cholecystokinin and Diabetes-Mellitus--Type-2

Several cases of cholelithiasis and cholecystitis have been reported in patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and GLP-2 receptor agonists (GLP-2RAs), respectively. Thus, the effects of GLP-1 and GLP-2 on gallbladder motility have been investigated. We have provided an overview of the mechanisms regulating gallbladder motility and highlight novel findings on the effects of bile acids and glucagon-like peptides on gallbladder motility.. The articles included in the present review were identified using electronic literature searches. The search results were narrowed to data reporting the effects of bile acids and GLPs on gallbladder motility.. Bile acids negate the effect of postprandial cholecystokinin-mediated gallbladder contraction. Two bile acid receptors seem to be involved in this feedback mechanism, the transmembrane Takeda G protein-coupled receptor 5 (TGR5) and the nuclear farnesoid X receptor. Furthermore, activation of TGR5 in enteroendocrine L cells leads to release of GLP-1 and, possibly, GLP-2. Recent findings have pointed to the existence of a bile acid-TGR5-L cell-GLP-2 axis that serves to terminate meal-induced gallbladder contraction and thereby initiate gallbladder refilling. GLP-2 might play a dominant role in this axis by directly relaxing the gallbladder. Moreover, recent findings have suggested GLP-1RA treatment prolongs the refilling phase of the gallbladder.. GLP-2 receptor activation in rodents acutely increases the volume of the gallbladder, which might explain the risk of gallbladder diseases associated with GLP-2RA treatment observed in humans. GLP-1RA-induced prolongation of human gallbladder refilling may explain the gallbladder events observed in GLP-1RA clinical trials.

Topics: Bile Acids and Salts; Cholecystitis; Cholecystokinin; Cholelithiasis; Diabetes Mellitus, Type 2; Gallbladder; Gallbladder Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glucagon-Like Peptides; Humans; Muscle Contraction; Muscle, Smooth; Obesity; Postprandial Period

Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival. Consequently, this has led to the development of enzymatically stable, biologically active, CCK peptide analogues with proposed therapeutic promise for both obesity and type 2 diabetes. In addition, several studies have demonstrated metabolic, and therapeutically relevant, complementary biological actions of CCK with those of the incretin hormones GIP and GLP-1, as well as with amylin and leptin. Thus, stable CCK derivatives not only offer promise as potential independent weight-reducing and glucose-lowering drugs, but also as effective adjunctive therapies. This review focuses on the recent and ongoing developments of CCK in the context of new therapies for obesity and type 2 diabetes.

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Obesity; Peptides; Receptor, Cholecystokinin B

Gut hormones have long been understood to regulate food intake and metabolism. Bariatric surgery significantly elevates circulating gut hormone levels and is proven to affect acute remission of type 2 diabetes before any weight loss is observed. Subsequent weight loss is accrued over weeks to months but is sustained into the long term. Hence, there exists great enthusiasm to recapitulate these changes in gut hormones in the form of novel combination drugs for type 2 diabetes and obesity.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Peptide YY

The effects of non-nutritive sweeteners (NNS) on glucose metabolism and appetite regulating hormones are not clear. There is an ongoing debate concerning NNS use and deleterious changes in metabolism.. The aim of this review is to analyze the scientific available evidence regarding the effects of NNS on glucose metabolism and appetite regulating hormones.. We identified human observational studies evaluating the relation between NNS consumption and obesity, diabetes, and metabolic syndrome, in addition to clinical trials evaluating the effects of NNS in glucose metabolism and appetite regulating hormones.. Fourteen observational studies evaluating the association between NNS consumption and the development of metabolic diseases and twenty-eight clinical trials studying the effects of NNS on metabolism were included. Finally, two meta-analyses evaluating the association between the consumption of NNS-containing beverages and the development of type 2 diabetes were identified.. Some observational studies suggest an association between NNS consumption and development of metabolic diseases; however, adiposity is a confounder frequently found in observational studies. The effects of the NNS on glucose metabolism are not clear. The results of the identified clinical trials are contradictory and are not comparable because of the major existing differences between them. Studies evaluating specific NNS, with an adequate sample size, including a homogeneous study group, identifying significant comorbidities, with an appropriate control group, with an appropriate exposure time, and considering adjustment for confounder variables such as adiposity are needed.

Topics: Carbonated Beverages; Cholecystokinin; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Ghrelin; Glucose; Humans; Non-Nutritive Sweeteners; Observational Studies as Topic; Peptide YY; Prospective Studies

Bariatric surgery (e.g. Roux-en-Y gastric bypass (RYGB)) has proven the most effective way of achieving sustainable weight losses and remission of type 2 diabetes (T2D). Studies indicate that the effectiveness of RYGB is mediated by an altered gastrointestinal tract anatomy, which in particular favours release of the gut incretin hormone glucagon-like peptide-1 (GLP-1). The EndoBarrier gastrointestinal liner or duodenal-jejunal bypass sleeve (DJBS) is an endoscopic deployable minimally invasive and fully reversible technique designed to mimic the bypass component of the RYGB. Not only GLP-1 is released when nutrients enter the gastrointestinal tract. Cholecystokinin (CCK), secreted from duodenal I cells, elicits gallbladder emptying. Traditionally, bile acids are thought of as essential elements for fat absorption. However, growing evidence suggests that bile acids have additional effects in metabolism. Thus, bile acids appear to increase GLP-1 secretion via activation of the TGR5 receptor on the intestinal L cell. Recently FXR receptors were postulated to contribute to GLP-1 secretion too. Furthermore, metformin has been shown to increase circulating GLP-1 levels but although the exact mechanism is not fully elucidated it may involve metformin-induced inhibition of bile acid reuptake from the small intestines. Small-sized studies reported varying degrees of weight loss and, in some, improvement of glucose metabolism. Therefore, the objectives of this thesis were to collect existing information on the DJBS in order to evaluate clinical efficacy and safety (study I and II). Furthermore, since the endocrine impact of the DJBS is not fully elucidated, and DJBS is expected to mimic RYGB, we investigated postprandial metabolic changes following 26 weeks of DJBS treatment in ten obese subjects with normal glucose tolerance (NGT) and nine matched patients with T2D (study III). Finally, we studied the single and combined effects of CCK induced gallbladder emptying and single-dose metformin on human GLP-1 secretion in ten healthy subjects (study IV). We hypothesized that metformin-induced GLP-1 secretion - at least partly - would be dependent on gallbladder emptying and the presence of bile acids in the gut. DJBS appears to lead to moderate weight losses in obese subjects compared to diet or lifestyle modifications (study II). DJBS had insignificant and small effects (compared to diet) on glycaemic regulation. Adverse events consisted mainly of mild-to-moderate tr

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Incretins; Metformin; Obesity; Weight Loss

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

Topics: Appetite; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Milk Proteins; Obesity; Peptide YY; Thermogenesis; Whey Proteins

