cholecystokinin and Insulin-Resistance

Obesity is one of the major challenges for public health in 21st century, with 1.9 billion people being considered as overweight and 600 million as obese. There are certain diseases such as type 2 diabetes, hypertension, cardiovascular disease, and several forms of cancer which were found to be associated with obesity. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Hormones such as ghrelin, glucagon like peptide 1 (GLP-1) peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) secreted by an endocrine organ gut, have an intense impact on energy balance and maintenance of homeostasis by inducing satiety and meal termination. Glucose and energy homeostasis are also affected by lipid sensing in which different organs respond in different ways. However, there is one common mechanism i.e. formation of esterified lipids (long chain fatty acyl CoAs) and the activation of protein kinase C δ (PKC δ) involved in all these organs. The possible role of gut microbiota and obesity has been addressed by several researchers in recent years, indicating the possible therapeutic approach toward the management of obesity by the introduction of an external living system such as a probiotic. The proposed mechanism behind this activity is attributed by metabolites produced by gut microbial organisms. Thus, this review summarizes the role of various physiological factors such as gut hormone and lipid sensing involved in various tissues and organ and most important by the role of gut microbiota in weight management.

Topics: Adipose Tissue; Brain; Cholecystokinin; Cholesterol, VLDL; Gastrointestinal Hormones; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Lipid Metabolism; Obesity; PPAR gamma

Polycystic ovary syndrome (PCOS) is an endocrine disease of women in reproductive age. It is characterized by anovulation and hyperandrogenism. Most often patients with PCOS have metabolic abnormalities such as dyslipidemia, insulin resistance, and glucose intolerance. It is not surprising that obesity is high prevalent in PCOS. Over 60 % of PCOS women are obese or overweight. Modulation of appetite and energy intake is essential to maintain energy balance and body weight. The gastrointestinal tract, where nutrients are digested and absorbed, plays a central role in energy homeostasis. The signals from the gastrointestinal tract arise from the stomach (ghrelin release), proximal small intestine (CCK release), and distal small intestine (GLP-1 and PYY) in response to food. These hormones are recognized as "appetite regulatory hormones." Weight loss is the key in the treatments of obese/overweight patients with PCOS. However, current non-pharmacologic management of body weight is hard to achieve. This review highlighted the gastrointestinal hormones, and discussed the potential strategies aimed at modifying hormones for treatment in PCOS.

Topics: Cholecystokinin; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Peptide YY; Polycystic Ovary Syndrome

Functions of the gut hormone cholecystokinin (CCK) include an important role in the regulation of gastric emptying, postprandial glucose homeostasis, and postmeal satiety. Postprandial CCK responses are significantly blunted in type 2 diabetic patients by unknown mechanisms. We hypothesized that hyperinsulinemia and lipid infusion influence circulating levels of biologically active CCK.. Eleven healthy subjects were studied in a cross-over design after 10-h overnight fasts, using euglycemic-hyperinsulinemic clamps for 443 min, with an additional infusion of lipid-heparin (1.25 ml.min(-1)) or saline (1.25 ml.min(-1)) for the last 300 min after constant plasma glucose levels were achieved.. Euglycemic-hyperinsulinemia resulted in a sustained, up to 5-fold increase of plasma CCK (P < 0.001). When adding lipid infusion instead of saline, CCK concentrations rapidly declined and returned to baseline levels (CCK(300 min) 1.1 +/- 0.2 vs. 3.3 +/- 0.3 pmol/liter, P < 0.001). Partial intraclass correlation showed an independent correlation of plasma CCK with free fatty acids (r(ic) = -0.377, P < 0.001) but not with serum insulin (r(ic) = 0.077, P = 0.32). Whole-body insulin sensitivity decreased in lipid-exposed subjects (M value 7.1 +/- 0.7 vs. 5.6 +/- 0.9 mg.kg.min(-1), P = 0.017) but was not independently correlated with CCK (r(ic) = 0.040, P = 0.61).. We report novel findings showing that circulating CCK markedly increased in the euglycemic-hyperinsulinemic state, possibly as a result of near-complete suppression of circulating free fatty acids. Moreover, raising blood lipids even moderately by lipid infusion rapidly and significantly interfered with this effect, suggesting that a negative feedback mechanism of blood lipids on circulating CCK might exist.

