0.1 mmol/L for HDL cholesterol, and 0.3 mmol/L for triglycerides. Highest versus lowest tertile of nonfasting total cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, ratio of total cholesterol to HDL cholesterol, and ratio of apolipoprotein B/apolipoprotein A1 and lowest versus highest tertile of nonfasting HDL cholesterol and apolipoprotein A1 predicted 1.7- to 2.4-fold increased risk of cardiovascular events. Lipid profiles at most change minimally in response to normal food intake in individuals in the general population. Furthermore, nonfasting lipid profiles predicted increased risk of cardiovascular events.

Association of fasting and nonfasting serum triglycerides with cardiovascular disease and the role of remnant-like lipoproteins and small dense LDL

The magnitude of the contribution of serum triglycerides to cardiovascular disease risk and the mechanisms by which triglyceride-rich lipoproteins exert their effect on the vascular wall are largely unknown. Postprandial lipemia likewise has been linked to atherosclerosis, but large prospective studies assessing the magnitude of this association are also lacking. Hypertriglyceridemia is characterized by the presence of cholesterol-rich remnant-like lipoproteins and small dense LDL particles, both of which are believed to contribute to cardiovascular disease risk. Several large prospective cohort studies and a meta-analysis have been published recently, investigating the association of fasting and nonfasting serum triglycerides with cardiovascular disease. Fasting triglycerides increase the adjusted hazard ratios for cardiovascular disease risk 1.7 x (comparing upper with lower tertile), and nonfasting levels around 2.0 x. Measurement of nonfasting triglycerides may be more feasible and more informative, but standardization of a test meal is necessary. For clinical practice, the concentration of the atherogenic lipoprotein subfractions in hypertriglyceridemia may be reflected best by measuring apolipoprotein B. Nonfasting triglyceride levels may replace fasting levels in assessing cardiovascular disease risk once standard reference values have been developed. Several atherogenic lipoprotein subfractions can be measured by including apolipoprotein B in addition to HDL, (nonfasting) triglycerides and LDL cholesterol.

Systematic error of serum triglyceride measurements during three decades and the effect of fasting on serum triglycerides in population studies

Background An uncontrolled systematic error in serum biomarkers may be a serious problem when comparing their trends both within and between populations. The aim of the study was to assess which factors are responsible for systematic errors in the measurement of serum triglycerides (Tg) and the effect of fasting on serum triglycerides in Finnish population surveys. Methods Data on precision and accuracy during 30 years for serum triglycerides were documented from participation in 492 rounds of five different external quality assessment (EQA) programs. Data on fasting and health status from questionnaires were combined from three population surveys comprising 27 131 participants. Results The mean annual accuracy (bias) of the Tg methods from all EQAs during 1978–2007 was − 1.54% (95% CI − 2.25, − 0.83). The mean relative change in triglyceride concentration per fasting hour was − 3.7% (95% CI − 4.2, − 3.1) in all subjects. A minimum serum Tg concentration was seen in men and women who had fasted for at least 8 and 7 h, respectively. Conclusions The mean bias in serum Tg analyses has been very small throughout the 30-year period. Fasting has a considerable effect on triglyceride levels, but they can be converted either to fasting or non-fasting levels using specific factors.

Metabolic and reproductive consequences of the serotonin transporter promoter polymorphism (5-HTTLPR) in adult female rhesus monkeys (Macaca mulatta)

