Estimating glomerular filtration rate in youth with obesity and type 2 diabetes: the iCARE study equation.

BACKGROUND: The validity of pediatric estimated glomerular filtration rate equations (eGFRs) in early stages of CKD including hyperfiltration is unknown. The purpose of this study was to develop an eGFR equation for adolescents with obesity and type 2 diabetes (T2D). METHODS: eGFRs were developed from iohexol-derived GFRs (iGFRs) in 26 overweight/obese (BMI > 85th percentile) youth and 100 with T2D from the iCARE (Improving renal Complications in Adolescents with T2D through REsearch) cohort. Twenty percent of the cohort was withheld as a validation dataset. Linear regression analyses were used to develop the best formula based on body size, sex, creatinine, urea, ± cystatin C. Comparable validity of commonly used eGFR equations was assessed. RESULTS: Mean age 15.4 + 2.4 years, BMI Z-score 2.5 + 1.2, 61% female, and mean iGFR 129.0 + 27.7 ml/min/ 1.73 m2. The best adjusted eGFR formula (ml/min/1.73 m2) was 50.7 × BSA0.816 × (height (cm)/creatinine)0.405 × 0.8994 if sex = female | 1 otherwise. It resulted in 53.8% of eGFRs within 10% of measured iGFR and 96.2% within 30%. Bland-Altman 95% limits of agreement in the external dataset were - 37.6 to 45.5 ml/min/1.73m2 (bias = 3.96), and the correlation was 0.62. This equation performed better than all previously published creatinine-based eGFRs. cystatin C did not significantly improve results; however, some other cystatin C formulas also performed well. CONCLUSIONS: The iCARE equation provides a more accurate creatinine-based eGFR in obese youth with and without T2D. Further studies are warranted to evaluate within-subject variability and applicability to lower GFRs and other populations.

Mapping and targeted viral activation of pancreatic nerves in mice reveal their roles in the regulation of glucose metabolism.

A lack of comprehensive mapping of ganglionic inputs into the pancreas and of technology for the modulation of the activity of specific pancreatic nerves has hindered the study of how they regulate metabolic processes. Here we show that the pancreas-innervating neurons in sympathetic, parasympathetic and sensory ganglia can be mapped in detail by using tissue clearing and retrograde tracing (the tracing of neural connections from the synapse to the cell body), and that genetic payloads can be delivered via intrapancreatic injection to target sites in efferent pancreatic nerves in live mice through optimized adeno-associated viruses and neural-tissue-specific promoters. We also show that, in male mice, the targeted activation of parasympathetic cholinergic intrapancreatic ganglia and neurons doubled plasma-insulin levels and improved glucose tolerance, and that tolerance was impaired by stimulating pancreas-projecting sympathetic neurons. The ability to map the peripheral ganglia innervating the pancreas and to deliver transgenes to specific pancreas-projecting neurons will facilitate the examination of ganglionic inputs and the study of the roles of pancreatic efferent innervation in glucose metabolism.

Differential effects of hypothalamic long-chain fatty acid infusions on suppression of hepatic glucose production.

Our objective was to investigate whether the direct bilateral infusion of the monounsaturated fatty acid (MUFA) oleic acid (OA) within the mediobasal hypothalamus (MBH) is sufficient to reproduce the effect of administration of OA (30 nmol) in the third cerebral ventricle, which inhibits glucose production (GP) in rats. We used the pancreatic basal insulin clamp technique (plasma insulin ∼20 mU/ml) in combination with tracer dilution methodology to compare the effect of MBH OA on GP to that of a saturated fatty acid (SFA), palmitic acid (PA), and a polyunsaturated fatty acid (PUFA), linoleic acid (LA). The MBH infusion of 200 but not 40 pmol of OA was sufficient to markedly inhibit GP (by 61% from 12.6 ± 0.6 to 5.1 ± 1.6 mg·kg(-1)·min(-1)) such that exogenous glucose had to be infused at the rate of 6.0 ± 1.2 mg·kg(-1)·min(-1) to prevent hypoglycemia. MBH infusion of PA also caused a significant decrease in GP, but only at a total dose of 4 nmol (GP 5.8 ± 1.6 mg·kg(-1)·min(-1)). Finally, MBH LA at a total dose of 0.2 and 4 nmol failed to modify GP compared with rats receiving MBH vehicle. Increased availability of OA within the MBH is sufficient to markedly inhibit GP. LA does not share the effect of OA, whereas PA can reproduce the potent effect of OA on GP, but only at a higher dose. It remains to be determined whether SFAs need to be converted to MUFAs to exert this effect or whether they activate a separate signaling pathway to inhibit GP.