Topics: Cholecystokinin; Cross-Over Studies; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hyperlipidemias; Infusion Pumps; Insulin; Insulin Resistance; Lipids; Male; Middle Aged

High-fat and high-carbohydrate diets lead to insulin resistance, gastrointestinal adaptation, and high plasma triacylglycerol concentrations. It is unclear, however, how rapidly these changes occur.. We sought to determine the effects of both high-fat and high-carbohydrate evening meals on parameters of insulin resistance, hypertriglyceridemia, and gastrointestinal hormones.. Twelve healthy men were studied on 4 separate occasions. On 2 occasions, the subjects received a high-fat evening meal (62% of energy from fat) and on the other 2 occasions the subjects received a low-fat evening meal (16% of energy from fat). The morning after each meal the subjects were administered either an oral-fat-tolerance test or an oral-glucose-tolerance test. Plasma samples were analyzed for glucose, insulin, fatty acids, 3-hydroxybutyrate, triacylglycerol, pancreatic polypeptide, peptide YY, and cholecystokinin. Postchallenge data were analyzed by two-way analysis of variance with interaction and fasting concentrations analyzed by repeated-measures analysis of variance.. Fasting plasma concentrations of triacylglycerol were significantly elevated 12 h after each evening meal, but fatty acid and 3-hydroxybutyrate concentrations were reduced. No effects on glucose or insulin concentrations were detected. The high-fat evening meals elevated plasma cholecystokinin concentrations, reduced fasting concentrations of pancreatic polypeptide, and had no significant effect on peptide YY concentrations. The ratio of fat to carbohydrate in the evening meal produced significant effects on plasma triacylglycerol and fatty acids during both the oral-fat-tolerance and oral-glucose-tolerance tests.. The present study showed that the effects of high-fat and high-carbohydrate evening meals persist at least overnight and suggests that knowledge of recent dietary history is essential to the effective design of metabolic studies.

Topics: 3-Hydroxybutyric Acid; Adult; Analysis of Variance; Area Under Curve; Blood Glucose; Cholecystokinin; Dietary Carbohydrates; Dietary Fats; Energy Metabolism; Fasting; Fatty Acids; Fatty Acids, Nonesterified; Gastrointestinal Hormones; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Triglycerides

Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, the role of ILDR1 in CCK-mediated regulation of satiety is unknown. In this study, we examined the effects of ILDR1 on food intake and metabolic activity using mice with genetically-deleted Ildr1.. The expression of ILDR1 in murine tissues and the measurement of adipocyte cell size were evaluated by light and fluorescence confocal microscopy. The effects of Ildr1 deletion on mouse metabolism were quantitated using CLAMS chambers and by targeted metabolomics assays of multiple tissues. Hormone levels were measured by ELISA. The effects of Ildr1 gene deletion on glucose and insulin levels were determined using in vivo oral glucose tolerance, meal tolerance, and insulin tolerance tests, as well as ex vivo islet perifusion.. ILDR1 is expressed in a wide range of tissues. Analysis of metabolic data revealed that although Ildr1-/- mice consumed more food than wild-type littermates, they gained less weight on a high fat diet and exhibited increased metabolic activity. Adipocytes in Ildr1-/- mice were significantly smaller than in wild-type mice fed either low or high fat diets. ILDR1 was expressed in both alpha and beta cells of pancreatic islets. Based on oral glucose and mixed meal tolerance tests, Ildr1-/- mice were more effective at lowering post-prandial glucose levels, had improved insulin sensitivity, and glucose-regulated insulin secretion was enhanced in mice lacking ILDR1.. Ildr1 loss significantly modified metabolic activity in these mutant mice. While Ildr1 gene deletion increased high fat food intake, it reduced weight gain and improved glucose tolerance. These findings indicate that ILDR1 modulates metabolic responses to feeding in mice.