Hormones from the gastrointestinal (GI) tract are released following food ingestion and trigger a range of physiological responses including the coordination of appetite and glucose homoeostasis. The aim of this review is to discuss the pathways by which food ingestion triggers secretion of cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and the altered patterns of gut hormone release observed following gastric bypass surgery. Our understanding of how ingested nutrients trigger secretion of these gut hormones has increased dramatically, as a result of physiological studies in human subjects and animal models and in vitro studies on cell lines and primary intestinal cultures. Specialised enteroendocrine cells located within the gut epithelium are capable of directly detecting a range of nutrient stimuli through a range of receptors and transporters. It is concluded that the arrival of nutrients at the apical surface of enteroendocrine cells is a major stimulus for gut hormone release, thereby coupling these endocrine signals to the arrival of absorbed nutrients in the bloodstream.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Eating; Enteroendocrine Cells; Gastrointestinal Tract; Glucagon-Like Peptide 1; Homeostasis; Humans; Obesity; Postprandial Period; Receptors, Gastrointestinal Hormone; Signal Transduction

Free fatty acids (FFAs) are not only essential nutrient components, but they also function as signaling molecules in various physiological processes. In the progression of genomic analysis, many orphan G-protein coupled receptors (GPCRs) are found. Recently, GPCRs deorphanizing strategy successfully identified multiple receptors for FFAs. In these FFA receptors (FFARs), GPR40 (FFAR1) and GPR120 are activated by medium- to long- chain FFAs. GPR40 is expressed mainly in pancreatic β-cell and mediates insulin secretion, whereas GPR120 is expressed abundantly in the intestine and regulates the secretion of cholecystokinin (CCK) and glucagons-like peptide-1 (GLP-1), it promotes insulin secretion. Due to these biological activity, GPR40 and GPR120 are potential drug target for type 2 diabetes and selective ligands have been developed. In this review, we provide recent development in the field and discuss their physiological roles and their potential as drug targets.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Intestinal Mucosa; Ligands; Mice; Molecular Targeted Therapy; Receptors, G-Protein-Coupled; Signal Transduction; Structure-Activity Relationship

Childhood obesity is a global epidemic and associated with an increased risk of hypertension, diabetes mellitus, and coronary heart disease, in addition to psychological disorders. Interventions such as bariatric surgery are highly invasive and lifestyle modifications are often unsuccessful because of disturbed perceptions of satiety. New signaling peptides discovered in recent years that are produced in peripheral tissues such as the gut, adipose tissue, and pancreas communicate with brain centers of energy homeostasis, such as the hypothalamus and hindbrain. This review discusses the major known gut- and adipose tissue-derived hormones involved in the regulation of food intake and energy homeostasis and their serum levels in childhood obesity before and after weight loss as well as their relationship to consequences of obesity. Since most of the changes of gastrointestinal hormones and adipokines normalize in weight loss, pharmacological interventions based on these hormones will likely not solve the obesity epidemic in childhood. However, a better understanding of the pathways of body weight- and food intake-regulating gut- and adipose tissue-derived hormones will help to find new strategies to treat obesity and its consequences.

Topics: Adipokines; Adipose Tissue; Child; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptides; Enteropeptidase; Exercise; Glucagon-Like Peptide 1; Health Behavior; Health Promotion; Humans; Hypothalamus; Life Style; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Rhombencephalon; Weight Loss

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

The biological clock mechanism was studied in both non-insulin-dependent and insulin-dependent diabetic model rats. Otsuka Long Evans Tokushima Fatty (OLETF) rats were used as a non-insulin-dependent model. Streptozotocin (STZ, 100 mg/kg, i.p.) was administered to 8- to 10-week-old Wistar rats for an insulin-dependent diabetic model. Both young non-diabetic OLETF and STZ-induced diabetic rats needed more days for re-entrainment to a new light-dark cycle than control rats on activity rhythm. In young OLETF rats, dim-light-induced Fos expression (50 and 100 lux) was significantly decreased in the suprachiasmatic nucleus. In diabetic OLETF rats, Fos expression was decreased by the exposure of light at 300 lux. In STZ-induced diabetic rats, Fos expression was also decreased by 300 lux of light. In OLETF rats, the phase delay by glutamate application was significantly smaller than that in control rats on the suprachiasmatic nucleus neuronal (SCN) activity rhythms. On the other hand, the same level of phase delay was observed between control and STZ-induced diabetic rats by glutamate application. These results suggest that entrainment function is disordered in OLETF rats before the onset of hyperglycemia. To clarify the entrainment function of STZ-induced diabetic rats, however, further study is necessary.

Topics: Animals; Biological Clocks; Cholecystokinin; Circadian Rhythm; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Motor Activity; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred OLETF; Rats, Wistar; Serotonin; Streptozocin; Suprachiasmatic Nucleus

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Eating; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Peptide Fragments; Protein Precursors

Cholecystokinin (CCK) act as hormones and neuropeptides on central and peripheral CCK receptors. The application of modern molecular biological techniques has identified two CCK receptors, CCK-A receptor (CCKAR) and CCK-B/gastrin receptor (CCKBR). The genes of CCKAR and CCKBR consist of five exons interrupted by four introns. We have reported that OLETF rats, which have been established as an animal model of NIDDM, revealed no expression of CCKAR gene (a naturally occurring CCKAR gene knockout rat). Pancreatic exocrine functions in OLETF rats are regulated by all neural and peptidergic agents except CCK. Therefore, we have proposed that OLETF rats may be a useful experimental model for examining the biological functions of the CCKAR.

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Cloning, Molecular; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Molecular Sequence Data; Pancreas; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

1. The incretin effect (i.e. the difference between the insulin response after oral and i.v. glucose) is reduced in type 2 diabetes although GIP secretion is normal or exaggerated. This suggests an insensitivity of the diabetic B-cell to GIP. However, it could also indicate the lack of another not yet defined "incretin". 2. While CCK is a potent incretin in rats and dogs, physiological concentrations of this hormone do not stimulate insulin secretion in man in presence of elevated blood levels of glucose or phenylalanine in the physiological range. It also does not interact with GIP. 3. Glucagon-like peptide I (7-36) is a potent glucose-dependent stimulator of insulin secretion in animals and man. Preliminary data suggest release after oral glucose despite localization of the GLPI containing cells predominantly in the ileum and colon. More data are needed before GLPI (7-36) can be regarded as a physiological incretin and its role in type 2 diabetes assessed.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Secretion; Intestines; Islets of Langerhans; Peptide Fragments

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Digestive System Physiological Phenomena; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Motilin; Neurotensin; Obesity; Pancreatic Polypeptide; Pentagastrin; Secretin; Somatostatin; Vasoactive Intestinal Peptide

Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.. In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed.. Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed.. Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.

Topics: Aged; Area Under Curve; Bile Acids and Salts; Blood Glucose; C-Peptide; Chelating Agents; Cholecystokinin; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Energy Metabolism; Female; Fibroblast Growth Factors; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Microbiome; Glucagon; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; RNA, Ribosomal, 16S; Sequestering Agents; Sevelamer; Triglycerides

Despite a position as the first-line pharmacotherapy in type 2 diabetes, the glucose-lowering mechanisms of metformin remain to be fully clarified. Gut-derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon-like peptide-1 (GLP-1) secretion, have been proposed.. The aim of this study was to assess the GLP-1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes.. Randomized, placebo-controlled, and double-blinded crossover study.. This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark.. Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study.. Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline.. Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve.. Single-dose metformin further enhanced bile acid-mediated induction of GLP-1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP-1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin-induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP-1-mediated induction of insulin secretion or suppression of glucagon was observed.. Metformin elicited an enhancement of the GLP-1 response to cholecystokinin-induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.