The serotonin (5HT) reuptake transporter (SERT) plays a key role in 5HT homeostasis by recycling 5HT into the presynaptic neurons. Recently, polymorphisms in the length of the promoter region of the gene that encodes SERT have been linked to functional differences in reactivity to psychosocial stress, as the short (s) promoter length allele shows reduced transcriptionally activity in vitro and is associated with reduced 5HT activity and increased vulnerability to affective disorders. Given 5HT's important role in appetite regulation, polymorphisms in the SERT gene could also affect metabolic parameters. In addition, since reduced 5HT activity may also predispose females to reproductive deficits, polymorphisms in the SERT gene may help explain individual differences in ovulatory function. The present study, using a rhesus monkey model, tested the hypothesis that the presence of the s-variant allele would be associated with altered metabolic regulation and impaired ovulatory cycles compared with the l/l genotype. Females homozygous for the long allele in the SERT gene (l/l, n = 19) were compared to those with the s-variant allele (l/s or s/s, n = 20). All females had similar social histories. Body weights (P = 0.026) but not heights (P = 0.618) were significantly lower in s-variant compared to l/l females. In addition, both BMI (P = 0.032) and sagittal abdominal diameters (SAD) (P = 0.031), as indices of adiposity, were significantly lower in s-variant females. Consistent with these differences, fasting and non-fasting levels of leptin were significantly lower in s-variant females (P = 0.002). While there were no genotype differences in non-fasting levels of insulin, s-variant females had significantly lower concentrations of insulin during a fast than did l/l females (P = 0.052). Neither glucose, T 3, T 4, nor ghrelin varied significantly between groups during either the fasted or non-fasted condition (P > 0.05). Analysis of a subset of females indicated that significantly fewer s-variant females (62.5%) exhibited ovulatory cycles than l/l females (100%, P < 0.05). However, there were no differences in serum estradiol or progesterone in l/l females and those s-variant females that did ovulate (P > 0.05). In addition, females with the s-variant genotype also had reduced 5HT activity (P = 0.030), assessed from the acute increase in serum prolactin following the administration of the 5HT reuptake inhibitor, citalopram. Finally, s-variant females were significantly less responsive to glucocorticoid negative feedback (P = 0.030) yet more responsive to corticotropin releasing hormone (CRH, P = 0.016) in terms of plasma cortisol than were l/l females. These data indicate that adult female rhesus monkeys with the s-variant polymorphism in the SERT gene exhibit metabolic and reproductive alterations in conjunction with reduced serotonergic responsivity and increased LHPA activity and suggest the possibility that this genotype may predispose females exposed to psychosocial stressors to further metabolic and reproductive deficits.

Nonfasting Triglycerides as an Indicator of Cardiovascular Risk

Studies focusing on fasting triglyceride (TG) levels and cardiovascular (CV) risk have yielded inconsistent and controversial findings. In this prospective study, investigators stratified 28,000 initially healthy participants in the Women’s Health Study into tertiles according to fasting and nonfasting TG levels and evaluated the incidence of CV events (myocardial infarction, stroke, coronary revascularization, or CV …

Lipid Changes in Patients Initiating Efavirenz- and Indinavir-Based Antiretroviral Regimens

Purpose: To evaluate nonfasting lipid levels in a large cohort of patients on three HAART regimens: efavirenz + zidovudine + lamivudine (EFV+ZDV+3TC), efavirenz + indinavir (EFV+IDV), and indinavir + zidovudine + lamivudine (IDV+ZDV+3TC). Method: Nonfasting lipid levels were analyzed from a large randomized multicenter treatment trial for HIV-infected patients initiating HAART. Treatment evaluations were carried out at prescribed intervals, and data were recorded and analyzed. Assessment was limited to high-density lipoprotein (HDL) and total cholesterol. Results: The results demonstrate an increase in the total cholesterol, ranging from 23 to 57 mg/dL, in the three combinations of HAART therapy. The increase was most significant in the EFV+IDV arm where the effects appear to be additive. HDL cholesterol also increased in all three arms, but the greatest increase was in the two groups containing EFV. In all three arms, the HDL cholesterol increased significantly in women while increases in men were seen only in the EFV-containing arms. Men taking either IDV-containing regimen had a greater increase in total cholesterol, and therefore the total/HDL cholesterol ratio rose significantly. Conclusion: EFV and IDV independently elevate lipid levels. Alterations in the lipid levels may lead to increased cardiovascular risk in men, possibly mitigated by elevations in HDL cholesterol. In addition, changes in HDL cholesterol were significantly different between men and women.

Lipid Changes in Patients Initiating Efavirenz- and Indinavir-Based Antiretroviral Regimens