Topics: Animals; Cholecystokinin; Diet, High-Fat; Gene Deletion; Glucose; Hyperglycemia; Insulin; Insulin Resistance; Mice; Mice, Inbred C57BL; Obesity; Receptors, Cell Surface

We studied the effect of CCK-8 on BP and blood content of CGRP in rats with hypertension caused by fructose or inhibition of NO synthase with L-NAME. The decrease in the CGRP content was found during the development of fructose-induced hypertension, but not L-NAME-caused hypertension. Administration of CCK-8 to fructose-fed animals reduced BP and increased the content of CGRP. In rats with hypertension caused by NO deficit, CCK-8 lowered BP, but did not affect the content of CGRP. These findings suggest that CGRP mediates the hypotensive effect of CCK-8 in fructose-induced hypertension, but not in NO-deficient hypertension.

Topics: Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Cholecystokinin; Fructose; Hypertension; Insulin Resistance; Male; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Rats; Rats, Wistar; Signal Transduction

The current prevalence of obesity in the US is strongly associated with excessive food intake and insufficient physical activity. This study examined whether changing the timing of exercise before or after two daily meals could alter human appetite for food. Fifty-four healthy postmenopausal women were matched by body weight and assigned to two groups: (1) two bouts of 2-h moderate-intensity exercise ending one hour before each weight-maintenance meal (XM,

Topics: Aged; Aged, 80 and over; Appetite; Cholecystokinin; Eating; Exercise; Feeding Behavior; Female; Gastrointestinal Hormones; Ghrelin; Glucagon; Humans; Hunger; Insulin Resistance; Intestines; Middle Aged; Postmenopause; Satiation

To observe the effect of electroacupuncture (EA) of ". Among the fifty 8-week-old healthy SPF male Wistar rats, 10 rats were randomly selected and fed with normal diet; after 8 weeks, 8 rats were randomly selected as a normal group. The remaining 40 rats were fed with high-fat diet to establish the model of obsesity IR; after 8 weeks, 24 rats with successful model of obsesity IR were randomly divided into a model group, an EA group and a sham EA group, 8 rats in each group. Eight weeks after model establishment, the rats in the EA group were intervened with EA at "Fenglong" (ST 40), "Zhongwan" (CV 12), "Guanyuan" (CV 4) and "Zusanli" (ST 36), with continuous wave, in frequency of 2 Hz, and current intensity of 1 mA, for 10 min each time. The rats in the sham EA group were intervened with EA at the points 5 mm next to the acupoints used in the EA group and no electricity was given; the sham EA was given for 10 min each time. Both the treatments were given once every other day for 8 weeks. The Lee's index and food intake were observed before the intervention as well as 2 weeks, 4 weeks, 6 weeks and 8 weeks into intervention; after the intervention, serum insulin (INS) and glucose infusion rate (GIR) were detected; serum cholecystokinin (CCK) level was detected by ELISA; c-fos expression in the area postrema (AP) and nucleus tractus solitarius (NTS) of medulla oblongata was detected by immunohistochemistry.. Before the intervention as well as 2 weeks, 4 weeks, 6 weeks and 8 weeks into intervention, the Lee's index and food intake in the model group were higher than those in normal group (. EA of "

Topics: Acupuncture Points; Animals; Cholecystokinin; Electroacupuncture; Insulin Resistance; Male; Obesity; Random Allocation; Rats; Rats, Wistar

Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.

Topics: Animals; Blood Glucose; Body Composition; Body Fat Distribution; Cholecystokinin; Diet; Diet, High-Fat; Gastric Emptying; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Obesity; Postprandial Period; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sucrose

To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis.. Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 μL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment.. Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-β-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1β were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture.. The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.