Topics: Aged; Bile Acids and Salts; Blood Glucose; Cholecystokinin; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gallbladder Emptying; Glucagon-Like Peptide 1; Humans; Male; Metformin; Middle Aged; Placebos

Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1(GCG)) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility.. In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined.. Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals.. In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

Topics: Adult; Aged; Area Under Curve; Bile; Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Cholecystokinin; Denmark; Diabetes Mellitus, Type 2; Dietary Fats; Female; Gallbladder Emptying; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrins; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Postprandial Period; Receptors, G-Protein-Coupled

We evaluated whether a whey preload could slow gastric emptying, stimulate incretin hormones, and attenuate postprandial glycemia in type 2 diabetes.. Eight type 2 diabetic patients ingested 350 ml beef soup 30 min before a potato meal; 55 g whey was added to either the soup (whey preload) or potato (whey in meal) or no whey was given.. Gastric emptying was slowest after the whey preload (P < 0.0005). The incremental area under the blood glucose curve was less after the whey preload and whey in meal than after no whey (P < 0.005). Plasma glucose-dependent insulinotropic polypeptide, insulin, and cholecystokinin concentrations were higher on both whey days than after no whey, whereas glucagon-like peptide 1 was greatest after the whey preload (P < 0.05).. Whey protein consumed before a carbohydrate meal can stimulate insulin and incretin hormone secretion and slow gastric emptying, leading to marked reduction in postprandial glycemia in type 2 diabetes.

Topics: Blood Glucose; Cholecystokinin; Diabetes Mellitus, Type 2; Dietary Proteins; Female; Gastric Emptying; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged

To investigate the weight-reducing effect of cimetidine in overweight patients with Type 2 diabetes.. A 12-week clinical intervention study of 400 mg cimetidine prescribed three times daily in a randomised, double-blind, placebo-controlled design.. Forty-three overweight patients with Type 2 diabetes (age 18-65 y, body mass index (BMI) 27.2-48.2 kg/m2).. Body weight, BMI, body fat, waist and hip circumference, waist/hip ratio, blood pressure, fasting blood glucose, HbA1c, plasma concentrations of insulin, insulin/glucose ratio and lipids at the start and after 12 weeks, and daily recordings of appetite.. Subjects given cimetidine (n = 19) and placebo (n = 24) lost 5.0 +/- 2.2 kg (mean +/- s.d.) and 1.3 +/- 1.1 kg, respectively. Significant reductions were observed in appetite, body fat (29.9 +/- 6.6% to 25.3 +/- 7.4%), waist circumference (111.5 +/- 10.3 cm to 107.4 +/- 10.6 cm), waist/hip ratio (0.96 +/- 0.08 to 0.94 +/- 0.08), and systolic and diastolic blood pressure (reductions of 6.9 +/- 11.4 mm Hg and 6.0 +/- 6.6 mm Hg, respectively) in cimetidine group only. Significant decreases in fasting concentrations of blood glucose, HbA1c, plasma insulin, insulin/glucose ratio, plasma triglycerides and a significant increase in plasma high-density lipoprotein cholesterol were observed in the cimetidine group only.. Cimetidine reduces appetite and body weight, and improves metabolic control in overweight subjects with Type 2 diabetes.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Body Constitution; Cholecystokinin; Cholesterol, HDL; Cimetidine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Histamine H2 Antagonists; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Triglycerides; Weight Loss

The role of glucose in the regulation of plasma cholecystokinin (CCK) level was investigated in healthy control subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma CCK concentration was determined by a specific and sensitive bioassay and by a highly sensitive and reliable double-antibody radioimmunoassay using OAL-656 as an antiserum. In control subjects, ingestion of Trelan G-75 (1,200 mOsm/L,225 mL), which is equivalent to 75 g glucose as metabolic products, caused a rapid and significant increase in plasma CCK bioactivity from 1.3 +/- 0.2 to a peak of 5.8 +/- 0.6 pmol/L and immunoreactive CCK concentration from 1.2 +/- 0.1 to 4.6 +/- 0.6 pmol/L. Ingestion of 75 g glucose in 225 mL water (33.3% solution) increased plasma CCK bioactivity to a similar degree to that observed following Trelan G-75 (peak response, 4.5 +/- 0.4 pmol/L). The same volume of 0.9% NaCl solution or water failed to increase plasma CCK concentration. A smaller dose of glucose (50 b/150 mL water) increased plasma CCK concentration, although the peak level (3.0 +/- 0.5 pmol/L) was less than that observed following 75 g glucose. In patients with NIDDM, Trelan G-75 ingestion increased CCK concentration, but the peak level was lower, albeit insignificantly, than that of normal subjects. When the maximal increment of plasma CCK above the basal value was compared between control and NIDDM subjects, the differences were statistically significant (NIDDM, 3.6 +/- 0.1 pmol/L; control, 5.0 +/- 0.4; P < .01). However, integrated CCK responses to Trelan G-75 in NIDDM (165.8 +/- 15.5 pmol/120 min) were not significantly different from those in control subjects (189.8 +/- 15.9 pmol/120 min). Peak CCK bioactivity occurred within 10 to 30 minutes of ingestion, preceding the increase in glucose and insulin. These results suggest a possible effect of CCK on insulin release in humans, and that the CCK secretory response to glucose in well-controlled diabetic patients is not significantly altered.

Topics: Administration, Oral; Adult; Atropine; Blood Glucose; Case-Control Studies; Cholecystokinin; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucose; Hormone Antagonists; Humans; Insulin; Male; Middle Aged; Proglumide; Radioimmunoassay; Receptors, Cholecystokinin

A semi-dynamic gastrointestinal device was employed to explore the link between protein structure and metabolic response upon digestion for two different substrates, a casein hydrolysate and the precursor micellar casein. As expected, casein formed a firm coagulum that remained until the end of the gastric phase while the hydrolysate did not develop any visible aggregate. Each gastric emptying point was subjected to a static intestinal phase where the peptide and amino acid composition changed drastically from that found during the gastric phase. Gastrointestinal digests from the hydrolysate were characterized by a high abundancy of resistant peptides and free amino acids. Although all gastric and intestinal digests from both substrates induced the secretion of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) in STC-1 cells, GLP-1 levels were maximum in response to gastrointestinal digests from the hydrolysate. The enrichment of protein ingredients with gastric-resistant peptides by enzymatic hydrolysis is proposed as strategy to deliver protein stimuli to the distal gastrointestinal tract to control food intake or type 2 diabetes.

Topics: Caseins; Cholecystokinin; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Peptides

Loss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.