Cellular remodeling of HCO3(-)-secreting cells in rabbit renal collecting duct in response to an acidic environment.

The renal cortical collecting duct (CCD) consists of principal and intercalated cells. Two forms of intercalated cells, those cells involved in H+/HCO3- transport, have recently been described. H+-secreting cells are capable of apical endocytosis and have H+ATPase on the apical membrane and a basolateral Cl-/HCO3- exchanger. HCO3(-)-secreting cells bind peanut agglutinin (PNA) to apical membrane receptors and have diffuse or basolateral distribution of H+ATPase; their Cl-/HCO3- exchanger is on the apical membrane. We found that 20 h after acid feeding of rabbits, there was a fourfold increase in number of cells showing apical endocytosis and a numerically similar reduction of cells binding PNA. Incubation of CCDs at pH 7.1 for 3-5 h in vitro led to similar, albeit less pronounced, changes. Evidence to suggest internalization and degradation of the PNA binding sites included a reduction in apical binding of PNA, decrease in pH in the environment of PNA binding, and incorporation of electron-dense PNA into cytoplasmic vesicles. Such remodeling was dependent on protein synthesis. There was also functional evidence for loss of apical Cl-/HCO3- exchange on PNA-labeled cells. Finally, net HCO3- flux converted from secretion to absorption after incubation at low pH. Thus, exposure of CCDs to low pH stimulates the removal/inactivation of apical Cl-/HCO3- exchangers and the internalization of other apical membrane components. Remodeling of PNA-labeled cells may mediate the change in polarity of HCO3- flux observed in response to acid treatment.

Carbon dioxide causes exocytosis of vesicles containing H+ pumps in isolated perfused proximal and collecting tubules.

In the turtle bladder it has recently been shown that CO2 stimulates H+ secretion, at least in part, by causing fusion of vesicles enriched in H+ pumps with the luminal plasma membrane. To test for the presence of this mechanism in the kidney we perfused collecting ducts and proximal straight tubules on the stage of an inverted epifluorescence microscope with fluorescein isothiocyanate dextran (70,000 mol wt) in CO2-free medium. After washout we noted punctate fluorescence in endocytic vesicles in some collecting ducts and in all proximal straight tubule cells. More cells took up fluorescent dextran in outer medullary than in cortical collecting ducts. Using the pH dependence of the excitation spectrum of fluorescein we found the pH of the vesicles to be acid (approximately pH 6). Addition of proton ionophores increased vesicular pH by 0.6 +/- 0.1 U, suggesting that the acidity of the vesicles was caused by H+ pumps. CO2 added to the medium (25 mmHg, pH 7.6 at 37 degrees C) reduced fluorescence intensity by 24 +/- 5% in cortical collecting ducts, 27 +/- 5% in medullary collecting ducts, and 25 +/- 5% in proximal straight tubules. Since this effect was prevented by the prior addition of colchicine to the bath, we believe that CO2 caused a decrease in cytoplasmic fluorescence by stimulating exocytotic fusion of the vesicles and thereby secretion of fluorescent dextran. This exocytotic fusion also occurred when tubules that were loaded with fluorescent dextran at a pCO2 of 37 mmHg were exposed isohydrically to a pCO2 of 114 mmHg; the mean decrease was 53 +/- 4%. We conclude that some cells in the collecting ducts and all cells in the proximal straight tubule incorporate fluorescent dextran into the apical cytoplasmic vesicles and acidify them with H+ pumps. CO2 causes fusion of these vesicles with the luminal membrane, but whether CO2 stimulates H+ secretion by increasing the number of functioning H+ pumps remains to be determined.

Adaptation of rabbit cortical collecting duct HCO3- transport to metabolic acidosis in vitro.