Topics: Administration, Oral; Animals; Biomarkers; Bombesin; Cell Proliferation; Cholecystokinin; Disease Models, Animal; DNA Replication; Esters; Gabexate; Guanidines; Hormone Antagonists; Insulin Resistance; Male; Pancreas; Pancreatic Function Tests; Pancreatitis; Proglumide; Rats, Wistar; Receptor, Cholecystokinin A; Recovery of Function; Taurocholic Acid; Time Factors

The relation between hunger, satiation, and integrated gastrointestinal motility and hormonal responses in morbidly obese patients after sleeve gastrectomy has not been determined.. The objective was to assess the effects of sleeve gastrectomy on hunger, satiation, gastric and gallbladder motility, and gastrointestinal hormone response after a liquid meal test.. Three groups were studied: morbidly obese patients (n = 16), morbidly obese patients who had had sleeve gastrectomy (n = 8), and nonobese patients (n = 16). The participants fasted for 10 h and then consumed a 200-mL liquid meal (400 kcal + 1.5 g paracetamol). Fasting and postprandial hunger, satiation, hormone concentrations, and gastric and gallbladder emptying were measured several times over 4 h.. No differences were observed in hunger and satiation curves between morbidly obese and nonobese groups; however, sleeve gastrectomy patients were less hungry and more satiated than the other groups. Antrum area during fasting in morbidly obese patients was statistically significant larger than in the nonobese and sleeve gastrectomy groups. Gastric emptying was accelerated in the sleeve gastrectomy group compared with the other 2 groups (which had very similar results). Gallbladder emptying was similar in the 3 groups. Sleeve gastrectomy patients showed the lowest ghrelin concentrations and higher early postprandial cholecystokinin and glucagon-like peptide 1 peaks than did the other participants. This group also showed an improved insulin resistance pattern compared with morbidly obese patients.. Sleeve gastrectomy seems to be associated with profound changes in gastrointestinal physiology that contribute to reducing hunger and increasing sensations of satiation. These changes include accelerated gastric emptying, enhanced postprandial cholecystokinin and glucagon-like peptide 1 concentrations, and reduced ghrelin release, which together may help patients lose weight and improve their glucose metabolism after surgery. This trial was registered at clinicaltrials.gov as NCT02414893.

Topics: Adult; Body Mass Index; C-Reactive Protein; Case-Control Studies; Cholecystokinin; Fasting; Female; Gastrectomy; Gastric Emptying; Gastrointestinal Hormones; Gastrointestinal Motility; Ghrelin; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hunger; Insulin Resistance; Male; Meals; Middle Aged; Obesity, Morbid; Postprandial Period; Satiation

Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS.

Topics: Adult; Altitude; Altitude Sickness; Blood Glucose; Cholecystokinin; Dexamethasone; Energy Intake; Erythropoietin; Female; Glucocorticoids; Homeostasis; Humans; Hydrocortisone; Hypoxia; Insulin Resistance; Insulin-Secreting Cells; Interleukin-6; Islet Amyloid Polypeptide; Male; Middle Aged; Models, Biological; Oxygen; Retrospective Studies; Time Factors; Young Adult

Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARγ are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARγ2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARγ2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels.. In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake.

Topics: Adult; Body Mass Index; Cholecystokinin; Female; Galanin; Genotype; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Polymorphism, Genetic; PPAR gamma; Satiation

Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping).. We examined eight obese non-diabetic patients before and within 2 weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50 g glucose dissolved in 200 mL of water) and a liquid mixed meal test (200 mL 300 kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY(3-36) (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance.. Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests.. Within 2 weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.