Purpose: To evaluate nonfasting lipid levels in a large cohort of patients on three HAART regimens: efavirenz + zidovudine + lamivudine (EFV+ZDV+3TC), efavirenz + indinavir (EFV+IDV), and indinavir + zidovudine + lamivudine (IDV+ZDV+3TC). Method: Nonfasting lipid levels were analyzed from a large randomized multicenter treatment trial for HIV-infected patients initiating HAART. Treatment evaluations were carried out at prescribed intervals, and data were recorded and analyzed. Assessment was limited to high-density lipoprotein (HDL) and total cholesterol. Results: The results demonstrate an increase in the total cholesterol, ranging from 23 to 57 mg/dL, in the three combinations of HAART therapy. The increase was most significant in the EFV+IDV arm where the effects appear to be additive. HDL cholesterol also increased in all three arms, but the greatest increase was in the two groups containing EFV. In all three arms, the HDL cholesterol increased significantly in women while increases in men were seen only in the EFV-containing arms. Men taking either IDV-containing regimen had a greater increase in total cholesterol, and therefore the total/HDL cholesterol ratio rose significantly. Conclusion: EFV and IDV independently elevate lipid levels. Alterations in the lipid levels may lead to increased cardiovascular risk in men, possibly mitigated by elevations in HDL cholesterol. In addition, changes in HDL cholesterol were significantly different between men and women.

Glucose Homeostasis in the Teleost Fish Tilapia: Insights from Brockmann Body Xenotransplantation Studies1

Certain teleost fish have large anatomically discrete islet organs called Brockmann bodies (BBs). When transplanted into streptozotocin diabetic athymic nude mice, tilapia BBs provide long-term normoglycemia. This has afforded us the opportunity to examine tilapia islet in vivo function in a non-piscine environment and compare this with in vivo function in the donor species. As expected, fasting and non-fasting glycemic levels in long-term murine recipients of tilapia BBs were analogous to corresponding values in donor tilapia, but, surprisingly, tilapia BB grafts provided mammalian-like glucose tolerance profiles. Teleost fish, in general, are severely glucose intolerant. When glucose tolerance tests were performed in tilapia, the mean glucose disappearance rates were very low; however, diabetic nude mice bearing long-term tilapia BB grafts were extremely glucose responsive. This suggested a severe or absolute peripheral resistance to the glucostatic effects of insulin. Using Western blotting with polyclonal antibodies and then confirmed by Northern analysis, tilapia peripheral tissues appear to be devoid of GLUT-4, the insulin-sensitive glucose transporter responsible for the hypoglycemic effect of insulin in mammals, but not GLUT-1, the insulin independent glucose transporter. This may explain why tilapia, and possibly other teleost fish, are severely glucose intolerant after pharmacologic glucose-loading. Because tilapia do not tend to consume large quantities of glucose in the wild, it is not surprising that they have evolved without a mechanism to move glucose rapidly from the bloodstream into muscle and fat. Nevertheless, insulin still appears to play an important role in maintaining normoglycemia in tilapia; however, this is mostly likely a result of its effect on glucose uptake in the liver. We also present comparative data on tilapia beta cell function, quantification of islet cell numbers and types, islet products, insulin gene structure and expression, and beta cell sensitivity to the diabetogenic drug streptozotocin.

Serum insulin-like growth factor-I and breast cancer.

Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91-2. 81]. The OR decreased to 1.49 (95% CI 0.80-2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07-4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82-4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50.

Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice.

Hepatic lipid synthesis is known to be regulated by food consumption. In rodents fasting decreases the synthesis of cholesterol as well as fatty acids. Refeeding a high carbohydrate/low fat diet enhances fatty acid synthesis by 5- to 20-fold above the fed state, whereas cholesterol synthesis returns only to the prefasted level. Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate genes involved in cholesterol and fatty acid synthesis. Here, we show that fasting markedly reduces the amounts of SREBP-1 and -2 in mouse liver nuclei, with corresponding decreases in the mRNAs for SREBP-activated target genes. Refeeding a high carbohydrate/low fat diet resulted in a 4- to 5-fold increase of nuclear SREBP-1 above nonfasted levels, whereas nuclear SREBP-2 protein returned only to the nonfasted level. The hepatic mRNAs for fatty acid biosynthetic enzymes increased 5- to 10-fold above nonfasted levels, a pattern that paralleled the changes in nuclear SREBP-1. The hepatic mRNAs for enzymes involved in cholesterol synthesis returned to the nonfasted level, closely following the pattern of nuclear SREBP-2 regulation. Transgenic mice that overproduce nuclear SREBP-1c failed to show the normal decrease in hepatic mRNA levels for cholesterol and fatty acid synthetic enzymes upon fasting. We conclude that SREBPs are regulated by food consumption in the mouse liver and that the decline in nuclear SREBP-1c upon fasting may explain in part the decrease in mRNAs encoding enzymes of the fatty acid biosynthetic pathway.