Topics: Animals; Apoptosis; Cholecystokinin; Cytokines; Diabetes Mellitus, Type 2; Humans; Islets of Langerhans; Mice; Mice, Inbred NOD; Mice, SCID

Diabetes mellitus induces neuropsychiatric comorbidities at an early stage, which can be ameliorated by exercise. However, the neurobiological mechanisms underlying this ameliorative effect remain unclear. The present study was conducted in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which develop diabetes with age, and aimed to investigate whether social and anxiety-like behaviors and neurobiological changes associated with these behavioral phenotypes were reversed by voluntary exercise and whether those were maintained in the later stage. We investigated the effects of exercise at different diabetic stages in OLETF rats by comparing with control rats. Three groups of OLETF rats were used: sedentary rats, rats exercising on a wheel for two weeks at 4-5 weeks of age (early voluntary exercise), and those exercising at 10-11 weeks of age (late voluntary exercise). In the elevated plus-maze test, both early and late voluntary exercises did not affect anxiety-like behavior. In the social interaction tests, both early and late voluntary exercises ameliorated impaired sociability, novel exploration deficits, and hypoactivity in OLETF rats. Both early and late voluntary exercises reversed the increases in cholecystokinin-positive neuron densities in the infralimbic cortex and hippocampal cornu ammonis area 3 in the OLETF rats, although they did not affect the area-reduction in the medial prefrontal cortex and the increase in cholecystokinin-positive neuron densities in the basolateral amygdala. These suggest that voluntary exercise has therapeutic effects on impaired sociability and novel exploration deficits associated with cholecystokinin-positive neurons in specific corticolimbic regions in OLETF rats, and those are maintained after early exercise.

Topics: Animals; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Neurons; Rats; Rats, Inbred OLETF; Social Behavior

A group of long-acting, peptide-based, and selective GLP-1R/CCK-2R dual agonizts were identified by rational design. Guided by sequence analysis, structural elements of the CCK-2R agonist moiety were engineered into the GLP-1R agonist Xenopus GLP-1, resulting in hybrid peptides with potent GLP-1R/CCK-2R dual activity. Further modifications with fatty acids resulted in novel metabolically stable peptides, among which 3d and 3 h showed potent GLP-1R and CCK-2R activation potencies and comparable stability to semaglutide. In food intake tests, 3d and 3 h also showed a potent reduction in food intake, superior to that of semaglutide. Moreover, the acute hypoglycemic and insulinotropic activities of 3d and 3 h were better than that of semaglutide and ZP3022. Importantly, the limited pica response following 3d and 3 h administration in SD rats preliminarily indicated that the food intake reduction effects of 3d and 3 h are independent of nausea/vomiting. In a 35-day study in db/db mice, every two days administration of 3d and 3 h increased islet areas and numbers, insulin contents, β-cell area, β-cell proliferation, as well as improved glucose tolerance, and decreased HbA1c, to a greater extent than ZP3022 and semaglutide. In a 21-day study in DIO mice, once-weekly administration of 3d and 3 h significantly induced body weight loss, improved glucose tolerance, and normalized lipid metabolism, to a greater extent than semaglutide. The current study showed the antidiabetic and antiobesity potentials of GLP-1R/CCK-2R dual agonizts that warrant further investigation.

Topics: Animals; Anti-Obesity Agents; Cholecystokinin; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Hypoglycemic Agents; Mice; Peptides; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B

Type 2 diabetes is a high-profile global public health problem, particularly in Asia. The young age of onset, low body mass index, and early appearance of pancreatic islet dysfunction are characteristics of Asian patients with T2DM. Metabolic surgery has become the standard treatment for T2DM patients and can significantly improve T2DM through a variety of mechanisms including modulation of energy homeostasis and reduction of body fat mass. Indeed, restoration of islet function also plays an integral role in the remission of T2DM. After metabolic surgery, islet function in Asian T2DM patients has improved significantly, with proven short-term and long-term effects. In addition, islet function is an important criterion and reference for patient selection prior to metabolic surgery. The mechanism of islet function improvement after metabolic surgery is not clear, but postoperative anatomical changes in the gastrointestinal tract leading to a number of hormonal changes seem to be the potential cause, including glucagon-like peptide-1, gastric inhibitory polypeptide, peptide YY, ghrelin, and cholecystokinin. The authors analyzed the current retrospective and prospective studies on the effect of metabolic surgery on the islet function of Asian T2DM patients with a low BMI and its mechanism, summarized the clinical evidence that metabolic surgery improved islet function in Asian T2DM patients with a low BMI, and discussed its underlying mechanism. It is of great significance for realizing personalized and precise treatment of metabolic surgery and further improving its clinical benefits.. 2型糖尿病（T2DM）是当前备受瞩目的全球性公共卫生问题，在亚洲地区尤为突出。发病年龄小、体质指数（BMI）低以及早期出现胰岛功能缺陷是亚洲T2DM患者的特征。代谢手术已经成为T2DM的标准治疗手段，其可通过调节能量稳态和降低体脂质量等多种机制显著改善T2DM。事实上，胰岛功能的恢复在T2DM的缓解过程中同样发挥着不可或缺的作用。代谢手术后，亚洲T2DM患者的胰岛功能显著改善，其短期及长期效果均已获得验证。不仅如此，胰岛功能还是代谢手术前进行患者选择的重要依据和参考指标。代谢手术后胰岛功能改善的机制尚不明确，但术后胃肠道的解剖改变所致的胰高血糖素样肽-1、抑胃肽、酪酪肽、胃饥饿素及胆囊收缩素等激素的变化可能参与其中。笔者分析了目前针对代谢手术对亚洲低BMI T2DM患者胰岛功能的影响及其机制的回顾性和前瞻性研究，总结了关于代谢手术改善亚洲低BMI T2DM患者胰岛功能的临床证据，并探讨其内在机制。这对于实现代谢手术的个性化、精准化治疗，进一步提高其临床效益具有重要意义。.

Topics: Bariatric Surgery; Body Mass Index; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Peptide YY; Prospective Studies; Retrospective Studies; Treatment Outcome

Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats.

Topics: Activating Transcription Factor 4; Animals; Behavior, Animal; Brain; Cholecystokinin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Male; Parvalbumins; Rats; Rats, Inbred OLETF

Of particular interest is the study of the peculiarities of clinical findings and diagnostics of gastroesophageal reflux disease (GERD) in patients with diabetes mellitus (DM). The aim of the research - to study the dynamics of cholecystokinin (CCK) level on the background of complex therapy using the ursodeoxycholic acid (UDCA) drug in patients with GERD with type 2 DM. 68 patients with combination of type 2 DM and GERD were examined. The levels of CCK were studied in these patients, depending on the clinical forms of GERD, as well as their dynamics on the background of UDCA therapy. More pronounced increase in the serum level of CCK in patients with combination of type 2 DM and extra-esophageal manifestations of GERD was observed. Decrease in the CCK level in 2,4 - 2,7 times was reached on the background of complex therapy with UDCA in patients with combination of type 2 DM and GERD (p<0,01). In patients with type 2 DM and GERD, an increase in blood serum CCK level is observed, especially in case of extra-esophageal form of reflux disease. The maximum concentration of CCK in blood serum was revealed in overweight patients with type 2 DM in case of an extra-esophageal form of GERD. The use of UDC medication in the complex treatment of patients with type 2 DM and GERD leads to a normalization tendency of blood serum CCK levels, as well as to a decrease in body mass in these patients.