Topics: Adult; Appetite; C-Peptide; Cholecystokinin; Confounding Factors, Epidemiologic; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Obesity, Morbid; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Somatostatin; Time Factors; Weight Loss

Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.. The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.. (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p < 0.05 to p < 0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p < 0.01 to p < 0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p < 0.05 to p < 0.001), accumulated food intake (p < 0.05 to p < 0.001), non-fasting glucose (p < 0.05) and triacylglycerol deposition in pancreatic (p < 0.01), adipose (p < 0.05) and liver (p < 0.001) tissue, and improved oral (p < 0.05) and i.p. (p < 0.05) glucose tolerance and insulin sensitivity (p < 0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.. These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

Topics: Animals; Cholecystokinin; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Glucose; Homeostasis; Insulin Resistance; Male; Mice; Mice, Obese; Obesity; Sincalide

Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis.. We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps.. CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in β-cell or islet size.. CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions.

Topics: Animals; Arginine; Cholecystokinin; Diet, Fat-Restricted; Dietary Fats; Glucose; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Knockout

An absolute or functional deficit in beta-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven beta-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptin(ob/ob) mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both alpha- and beta-cells. We bred a null Cck allele into the C57BL/6-Leptin(ob/ob) background and investigated beta-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced beta-cell mass through increased beta-cell death. CCK deficiency and decreased beta-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect beta-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase beta-cell survival and expand beta-cell mass to compensate for obesity-induced insulin resistance.

Topics: Animals; Cell Count; Cell Survival; Cells, Cultured; Cholecystokinin; Diabetes Mellitus; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity; Organ Size; Up-Regulation

The objective of the study was to investigate the role of cholecystokinin (CCK) on the food-induced insulin sensitization phenomenon in healthy Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats. Whole body insulin sensitivity determined by hyperinsulinaemic euglycaemic glucose clamping and the rapid insulin sensitivity test served as endpoints. Determinations were done in both fasted and re-fed animals. The involvement of CCK in post-prandial insulin sensitization was assessed by using proglumide, a CCK receptor blocker, by assessment of hypothalamic CCK-1/CCK-2 receptor expression by rt-PCR technique and by plasma insulin immunoreactivity determinations by means of radioimmunoassay as pharmacological, genetic and analytical approaches, respectively. The body weight of the OLETF rats and the amount of food consumed much exceeded those seen with LETO rats. The post-prandial increase in insulin sensitivity was marked in LETO, but not in OLETF rats. Intravenous proglumide attenuated post-prandial insulin sensitivity in LETO rats, with no effect in OLETF rats. Nevertheless, baseline insulin sensitivity was much lower in OLETF than in LETO rats. Treatment with rosiglitazone increased baseline insulin sensitivity of OLETF rats and evoked an increase in CCK-1 receptor gene expression in LETO rats. The results provide evidence for the involvement of CCK receptors in adjustment of both fasting and post-prandial insulin sensitivity. The data obtained with OLETF rats strongly suggest the predominant role of CCK-1 receptors.

Topics: Animals; Cholecystokinin; Gene Expression Regulation; Glucose Clamp Technique; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Obesity; Polymerase Chain Reaction; Postprandial Period; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Rosiglitazone; Thiazolidinediones

Cholecystokinin (CCK) is a peptide hormone that is released from the gut in response to nutrients such as lipids to lower food intake. Here we report that a primary increase of CCK-8, the biologically active form of CCK, in the duodenum lowers glucose production independent of changes in circulating insulin levels. Furthermore, we show that duodenal CCK-8 requires the activation of the gut CCK-A receptor and a gut-brain-liver neuronal axis to lower glucose production. Finally, duodenal CCK-8 fails to lower glucose production in the early onset of high-fat diet-induced insulin resistance. These findings reveal a role for gut CCK that lowers glucose production through a neuronal network and suggest that intestinal CCK resistance may contribute to hyperglycemia in response to high-fat feeding.