Insulin Sensitivity in Adult Female Rats Subjected to Malnutrition During the Pering the Perinatal Period

Objective:The purpose of the present study was to investigate insulin sensitivity in adult rats after perinatal malnutrition.Methods:Wistar rats were food-restricted (about 50% of normal food intake) during pregnancy (group A) or during pregnancy and lactation (group B) and compared with rats fed ad libitum during pregnancy and lactation (group C). The insulin sensitivity in the adult female offspring was assessed with the hyperinsulinemic euglycemic clamp technique in combination with isotopic measurement of glucose turnover. Hepatic and peripheral insulin sensitivities were determined in the basal state and after 3, 10, or 50 mU/kg/minute insulin.Results:Group A and group B rats had lower non-fasting plasma insulin levels (0.15 ± 0.07 and 0.15 ± 0.01 nmol/L, respectively) than group C rats (0.26 ± 0.03 nmol/L) (P < .001). During hyperinsulinemia, the steady-state glucose infusion rate was lower in groups A and B, with 10 and 50 mU/kg/minute insulin, indicating insulin resistance. Hepatic glucose product...

Reduced cholecystokinin mediates the inhibition of pancreatic growth induced by bile salts

The effects of luminal bile salts on plasma levels of cholecystokinin (CCK) and growth of the pancreas in mice were studied. Nonfasting levels of plasma CCK in control mice were 8.1 +/- 1.5 pM. Feeding mice a 0.5% (wt/wt) sodium taurocholate-supplemented diet for 1 wk significantly lowered nonfasting levels of plasma CCK to 4.1 +/- 0.5 pM and decreased the total contents of pancreatic DNA by 22%, RNA by 25%, and protein by 24%. All of the inhibitory effects of taurocholate on pancreatic growth were completely reversed by the simultaneous administration of CCK-8 (3 micrograms/kg, 3 times daily). In contrast, intraluminal neutralization of endogenous bile salts by feeding a 4% (wt/wt) cholestyramine-supplemented diet for 1 wk significantly elevated nonfasting levels of plasma CCK to 14.7 +/- 1.5 pM and increased the total contents of pancreatic DNA by 34%, RNA by 40%, and protein by 35%. All of the stimulatory actions of cholestyramine on pancreatic growth were completely abolished by the administration of the highly potent and specific CCK-receptor antagonist L364,718 (1 mg/kg, twice daily). These findings, therefore, indicate that bile salts appear to play a physiological role in pancreatic growth by regulation of plasma levels of CCK.

Greatly enhanced bioavailability of theophylline on postprandial administration of a sustained release tablet

The bioavailability of theophylline after oral administration of a new sustained release tablet Theograd-250 mg was studied in 7 healthy volunteers, under fasting and non-fasting conditions. Whilst fasting the bioavailability was moderate at 64 +/- 22% (mean +/- SD), whereas in the non-fasting state the relatively high bioavailability of 90 +/- 13% was found. The drug appeared to be significantly more slowly absorbed when a tablet was taken after a meal, than when it was ingested on an empty stomach. In the former case, the peak level was reached after 6.9 +/- 1.0 h, whereas in the fasting state the maximum serum concentration occurred 4.0 +/- 1.7 h after administration of the drug. Despite the slow absorption, the peak non-fasting level of 4.4 +/- 1.4 mg . 1(-1) was significantly higher than the 3.1 +/- 1.0 mg . 1(-1) observed in the fasting state. The profiles of the serum concentration-time curves showed that the concentration remained above 75% of Cmax for 8.7 +/- 1.3 h in the fasting and 9.0 +/- 1.1 h in the non-fasting state. It was concluded that to define the optimal dosage regime for sustained release oral dosage forms of theophylline, the influence of food on absorption from these preparations should be taken into account. Based on the present results, Theograd-250 mg tablets have predictable absorption and a high (90%) bioavailability if taken after a meal.

The influence of starvation on intestinal cholecystokinin-like activity and pancreatic growth.