Net HCO3- transport in the rabbit kidney cortical collecting duct (CCD) is mediated by simultaneous H+ secretion and HCO3- secretion, most likely occurring in a alpha- and beta-intercalated cells (ICs), respectively. The polarity of net HCO3- transport is shifted from secretion to absorption after metabolic acidosis or acid incubation of the CCD. We investigated this adaptation by measuring net HCO3- flux before and after incubating CCDs 1 h at pH 6.8 followed by 2 h at pH 7.4. Acid incubation always reversed HCO3- flux from net secretion to absorption, whereas incubation for 3 h at pH 7.4 did not. Inhibition of alpha-IC function (bath CL- removal or DIDS, luminal bafilomycin) stimulated net HCO3- secretion by approximately 2 pmol/min per mm before acid incubation, whereas after incubation these agents inhibited net HCO3- absorption by approximately 5 pmol/min per mm. Inhibition of beta-IC function (luminal Cl- removal) inhibited HCO3- secretion by approximately 9 pmol/min per mm before incubation, whereas after incubation HCO3- absorption by only 3 pmol/min per mm. After acid incubation, luminal SCH28080 inhibited HCO3- absorption by only 5-15% vs the circa 90% inhibitory effect of bafilomycin. In outer CCDs, which contain fewer alpha-ICs than midcortical segments, the reversal in polarity of HCO3- flux was blunted after acid incubation. We conclude that the CCD adapts to low pH in vitro by downregulation HCO3- secretion in beta-ICs via decreased apical CL-/base exchang activity and upregulating HCO3- absorption in alpha-ICs via increased apical H+ -ATPase and basolateral CL-/base exchange activities. Whether or not there is a reversal of IC polarity or recruitment of gamma-ICs in this adaptation remains to be established.

Metabolic acidosis stimulates H+ secretion in the rabbit outer medullary collecting duct (inner stripe) of the kidney.

The outer medullary collecting duct (OMCD) absorbs HCO3- at high rates, but it is not clear if it responds to metabolic acidosis to increase H+ secretion. We measured net HCO3- transport in isolated perfused OMCDs taken from deep in the inner stripes of kidneys from control and acidotic (NH4Cl-fed for 3 d) rabbits. We used specific inhibitors to characterize the mechanisms of HCO3- transport: 10 microM Sch 28080 or luminal K+ removal to inhibit P-type H+,K+-ATPase activity, and 5-10 nM bafilomycin A1 or 1-10 nM concanamycin A to inhibit H+-ATPase activity. The results were comparable using either of each pair of inhibitors, and allowed us to show in control rabbits that 65% of net HCO3- absorption depended on H+-ATPase (H flux), and 35% depended on H+,K+-ATPase (H,K flux). Tubules from acidotic rabbits showed higher rates of HCO3- absorption (16.8+/-0.3 vs. 12.8+/-0.2 pmol/min per mm, P < 0.01). There was no difference in the H,K flux (5.9+/-0.2 vs. 5.8+/-0.2 pmol/min per mm), whereas there was a 61% higher H flux in segments from acidotic rabbits (11.3+/-0.2 vs. 7.0+/-0.2 pmol/min per mm, P < 0.01). Transport was then measured in other OMCDs before and after incubation for 1 h at pH 6.8, followed by 2 h at pH 7.4 (in vitro metabolic acidosis). Acid incubation in vitro stimulated HCO3- absorption (12.3+/-0.3 to 16.2+/-0.3 pmol/min per mm, P < 0.01), while incubation at pH 7.4 for 3 h did not change basal rate (11.8+/-0.4 to 11.7+/-0.4 pmol/min per mm). After acid incubation the H,K flux did not change, (4.7+/-0.4 to 4.6+/-0.4 pmol/min per mm), however, there was a 60% increase in H flux (6.6+/-0.3 to 10.8+/-0.3 pmol/min per mm, P < 0.01). In OMCDs from acidotic animals, and in OMCDs incubated in acid in vitro, there was a higher basal rate and a further increase in HCO3- absorption (16.7+/-0.4 to 21.3+/-0.3 pmol/min per mm, P < 0.01) because of increased H flux (11.5+/-0.3 to 15.7+/-0.2 pmol/min per mm, P < 0.01) without any change in H,K flux (5.4+/-0.3 to 5.6+/-0.3 pmol/min per mm). These data indicate that HCO3- absorption (H+ secretion) in OMCD is stimulated by metabolic acidosis in vivo and in vitro by an increase in H+-ATPase-sensitive HCO3- absorption. The mechanism of adaptation may involve increased synthesis and exocytosis to the apical membrane of proton pumps. This adaptation helps maintain homeostasis during metabolic acidosis.