Topics: Animals; Cholecystokinin; Devazepide; Dietary Fats; Duodenum; Glucose; Insulin; Insulin Resistance; Male; Nerve Net; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A

Metabolic syndrome (MS), defined as central obesity, hyperinsulinemia, insulin resistance, hypertension, dyslipidemia and glucose intolerance, has been associated with inflammatory biomarkers and cardiovascular diseases. This study was carried out on three groups of women; lean controls, moderately obese with MS (OB-MS) and morbidly obese with MS (MOB-MS). The main objectives were: 1. to analyze the plasma levels of total and acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), gastrin and insulin levels under basal conditions and in response to a standard mixed meal, and 2. to elucidate the relationship between the plasma levels of these gut peptides and metabolic syndrome parameters. Plasma levels of the gut hormones were measured by radioimmunoassays at time 0 just before the meal and at 30, 60 and 120 min after a meal ingestion. Traditional lipid profile and high-sensitivity C reactive protein (hs-CRP), the strongest biomarker of inflammation were also determined in OB-MS and MOB-MS. When compared to OB-MS, MOB-MS exhibited much higher anthropometric parameters such as waist circumference, higher fat mass and higher plasma levels of low density lipoprotein-cholesterol (LDL-C) and hs-CRP. Both these obese groups revealed significantly higher values of body mass index (BMI), fat mass, total cholesterol (TC), LDL-C, fasting glucose, fasting insulin, insulin resistance (IR) calculated from homeostatic model assessment (HOMA) and hs-CRP compared to the values recorded in lean subjects. Fasting PYY(3-36) level was lower, while fasting acylated ghrelin was higher in MOB-MS than in OB-MS. Plasma total and acylated ghrelin levels were significantly lower in OB-MS compared to lean women. In MOB-MS women the fasting PYY(3-36) levels were lower compared to lean controls and OB-MS, whilst postprandially in both OB-MS and MOB-MS, it was much lower than in lean women. The fasting plasma levels of total and acylated ghrelin and their postprandial decrease were significantly smaller in both obese groups compared to lean subjects. Plasma hs-CRP levels correlated positively with BMI, waist circumference, fat mass, fasting glucose, HOMA IR and fasting active ghrelin, whilst it negatively correlated with plasma fasting and total ghrelin. Moreover, plasma fasting acylated ghrelin correlated positively with fat mass. Fasting total ghrelin correlated positively with BMI, HDL-C and negatively with HOMA IR. We conclude that MS features of obesity are closely

Topics: Acylation; Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Cholecystokinin; Cholesterol, LDL; Fasting; Female; Gastrins; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Obesity; Obesity, Morbid; Peptide Hormones; Peptide YY; Poland; Postprandial Period

Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione that has been shown to improve insulin resistance. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice fed a 25% carbohydrate diet.. Twenty eight-week-old insulin-resistant obese (Lep(ob)) mice fed a 25% carbohydrate diet for 4 weeks. Half of the animals had 0.3 g/kg pioglitazone added to their diet. At 12 weeks all animals were fasted and underwent cholecystectomy. Gallbladder volume and weight were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine (ACh 10(-5)M), neuropeptide Y (NPY 10(-8,-7,-6)M) and cholecystokinin (CCK 10(-10,-9,-8,-7)M). Serum glucose and insulin were measured, and HOMA Index, a measure of insulin resistance, was calculated.. Fasting serum insulin and HOMA Index were significantly decreased (P < 0.03), but gallbladder volume was significantly increased (P < 0.03) in the pioglitazone treated group. Pioglitazone did not alter gallbladder weight or response to ACh, NPY, or CCK.. These data suggest that in insulin-resistant obese mice pioglitazone 1) lowers insulin-resistance, 2) increases resting gallbladder volume, and 3) does not alter gallbladder response to neurotransmitters. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.