1. This study examines the influence of starvation on intestinal CCK content and pancreatic growth. Intestinal CCK content was determined by measuring the CCK-like activity using an in vitro gall-bladder bio-assay. Starvation for up to 72 hr causes a parallel fall in intestinal CCK content and pancreatic DNA synthesis. Since there was no significant decrease in liver DNA synthesis, the effect of starvation was probably not simply a consequence of malnutrition. Furthermore there was little effect of starvation on pancreatic protein and DNA content, suggesting that pancreatic cell turnover is particularly sensitive to changes in dietary stimulation.2. With refeeding after starvation CCK-like activity in intestinal extracts gradually increased, approaching non-fasting levels 72 hr after refeeding. Pancreatic DNA synthesis also returned to non-fasting levels after feeding but this rose faster than the intestinal CCK content.3. Pentagastrin treatment prevented the atrophy of both the pancreas and the gastrointestinal tract with starvation without influencing the fall in intestinal CCK-like activity. This suggests that the control of CCK-containing cells is different from that of the surrounding intestinal parenchyma.4. The effect of starvation was also studied in antrectomized rats. Antrectomy alone did not reduce pancreatic DNA synthesis although DNA synthesis of the small intestine was significantly reduced. When antrectomized rats were starved pancreatic DNA synthesis fell to the same degree as was found in unoperated animals. The pancreatic atrophy was also accompanied by a drop in intestinal CCK content. Starvation of antrectomized rats, however, did not further depress the already greatly reduced plasma gastrin concentration.

Reversal of diabetes by allogenic islet transplantation without immunosuppression.

Streptozotocin-induced diabetes is temporarily reversed following the allo-transplantation of BALB/c (H-2d) islet tissue to normal CBA (H-2k) recipients, but by 2-4 week post-transplantation these animals return to their initial diabetic condition. Organ culture of allogeneic islet tissue in 95% O2 and 5% CO2 for 7 days prior to transplantation reduces the immunogenicity of the tissue, and cultured allografts give prolonged (greater than 110 days) reversal of diabetes in normal allogeneic recipients. The non-fasting blood sugar level remains in or very close to the normal range, urine glucose output is one to two orders of magnitude less than that of diabetic control animals and allografted animals regain their pre-morbid body weight within 60 days of transplantation. Surgical removal of the allograft results in a rapid return of the animal to the initial diabetic condition.

Metabolic Responsiveness of Different Size Adipocytes to Fasting and Refeeding in the Pig

The effects of fasting (F) and fasting-refeeding (FR) on [U-14C]glucose and [1-14C]palmitate metabolism were examined in pig middle subcutaneous (MSQ) adipocytes fractionated into 20--63, 63--102 and 102--153 microns diameter ranges. Fasting caused a similar decrease in de novo glyceride fatty acid (GFA) and glyceride-glycerol (GG) synthesis from glucose among adipocytes of different size. After refeeding for 2 days, glucose metabolism significantly increased in all fractions, however, the increase did not reach non-fasting levels. There was a disparate increase in glucose metabolism among adipocyte fractions after refeeding. Adipocytes 102--153 microns in diameter had a larger increase in glucose metabolism than smaller adipocytes. Fasting suppressed palmitate esterification rates in 20--63 and 63--102 microns fractions. Esterification by adipocyted 102--153 microns in diameter was not diminished after fasting. An "overshoot" in esterification by adipocytes 63--102 and 102--153 microns in diameter relative to control adipocytes was observed after refeeding; no "overshoot" occurred in 20--63 microns adipocytes. These results indicate that adipocytes of different size have markedly different capacities for substrate utilization after F or FR as well as different metabolic adaptations to F or FR.

Responses of essential fatty acid-deficient rats to fasting-refeeding and partial hepatectomy.

SummaryEssential fatty acid-deficient rats were subjected to fasting-refeeding or partial hepatectomy to stimulate liver phos-pholipid and membrane formation under conditions of limited essential fatty acid (EFA) supply. Refeeding after fasting decreased the proportion of arachidonate in liver phospholipid fatty acids only slightly, i.e., from 6.8% in nonfasted rats to 5.3% after 3 or 7 days of refeeding, whereas ei-cosatrienoate decreased from 19.8% in nonfasted rats to 13.0% after 3 days of refeeding, with a return to nonfasted levels after 7 days. Activities of liver glucose-6-phosphate dehydrogenase and fatty acid synthetase in fasted-refed EFA-deficient rats did not differ significantly from values in deficient rats fed ad libitum. Considerable increase in liver weight (ca. 3-8 g or at least 50% of the estimated preoperative weight) occurred after partial hepatectomy of EFA-deficient rats. The proportion of arachidon-ate in phospholipid fatty acids was slightly lower after hepatectomy than before.The...