Maturation of aldose reductase expression in the neonatal rat inner medulla.

Newborns are less able to concentrate urine than adults are. With development of the concentrating system and a hypertonic medullary interstitium, there is a need to generate intracellular osmolytes such as sorbitol, which is produced in a reaction catalyzed by the enzyme aldose reductase. We sought to discriminate between two possible mechanisms of aldose reductase induction during development: (a) a response to an osmotic stimulus generated by the concentrating mechanism; or (b) part of the genetic program for development of the kidney. We measured the change in aldose reductase mRNA and activity in terminal inner medullary collecting ducts (IMCDs) microdissected from Sprague-Dawley rats during the first month of life. Aldose reductase mRNA was assayed by Northern analysis of total RNA from inner medulla and by detection of the reverse transcription-polymerase chain reaction (RT-PCR) product obtained from single IMCDs using aldose reductase-specific primers. Aldose reductase activity was measured in IMCDs taken from the same rats using a fluorescent microassay. Newborn rat IMCDs had minimal aldose reductase mRNA or activity, however mRNA was readily detected in IMCDs from rats older than 3 d of age, with peak expression occurring at 1-3 wk of age before decreasing to adult levels. In contrast, the mRNA level for a housekeeping metabolic enzyme, malate dehydrogenase, did not change during maturation. Aldose reductase enzyme activity was readily detectable by 6 d of age, peaked at 20 d, then decreased to adult levels. Urine osmolality remained < 600 mosmol/kg until 16 d, then increased to > 1,100 mosmol/kg after 20 d. Thus, aldose reductase mRNA and activity increased before urinary osmolality reached 870 mosmol/kg. Because urine osmolality may not be indicative of inner medullary osmolality and because mother's milk may provide excessive free water to the pups under 3 wk of age, half of the animals in several litters were separated from their mothers for 1 d and inner medullary osmolality, in addition to urine osmolality, was measured by vapor pressure osmometry, while aldose reductase mRNA was assessed densitometrically in IMCDs after RT-PCR. Although fluid restriction resulted in a near doubling of urine osmolality and a tendency towards increased aldose reductase mRNA, there was no consistently significant increase in aldose reductase mRNA or inner medullary osmolality during the first 13 d of life compared to the suckling animals. On the other hand, 2-3-wk-old rats showed significant increases in aldose reductase mRNA, accompanied by increases in inner medullary osmolality, after fluid restriction. Thus, the dissociation between the increases in aldose reductase expression and inner medullary hyperosmolality indicates that the maturational induction of the aldose reductase gene is not a consequence of osmotic stimulation, but rather, part of the developmental program of the kidney.

Acute and chronic administration of immunomodulators induces anorexia in Zucker rats.

To investigate the possible involvement of leptin signaling in lipopolysaccharide (LPS) anorexia, we compared the anorectic effect of LPS in genetically obese (fa/fa) Zucker rats and in their lean (Fa/?) counterparts. The effects of interleukin-1beta (IL-1beta) and muramyl dipeptide (MDP) were also tested. LPS [100 microg/kg body weight (BW)], IL-1beta (2 microg/kg BW) and MDP (2.2 mg/kg BW) injected intraperitoneally (i.p.) at lights out reduced food intake similarly in obese and lean rats. LPS injection at 500 or 1000 microg/kg BW (i.p.) also reduced food intake and BW similarly in obese and lean rats, but obese regained BW faster than lean rats. LPS (2.45 microg or 9.8 microg/h/rat) administered chronically with i.p. implanted osmotic pumps reduced food intake similarly on experimental day 1, regardless of the genotype. After day 3, the lean rats' anorectic response and recovery were dose-dependent, whereas the anorectic response in obese rats was minimally affected by dose (significant dose effect only on day 3). Again, obese rats regained lost BW faster than lean rats. These results do not support a role for leptin as the sole mediator of anorexia induced by bacterial products (LPS and MDP) and IL-1beta.

Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection.

Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.

Sub-diaphragmatic vagal afferent integration of meal-related gastrointestinal signals.