Topics: Acetylcholine; Age Factors; Animals; Blood Glucose; Cholecystokinin; Cholinergic Agents; Dietary Carbohydrates; Female; Gallbladder; Gallstones; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Peptide Fragments; Pioglitazone; Thiazolidinediones

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear transcription factors belonging to the nuclear hormone receptors. Troglitazone, a specific ligand for PPAR-gamma is shown to regulate not only lipids and glucose metabolism, but also cell cycle, differentiation, and apoptosis.. To examine the effect of chronic oral administration of troglitazone on the age-related changes of insulin resistance, plasma CCK levels, and pancreatic growth in normal rats.. A troglitazone-rich diet (0.2%) was given from 12 to 28 weeks of age or from 12 or 28 weeks of age to 72 weeks of age.. Fasting serum glucose concentrations in control rats increased progressively with age, which was almost completely prevented by troglitazone treatment. Serum insulin concentrations and pancreatic insulin content in the control rat markedly increased at 28 weeks of age but decreased at 72 weeks of age. These parameters in troglitazone-treated rats remained at nearly the same concentrations at all ages. Insulin concentration relative to DNA in the control rats increased with age, whereas in the troglitazone-treated rats it remained at nearly the same concentrations throughout the observation periods and was significantly lower than that in the controls. Insulin resistance in control rats showed a great increase at 72 weeks of age, whereas it was nearly the same at all ages in troglitazone-treated rats and was significantly lower than those in the control rats. Plasma cholecystokinin concentrations in control rats slightly but insignificantly increased with age, whereas pancreatic weight decreased age-dependently when corrected for body weight. Although troglitazone treatment appeared to decrease plasma cholecystokinin concentrations compared with those in the control rats, it significantly increased pancreatic weight and prevented age-dependent decrease. Troglitazone treatment significantly increased pancreatic protein and DNA contents, but the protein per DNA ratio, an indicator of cellular size, remained at nearly the same concentrations at all ages. The contour of the islets in the control rats at 72 weeks of age was somewhat irregular with structural disarrangement and fibrosis. Moreover, the islets were separated into small sections (cluster) by fibrosis. Troglitazone treatment prevented or reversed these age-related changes of the islets to those in rats at 12 weeks of age.. Our results indicate that troglitazone stimulates pancreatic growth in the normal rat not only by reducing insulin resistance and improving glucose metabolism, but also by suppressing fibrosis of the islets.

Topics: Aging; Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholecystokinin; Chromans; Diet; DNA; Eating; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Organ Size; Pancreas; Proteins; Rats; Rats, Long-Evans; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone

To investigate whether total body fat mass or fat distribution and associated metabolic disturbances in glucose and lipid metabolism influence the well known gallstone pathogenetic factors in obese subjects in order to explain why some obese subjects develop gallstones and some do not.. Cross sectional study of gallstone pathogenetic factors, body composition, fat distribution, glucose and lipid metabolism.. 57 healthy overweight subjects (aged 26-64y, body mass index (BMI) 30-45 kg/m2).. Total and intra-abdominal fat masses were measured by dual X-ray absorptiometry and abdominal CT scanning, respectively. The lithogenic index was measured in aspirated bile. The gallbladder volume was determined by ultrasound and the gallbladder ejection fraction% by dynamic cholescintigraphy. Plasma cholecystokinin (CCK) concentrations during a meal were measured with a specific radioimmunoassay. Insulin sensitivity was measured by the Minimal Model and glucose tolerance by an oral glucose tolerance test (OGTT). Serum lipid concentrations were measured by standard methods.. The gallbladder volume in the fasting state increased with increasing intra-abdominal fat mass (P=0.006) and was increased in subjects with impaired glucose tolerance (41 vs 27 ml, P=0.001). The lithogenic index was > 1 in all subjects and correlated with total fat mass (P=0.04).. Gallstone pathogenesis in obesity seems to be influenced by the total body fat mass and its regional distribution possibly via mutual association with the glucose tolerance.

Topics: Abdomen; Absorptiometry, Photon; Adipose Tissue; Adult; Blood Glucose; Body Composition; Cholecystokinin; Cholelithiasis; Cohort Studies; Cross-Sectional Studies; Dietary Fats; Fasting; Female; Gallbladder; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Tomography, X-Ray Computed

Topics: Adult; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Female; Glucagon; Hormones; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Prediabetic State; Secretin; Tolbutamide