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Gastroesophageal Reflux; Humans; Ursodeoxycholic Acid

Cholecystokinin (CCK) is a gut hormone originally known for its effects on gallbladder contraction and release of digestive enzymes. CCK, however, also mediates satiety and stimulate insulin secretion. Knowledge of the distribution of CCK-producing enteroendocrine cells (I cells) in humans is sparse. The general notion, based on animal data, is that I cells are present mainly in the proximal small intestine. We examined the occurrence of I cells (immunohistochemically) and the expression of CCK messenger RNA (mRNA) as well as CCK1 and CCK2 receptor mRNA along the intestines in healthy individuals and patients with type 2 diabetes.. Mucosal biopsies collected with 30-cm intervals in the small intestine and from seven anatomical locations in the large intestine (using double-balloon enteroscopy) from 12 patients with type 2 diabetes and 12 gender-, age-, and body mass index-matched healthy individuals were analyzed using mRNA sequencing and immunohistochemical staining.. We observed a gradual decrease in CCK mRNA expression and density of CCK-immunoreactive cells from duodenum to ileum. Very few CCK-immunoreactive cells and nearly undetectable CCK mRNA expression were found in the large intestine. No significant differences were seen between the groups. Expression of CCK receptors was observed in the duodenum of both groups.. Both density of CCK cells and expression of CCK mRNA decreased through the small intestine in both groups with low levels in the large intestine. Patients with type 2 diabetes did not have altered density of CCK cells or expression of CCK mRNA in intestinal mucosa.

Topics: Adult; Aged; Cholecystokinin; Diabetes Mellitus, Type 2; Female; Humans; Intestinal Mucosa; Intestine, Small; Male; Middle Aged; Receptors, Cholecystokinin

Excluding the foregut (distal stomach and duodenum) from food transit in RYGB normalizes glucose tolerance. Excluding/removing the duodenal mucosa partly improves glycemic control. So far, the effect of excluding/removing the gastric mucosa remains unknown.. To observe the effect of removing the distal gastric mucosa on glucose tolerance.. Thirty fatty Sprague-Dawley rats received low-dose streptozotocin (STZ) to induce type 2 diabetes (T2D), then randomly assigned to Roux-en-Y gastric bypass (RYGB, n = 8), distal gastric mucosa removal (DGMR, n = 8), duodenal-jejunal bypass (DJB, n = 8), and Sham (n = 6) groups. In the DGMR group, the distal third of the gastric mucosa was removed by thermal ablation using an electrocautery. Rats were followed for 8 weeks postoperatively. Preoperative oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and mixed-meal tolerance test (MMTT) were repeated 3 and 6 weeks postoperatively. Changes in body weight, food intake, and fasting blood glucose were also recorded.. Gastrin AUC decreased significantly (p < 0.05) in the DGMR group after surgery. A significantly increased GLP-1 AUC was found in the RYGB, DGMR, and DJB groups at week 3 and only the RYGB group at week 6 postoperatively. The improved glucose tolerance in the RYGB group was significantly greater than the improved glucose tolerance in the DGMR and DJB groups. The improved glucose tolerance 3 and 6 weeks after surgery in the DGMR group was significantly greater than the improved glucose tolerance in the DJB group. Body weight decreased significantly in the RYGB, DGMR, and DJB groups postoperatively.. Removing the distal gastric mucosa induced significant weight loss and improved glycemic control in T2D SD rat model. Therefore, the gastric mucosa exclusion in RYGB may be key to the weight loss and diabetes remission, which perhaps warrants a new theory.

Topics: Animals; Area Under Curve; Bile Acids and Salts; Blood Glucose; Body Weight; C-Reactive Protein; Cholecystokinin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Feeding Behavior; Gastric Bypass; Gastric Mucosa; Glucose Tolerance Test; Glycemic Control; Insulin; Male; Rats, Sprague-Dawley; Weight Loss

Metabolic disorders can induce psychiatric comorbidities. Both brain and neuronal composition imbalances reportedly induce an anxiety-like phenotype. We hypothesized that alterations of localized brain areas and cholecystokinin (CCK) and parvalbumin (PV) expression could induce anxiety-like behavior in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Twenty-week-old OLETF and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used. The areas of corticolimbic regions were smaller in OLETF rats. The densities of CCK positive neurons in the lateral and basolateral amygdala, hippocampal cornu ammonis area 2, and prelimbic cortex were higher in OLETF rats. The densities of PV positive neurons were comparable between OLETF and LETO rats. Locomotion in the center zone in the open field test was lower in OLETF rats. These results suggest that imbalances of specific brain region areas and neuronal compositions in emotion-related areas increase the prevalence of anxiety-like behaviors in OLETF rats.

Topics: Animals; Anxiety; Behavior, Animal; Brain; Cholecystokinin; Diabetes Mellitus, Type 2; Disease Models, Animal; Emotions; Locomotion; Male; Neurons; Open Field Test; Parvalbumins; Rats, Inbred OLETF

Diabetes-specific nutritional formulas (DSNFs) are frequently used by patients with type 2 diabetes (T2D) as part of nutrition therapy to improve glycemic control and reduce body weight. However, their effects on hunger and satiety hormones when compared to an isocaloric standardized breakfast are not fully understood. This study aims to evaluate the postprandial effects of two DSNFs-Glucerna (GL) and Ultra Glucose Control (UGC)-versus oatmeal on selected satiety and hunger hormones.. After an overnight fast, 22 patients with T2D (mean age 62.3 ± 6.8 years, A1C 6.8 ± 0.7%, body weight 97.4 ± 21.3 kg, and BMI 33.2 ± 5.9 kg/m²) were given 200 kcal of each meal on three separate days. Blood samples for amylin, cholecystokinin (CCK), ghrelin, glucagon, leptin, and peptide-YY (PYY) were collected at baseline and 30, 60, 90, 120, 180, and 240 min after the start of each meal. Incremental area under the curve (iAUC. iAUC. Intake of DSNFs significantly increases secretion of PYY and glucagon, two important satiety hormones. While subjective satiety was not directly evaluated, the increased effect on satiety hormones may partially explain the mechanism of body weight loss associated with DSNF use.

Topics: Aged; Blood Glucose; Cholecystokinin; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Food, Formulated; Ghrelin; Glucagon; Humans; Hunger; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Peptide YY; Postprandial Period; Satiation

The duodenal-jejunal bypass sleeve ((DJBS) or EndoBarrier Gastrointestinal Liner) induces weight loss in obese subjects and may improve glucose homeostasis in patients with type 2 diabetes (T2D). To explore the underlying mechanisms, we evaluated postprandial physiology including glucose metabolism, gut hormone secretion, gallbladder emptying, appetite and food intake in patients undergoing DJBS treatment.. A total of 10 normal glucose-tolerant (NGT) obese subjects and 9 age-, body weight- and body mass index-matched metformin-treated T2D patients underwent a liquid mixed meal test and a subsequent ad libitum meal test before implantation with DJBS and 1 week (1w) and 26 weeks (26w) after implantation.. At 26w, both groups had achieved a weight loss of 6 to 7 kg. Postprandial glucagon-like peptide-1 (GLP-1) and peptide YY responses increased at 1w and 26w, but only in T2D subjects. In contrast, glucose-dependent insulinotropic polypeptide responses were reduced only by DJBS in the NGT group. Postprandial glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin responses were unaffected by DJBS in both groups. Satiety and fullness sensations were stronger and food intake was reduced at 1w in NGT subjects; no changes in appetite measures or food intake were observed in the T2D group. No effect of DJBS on postprandial gallbladder emptying was observed, and gastric emptying was not delayed.. DJBS-induced weight loss was associated with only marginal changes in postprandial physiology, which may explain the absence of effect on postprandial glucose metabolism.