We have established a method to investigate the range of mechanical, nutrient chemical and peptidergic meal-related stimuli t hat may generate vagal afferent neurophysiological signals critical to the negative feedback control of food intake in the rat. We have identified populations of fibers that respond with increased neurophysiological discharge rates to gastric loads, duodenal loads, and close celiac arterial administration of a brain-gut peptide, cholecystokinin. Load-sensitive fibers with gastric and duodenal mechanoreceptive fields are able to integrate information arising from mechanical and peptidergic stimulation, where cholecystokinin octapeptide (CCK) administration potentiates subsequent responses to distending loads, and synergizes with distending loads to produce greater excitation than either load stimulus alone or peptide stimulation alone. In addition, we have identified situations where the duodenal presence of nutrients modifies the vagal afferent activity of gastric load-sensitive fibers. Thus, our approach can mimic the temporal and spatial distribution of meal-related stimuli in the gut, and reveals the potential for nutrients in one gastrointestinal compartment to affect neutral signals arising from another gut compartment.

Video fluorescence microscopy as a tool for the study of cellular heterogeneity in epithelia.

The use of functional fluorescent dyes has allowed us to monitor intracellular pH in individually identified cells in renal epithelia. Using video microscopy we simultaneously measured the change in intracellular pH in several contiguous cells in response to various maneuvers. The video equipment included a silicon intensified target camera, a VHS videocassette recorder, a high resolution monochrome monitor, a video photometric analyzer and a 2-channel chart recorder. This equipment had a spatial resolution of 1 micron by light microscopy and a response time of less than 200 ms; it allowed us to perform double fluorescent labeling and obtain reliable measurements of intracellular pH, independent of gain, regardless of the location of the image on the screen. Using this video system we have shown that there is substantial heterogeneity in activity of H+/HCO3- transport pathways among adjacent cells in a monolayer of cells cultured from the rat renal inner medullary collecting duct. In isolated perfused rabbit renal cortical collecting ducts, video microscopy allowed us to show that there are two different types of intercalated cells: one that exhibits apical Cl-/HCO3- exchange and one that does not. Both show alkaline intracellular pH with respect to non-acid-base transporting epithelia. Video microscopy has several advantages over conventional microspectrophotometry. It provides rapid data acquisition along with increased sensitivity and the capacity for some subcellular analyses. One is able to analyze several individually identified cells during an experimental maneuver. The present video system was assembled for less than $15,000 and permits a more complete analysis of an epithelium than either single-cell photometry or spectrophotometric analysis of thousands of cells in suspension or monolayers.

Novel method for performing carbonic anhydrase histochemistry and immunocytochemistry on cryosections.

It is difficult to correlate structure with function in the kidney because of the extensive cell heterogeneity. Carbonic anhydrase (CA) is an enzyme that mediates renal acidification and is found predominantly in proximal tubule and collecting duct cells. We modified Hansson's method for histochemically identifying cellular CA activity on PLP-fixed rabbit kidney sections mounted on Millipore filters, and then removed the filters to perform peanut lectin and antibody labeling on the same sections. There was adequate preservation of morphology, and individual cells could be identified with CA activity in the cytosol and specific antibody or lectin labeling on the cell surfaces.

A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine.

Based on statistical analysis of data in 186 children, a formula was derived which allows accurate estimation of glomerular filtration rate (GFR) from plasma creatinine and body lenght (GFR(ml/min/1.73 sq m) = 0.55 length (cm)/Per (mg/dl). Its application to clearance data in a separate group of 223 children reveals excellent agreement with GFR estimated by the Ccr (r = .935) or Cin (r = .905). This formula should be useful for adjusting dosages of drugs excreted by the kidney and detecting significant changes in renal function.

Neurobiology of cholecystokinin.

The peptide cholecystokinin (CCK) is widely distributed throughout the mammalian brain where it functions as a neurotransmitter and neuromodulator. CCK is colocalized with other neurotransmitters at a variety of brain sites. CCK receptor subtypes have been identified and their distributions mapped in the brain and the periphery. Exogenous CCK exerts a variety of effects depending on the site of administration, and many of these effects mimic actions of the endogenous peptide. Progress in understanding of the potential role of CCK in brain and behavior has focused on four main areas: CCK/dopamine interactions, CCK in anxiety and panic states, CCK in opioid nociception, and CCK in satiety. CCK's actions in modulating the activity of other neurotransmitters systems or in affecting behavior may serve as the bases for future therapeutic interventions.

Diagnosis and treatment of renal tubular disorders.

There is a wide variety of renal tubular disorders affecting children. Understanding the pathophysiology of each disease assists in the recognition and treatment of these diseases, which can have profound effects on a child's growth and development. We review some of the more common tubular disorders found in children, emphasizing those conditions in which recent advances have been made in understanding of the specific genetic or physiological defect responsible: Fanconi's syndrome, cystinuria, renal tubular acidosis, and the hypokalemic metabolic alkaloses. Current recommendations are presented for diagnosing and treating these conditions.

Central gustatory lesions: I. Preference and taste reactivity tests.

Bilateral electrophysiologically guided lesions were placed in the nucleus of the solitary tract (NST), the parabrachial nucleus (PBN), and the ventral posteromedial thalamic nucleus (VPMpc) of rats, and 15-min intake and taste reactivity (TR) responses elicited by 3 concentrations each of sucrose, NaCl, HCl, and quinine (Q) HCl were subsequently measured. Compared with controls, NST lesions had no significant effects on intake, and rats with PBN lesions consumed significantly more QHCl, sucrose, NaCl, and HCl. Thalamic lesions decreased sucrose intake. Analysis of TR responses showed that the QHCl threshold for aversive responses increased after VPMpc, PBN, and NST lesions. Rats with NST or PBN lesions were unresponsive to increasing sucrose concentration. TR responses elicited by NaCl and HCl were similar across the groups.

Bombesin and cholecystokinin differentially affect ingestive microstructural variables whether given alone or in combination.

The ability of dose combinations of cholecystokinin (CCK) and bombesin to inhibit liquid glucose (0.125 gm/ml) intake and affect microstructural components of ingestive behavior in rats was examined. Five minutes before access to the glucose solution, rats were injected with dose pairs of CCK and bombesin. Both CCK and bombesin inhibited intake in a dose-related fashion. The magnitude of the inhibition produced by dose combinations was never greater than the sum of the inhibitions produced by the individual doses. CCK and bombesin affected different microstructural components of ingestion. CCK reduced burst size and cluster size, whereas bombesin reduced burst number and cluster number. These effects of the 2 peptides were not altered by the presence of the other peptide. These results suggest that different mechanisms of action underlie the feeding inhibitory actions of the 2 peptides.

CCK elicits and modulates vagal afferent activity arising from gastric and duodenal sites.

We have begun to identify and characterize the locations and response profiles of vagal afferent fibers sensitive to CCK in the rat upper gastrointestinal tract. We found gastric and duodenal vagal afferent fibers that respond to CCK and to intraluminal loads. CCK both sensitizes and amplifies the response to loads in these fibers but may do so through separate transduction mechanisms. Thus, meal-related signals arising from the presence of gastroduodenal loads and the release of endogenous CCK can be integrated at the level of the peripheral afferent vagus nerve. These findings are consistent with behavioral results, demonstrating that combinations of gastric loads and exogenous CCK are more effective in suppressing food intake than is either stimulus presented alone. Our findings that both gastric and duodenal vagal afferent fibers are sensitive to CCK suggest that meal-related CCK may act at a range of peripheral neural sites linking the upper gastrointestinal tract to the central nervous system substrates underlying the control of food intake. The mode of activation of gastric vagal afferent by endogenously released CCK may be an endocrine action of intestinally derived CCK. Alternatively, the novel finding of duodenal load-sensitive vagal afferents close to a site of CCK release provides a potential for local paracrine actions of endogenous CCK in the mediation of satiety.

Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain.

Palatable food stimulates neural systems implicated in drug dependence; thus sugar might have effects like a drug of abuse. Rats were given 25% glucose solution with chow for 12 h followed by 12 h of food deprivation each day. They doubled their glucose intake in 10 days and developed a pattern of excessive intake in the first hour of daily access. After 30 days, receptor binding was compared to chow-fed controls. Dopamine D-1 receptor binding increased significantly in the accumbens core and shell. In contrast, D-2 binding decreased in the dorsal striatum. Binding to dopamine transporter increased in the midbrain. Opioid mu-1 receptor binding increased significantly in the cingulate cortex, hippocampus, locus coeruleus and accumbens shell. Thus, intermittent, excessive sugar intake sensitized D-1 and mu-1 receptors much like some drugs of abuse.