Topics: Adult; Appetite; Bariatric Surgery; Blood Glucose; Body Composition; C-Peptide; Case-Control Studies; Cholecystokinin; Comorbidity; Diabetes Mellitus, Type 2; Eating; Female; Gallbladder Emptying; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Satiety Response; Treatment Outcome

Bariatric procedures that exclude the proximal small intestine lead to significant weight loss which is probably mediated by changes in hormones that alter appetite, such as peptide YY (PYY), ghrelin, cholecystokinin (CCK), and leptin. Here, the effect of the non-surgical duodenal-jejunal bypass liner (DJBL) on concentrations of hormones implicated in appetite control was investigated.. A two-center prospective study was conducted between January and December 2010. Seventeen obese subjects with type 2 diabetes were treated with the DJBL for 24 weeks. Fasting concentrations of leptin and meal responses of plasma PYY, CCK, and ghrelin were determined prior to and after implantation of the DJBL.. At baseline, subjects had an average body weight of 116.0 ± 5.8 kg. One week after implantation, subjects had lost 4.3 ± 0.6 kg (p < 0.01), which progressed to 12.7 ± 1.3 kg at week 24 (p < 0.01). Postprandial concentrations of PYY and ghrelin increased (baseline vs. week 1 vs. week 24 PYY: 2.6 ± 0.2 vs. 4.1 ± 0.4 vs. 4.1 ± 0.7 nmol/L/min and ghrelin: 7.8 ± 1.8 vs. 11.0 ± 1.8 vs. 10.6 ± 1.8 ng/mL/min, all p < 0.05). In parallel, the CCK response decreased (baseline vs. week 1 vs. week 24: 434 ± 51 vs. 229 ± 52 vs. 256 ± 51 pmol/L/min, p < 0.01). Fasting leptin concentrations also decreased (baseline vs. week 24: 98 ± 17 vs. 53 ± 10 ng/mL, p < 0.01).. DJBL treatment induces weight loss paralleled by changes in concentrations of hormones involved in appetite control.

Topics: Bariatrics; Cholecystokinin; Diabetes Mellitus, Type 2; Duodenum; Female; Ghrelin; Humans; Jejunum; Leptin; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postprandial Period; Prospective Studies; Treatment Outcome

Exact cause of the metabolic syndrome [MS], a global epidemic, is still unclear. Man has same fundamental needs to live as animals but modern man's life-style compels him to acquire certainty of resources for all his needs in a complex social network. Today money has become the sole life essential need. Contrarily none of the animals needs to earn money. Brain is also an organ of the human body with a unique thought process to define logical actions to achieve a person's goals. This way life is a flow of desires followed by logical actions. The person struggles to attain desired goals via the allostatic load but a perceived insurmountable threat can make his flow of life stalled to freeze him. Published data from varied branches of medical science indicates role of hormones in overall homeostasis. Particularly multifaceted role of serotonin is well documented. Adrenalin being the primary mediator of Cori cycle is also well known. From the integration of observations from published data with reference to common human's modern lifestyle, it is hypothesized that a perceived trapped situation in life creates acute chaos of thoughts in brain, which results in acute excess of stress hormones and concurrent depletion of resting hormones, which in turn triggers MS. In global terms, MS indicates an acute imbalance of a few hormones and implies psychosomatic roots of the disorder. This may pave a better way in deciding a personalized holistic protocol with combination of counter regulatory psychoactive medications.

Topics: Acidosis, Lactic; Allostasis; Animals; Brain; Cardiovascular Diseases; Cholecystokinin; Cholesterol; Diabetes Mellitus, Type 2; Diet; Dopamine; Epinephrine; Exercise; Homeostasis; Hormones; Humans; Hypertension; Life Style; Metabolic Syndrome; Microbiota; Models, Theoretical; Motivation; Obesity; Oxytocin; Psychophysiologic Disorders; Risk Factors; Serotonin

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Topics: Adult; Aged; Cholecystokinin; Cross-Over Studies; Diabetes Mellitus, Type 2; Energy Intake; Female; Gallbladder Emptying; Gastric Emptying; Humans; Male; Middle Aged; Postprandial Period

We studied the impact of Roux-en-Y gastric bypass (RYGB) on the density and hormonal gene expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes.. Twelve patients with diabetes and 11 age- and BMI-matched controls underwent RYGB followed by enteroscopy ~10 months later. Mucosal biopsies taken during surgery and enteroscopy were immunohistochemically stained for glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and prohormone convertase 2 (PC2) and the expression of GCG (encoding preproglucagon), PYY, CCK, GIP, GHRL (encoding ghrelin), SCT (encoding secretin), NTS (encoding neurotensin) and NR1H4 (encoding farnesoid X receptor) was evaluated.. The density of cells immunoreactive for GLP-1, CCK and GIP increased in patients after RYGB and the density of those immunoreactive for GLP-1, PYY, CCK and PC2 increased in controls. In both groups, GHRL, SCT and GIP mRNA was reduced after RYGB while PYY, CCK, NTS and NR1H4 gene expression was unaltered. GCG mRNA was upregulated in both groups.. Numerous alterations in the distribution of enteroendocrine cells and their expression of hormonal genes are seen after RYGB and include increased density of GLP-1-, PYY-, CCK-, GIP- and PC2-positive cells, reduced gene expression of GHRL, SCT and GIP and increased expression of GCG.

Topics: Adult; Cholecystokinin; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Obesity, Morbid; Peptide YY; Proprotein Convertase 2; Treatment Outcome

Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic β-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced β-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from β-cell apoptosis. To determine the specific role of β-cell-derived CCK in β-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the β-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain β-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased β-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced β-cell apoptosis. Directed CCK overexpression in cultured β-cells also protects from cytokine-induced apoptosis. We have identified an important new paracrine/autocrine effect of CCK in protection of β-cells from apoptotic stress. Understanding the role of β-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect β-cells from apoptosis.

Topics: Aging; Animals; Apoptosis; Cell Line; Cholecystokinin; Cytokines; Diabetes Mellitus, Type 2; Down-Regulation; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Transgenic; Promoter Regions, Genetic; Rats; Recombinant Proteins; Streptozocin; Stress, Physiological; Tissue Culture Techniques

To investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic UC Davis type 2 diabetes mellitus (UCD-T2DM) rat.. Two-month old male UCD-T2DM rats underwent either sham (n=5) or IT (n=5) surgery. Intestines were collected 1.5months after surgery. The jejunum, ileum and colon regions were processed for histochemical and immunohistochemical labeling and stereological analyses of changes in gut morphometry and number of enteroendocrine cells.. Stereological analysis showed that intestinal volume, luminal surface area and the number of all chromogranin A-positive enteroendocrine cells were markedly increased in the IT rats compared with sham-operated animals. Subanalyses of the glucagon-like peptide 2, cholecystokinin, serotonin cells and the neurotensin immunoreactive sub-pool of enteroendocrine cells in the IT region revealed an increase in numbers across phenotypes. However, the density of the different cell types varied.. IT surgery in the UCD-T2DM rat leads to rapid alterations in gut morphometry and an increase in the number of enteroendocrine cells. This effect may potentially explain why IT surgery delays the onset of type 2 diabetes in the UCD-T2DM rat.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Glucagon-Like Peptide 2; Ileum; Lipid Metabolism; Male; Rats; Serotonin

Obese patients with type II diabetes who undergo bariatric surgery revert to normal blood glucose and insulin levels, and develop a dramatic increase in insulin sensitivity. However, the mechanisms involved are unknown. This study characterized pancreatic islet and duodenojejunal enteroendocrine cells in normal mice and those with diabetes induced by a high-fat diet (HFD) following duodenojejunal bypass (DJB).. C57BL/6J mice, fed for 8 weeks either a normal diet (n = 10) or a HFD (n = 10) resulting in a hyperglycaemic state, underwent DJB (connection of the distal end of the jejunum to the distal stomach and direction of biliopancreatic secretions to the distal jejunum). Metabolic and immunohistological analyses were carried out on the pancreas and gastrointestinal tract.. A significant decrease in fasting blood glucose was observed in normal-DJB and HFD-DJB mice 1 week after the operation, with improved glucose tolerance at 4 weeks. There were no changes in pancreatic β-cell mass, but an increase in the ratio of α-cell to β-cell mass was observed in the DJB groups. Furthermore, the number of cells expressing Pdx-1, glucagon-like peptide 1, pancreatic polypeptide and synaptophysin was increased in the bypassed duodenum and/or gastrojejunum of the DJB groups.. Both normal and obese diabetic mice that underwent DJB displayed improved glucose tolerance and a reduction in fasting blood glucose, which mimicked findings in obese diabetic patients following bariatric surgery. The present data suggest that an increase in specific enteroendocrine cell populations may play a critical role in normalizing glucose homeostasis.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Body Weight; Cholecystokinin; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Duodenum; Eating; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Homeodomain Proteins; Homeostasis; Islets of Langerhans; Jejunum; Mice; Mice, Inbred C57BL; Mice, Obese; Trans-Activators

The aim of this study was to investigate the morphological, immunohistochemical and ultrastructural changes of cholecystokinin-producing (I) cells of gastrointestinal mucosa in dexamethasone-treated rats (D). After 12-daily intraperitoneal administration of 2mg/kg dexamethasone, rats developed diabetes similar to human diabetes mellitus type 2. The mean diameter of the duodenum was significantly decreased due to significant reduction of volume fraction and profile area of lamina propria. There was a decrease in volume fraction and number of cholecystokinin (CCK)-producing cells per mm(2) of mucosa, as well as their numerical density, but without statistical significance. Also, dexamethasone induced appearance of hyperactive duodenal I-cells with small number of granules and dilated endoplasmic reticulum. In conclusion, the present study showed that morphological changes in duodenum cholecystokinin-producing (I) cells occurred in diabetic rats, in a manner which, suggests compensatory effort of CCK cells in diabetic condition.

Topics: Animals; Cholecystokinin; Dexamethasone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Endoplasmic Reticulum; Intestinal Mucosa; Male; Prediabetic State; Rats; Rats, Wistar

Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes and hypercholesterolemia. We investigated the mechanism of the hypoglycemic activity of colestimide by examining changes in serum cholecystokinin (CCK) and insulin concentrations before and after its 2-week oral administration. A total of seven type 2 diabetes inpatients with hypercholesterolemia received colestimide after their blood glucose levels had stabilized. We daily measured plasma glucose levels and serum lipid concentrations, calculated Body Mass Index (BMI), and determined whole-day changes in serum immunoreactive insulin (IRI) and CCK concentrations in all study subjects. We daily measured plasma glucose levels, as well as serum IRI and CCK concentrations at 10 time points for measurement. Plasma glucose levels, as well as serum IRI and CCK concentrations before and after the 2-week oral administration of colestimide were compared. The means of total cholesterol levels and BMI decreased significantly after administration. At time points for measurement (10 : 00 and 12 : 00), plasma glucose levels decreased significantly after administration (P=0.026 and P=0.009, respectively). Diurnal changes in serum IRI and CCK concentrations were not observed after administration, except for the IRI concentration at 20: 00. The effect of colestimide on CCK may not explain the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes and hypercholesterolemia.

Topics: Aged; Anion Exchange Resins; Blood Glucose; Cholecystokinin; Diabetes Mellitus, Type 2; Epichlorohydrin; Female; Humans; Hypercholesterolemia; Imidazoles; Male; Resins, Synthetic

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.

Topics: Body Constitution; Body Mass Index; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Insulin; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity

Hyperglycaemia slows gastric emptying in both normal subjects and patients with diabetes mellitus. The mechanisms mediating this effect, particularly the potential role of insulin, are uncertain. Hyperinsulinaemia has been reported to slow gastric emptying in normal subjects during euglycaemia. The purpose of this study was to evaluate the effect of euglycaemic hyperinsulinaemia on gastric emptying in Type I (insulin-dependent) and Type II (noninsulin-dependent) diabetes mellitus. In six patients with uncomplicated Type I and eight patients with uncomplicated Type II diabetes mellitus, measurements of gastric emptying were done on 2 separate days. No patients had gastrointestinal symptoms or cardiovascular autonomic neuropathy. The insulin infusion rate was 40 mU x m(-2) x min(-1) on one day and 80 mU x m(-2) x min(-1) on the other. Gastric emptying and intragastric meal distribution were measured using a scintigraphic technique for 3 h after ingestion of a mixed solid/liquid meal and results compared with a range established in normal volunteers. In both Type I and Type II patients the serum insulin concentration had no effect on gastric emptying or intragastric meal distribution of solids or liquids. When gastric emptying during insulin infusion rates of 40 mU x m(-2) x min(-1) and 80 mU x m(-2) x min(-1) were compared the solid T50 was 137.8+/-24.6 min vs. 128.7+/-24.3 min and liquid T50 was 36.7+/-19.4 min vs. 40.4+/-15.7 min in the Type I patients; the solid T50 was 94.9+/-19.1 vs. 86.1+/-10.7 min and liquid T50 was 21.8+/-6.9 min vs. 21.8+/-5.9 min in the Type II patients. We conclude that hyperinsulinaemia during euglycaemia has no notable effect on gastric emptying in patients with uncomplicated Type I and Type II diabetes; any effect of insulin on gastric emptying in patients with diabetes is likely to be minimal.

Topics: Adult; Amyloid; Blood Glucose; C-Peptide; Cholecystokinin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Islet Amyloid Polypeptide; Male; Peptide Fragments; Protein Precursors

Patients with early non-insulin-dependent diabetes mellitus (NIDDM) empty glucose solutions from their stomachs more rapidly than non-diabetic control subjects, and this exacerbates postprandial hyperglycaemia. To determine if accelerated gastric emptying occurred in a rat model of NIDDM and influenced postprandial hyperglycaemia, gastric emptying of glucose was measured, and the effect of slowing the gastric emptying rate on postprandial hyperglycaemia was observed. We tested eight male obese Zucker diabetic rats and eight age-matched lean Zucker controls at 10-13 weeks of age to measure gastric emptying of glucose (by gamma scintigraphy). Rats fasted overnight were gavaged with 30% glucose at 1 ml/100 g body weight. Separately, six Zucker diabetic rats and six lean controls were tested for sensitivity to the inhibitory effects of cholecystokinin and secretin on gastric emptying. The diabetic rats emptied glucose significantly faster than controls (t1/2 = 37.3 +/- 1.5 vs 58.8 +/- 2.3 min in controls), and aging exaggerated this differential. Camostat, a stimulant of cholecystokinin and secretin release, added to the glucose meal significantly slowed gastric emptying (t1/2 = 123 +/- 23 and 166 +/- 19 min, diabetic vs lean, respectively), and significantly reduced postprandial hyperglycaemia in diabetic rats. Compared to Zucker lean controls, Zucker diabetic rats were as sensitive (cholecystokinin) or more sensitive (secretin) to gastrointestinal hormones that inhibit gastric emptying. The results demonstrate accelerated gastric emptying in a rat model of NIDDM, consistant with similar observations in humans with early NIDDM. These results also support the proposal that interventions to slow gastric emptying improve glucose control in this disease.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Esters; Gabexate; Gastric Emptying; Glucose; Guanidines; Hyperglycemia; Male; Postprandial Period; Rats; Rats, Zucker; Secretin; Trypsin Inhibitors

To investigate gallbladder motility and its regulation in patients with diabetes mellitus (DM), we examined the gallbladder response to an intraduodenal test meal by measuring the temporal course of plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) levels. Eighteen patients with type 2 DM and 7 healthy subjects (controls) were enrolled. The gallbladder volume was calculated by the sum-of-cylinders method from ultrasonographic images, and plasma CCK and PP were measured by radioimmunoassays. No significant difference was found in either the gallbladder response or in the CCK response between patients with DM and controls. However, the fasting plasma PP level of patients with DM was more than tenfold higher than that of controls. The integrated PP response (IPPR) of patients with DM to the test meal was 8.3-fold higher than that of controls. When patients with DM were grouped according to whether they had been treated with insulin or not, the fasting plasma PP of patients with DM without insulin treatment was significantly higher than the level in those treated with insulin. These results suggest that overproduction of PP-like immunoreactive substance(s) may occur in patients with DM, but the high plasma PP immunoreactivity does not appear to be related to the fasting gallbladder volume or to gallbladder emptying and filling.

Topics: Adult; Aged; Cholecystokinin; Diabetes Mellitus, Type 2; Diet; Female; Gallbladder Emptying; Humans; Male; Middle Aged; Pancreatic Polypeptide; Postprandial Period; Radioimmunoassay

Cholecystokinin (CCK) has been suggested to modulate insulin output. We have shown that Otsuka Long-Evans Tokushima Fatty (OLETF) rats show little or no expression of the CCK-A receptor gene in the pancreas. We examined whether the CCK-A and CCK-B receptor genes are expressed in the islets and the role of CCK-A receptor in insulin secretion. Gene expressions of CCK receptors were determined by the reverse-transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot hybridization and Northern transfer analysis using LETO rats as controls. Pancreatic endocrine function was examined in perfusion (exogenous CCK stimulation) and meal ingestion (endogenous CCK stimulation) studies. CCK-A receptor mRNA was detected in the islets of LETO rats but not OLETF rats. Expression of the CCK-B receptor gene was detected in both strains by RT-PCR. Insulin secretion was impaired in OLETF rats, but the insulin contents of OLETF and LETO rats were not different. No abnormalities were detected histologically in either strain. These results suggest that the occurrence of pancreatic endocrine dysfunction in OLETF rats may be due to a defect in expression of the CCK-A receptor gene, not to insulin deficiency.

Topics: Animals; Base Sequence; Blood Glucose; Blotting, Northern; Cholecystokinin; Diabetes Mellitus, Type 2; Food; Gene Expression; Glucagon; Insulin; Insulin Secretion; Male; Molecular Sequence Data; Pancreatic Diseases; Perfusion; Rats; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; RNA, Messenger

Expression of the CCK-A receptor gene in the pancreas and pancreatic exocrine function was examined in diabetic model rats (OLETF) at 5 wks of age. Little or no CCK-A receptor was detected in the pancreas of OLETF rats. Pancreatic exocrine function in response to exogenous CCK and to bile-pancreatic juice diversion (endogenous CCK) was impaired in conscious OLETF rats. The pancreatic insulin and protein contents of OLETF (Otsuka Long-Evans Tokushima Fatty) and control LETO (Long-Evans Tokushima Otsuka) rats were not significantly different. No histological abnormalities or expression of pancreatitis associated protein (PAP) mRNA was detected in the pancreas in either group. These results suggest that OLETF rats are a new experimental model for congenital deficiency of CCK-A receptor in the pancreas.

Topics: Animals; Antigens, Neoplasm; Base Sequence; Biomarkers, Tumor; Blotting, Northern; Cholecystokinin; Cytoplasmic Granules; Diabetes Mellitus, Type 2; Gene Expression; Lectins, C-Type; Male; Microscopy, Electron; Molecular Sequence Data; Oligonucleotide Probes; Pancreas; Pancreatic Juice; Pancreatitis-Associated Proteins; Protein Biosynthesis; Rats; Rats, Mutant Strains; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; RNA, Messenger; Sincalide

The plasma cholecystokinin (CCK) response to a test meal was studied in 16 control subjects and 15 patients with noninsulin-dependent diabetes mellitus (NIDDM). Basal CCK levels were approximately 1 pmol in both groups. However, after the test meal, plasma CCK levels were 2-fold greater in the controls when compared to the diabetics. In controls, CCK levels maximally increased by 5.6 +/- 0.8 pmol (mean +/- SEM) 10 min after feeding, whereas in the NIDDM patients this value was 1.9 +/- 0.6 pmol (P < 0.001). After the test meal, the normal subjects showed no postprandial rise in blood glucose, whereas the diabetic patient showed a rise of 2.6 +/- 0.7 mmol. To determine whether the decreased CCK levels may have been related to the postprandial hyperglycemia, 7 diabetic subjects were infused with CCK. With this CCK infusion, postprandial glucose levels did not rise. These data suggest, therefore: 1) a role for cholecystokinin in regulating postprandial hyperglycemia in man, 2) abnormalities in CCK secretion occur in NIDDM and may contribute to the hyperglycemia seen in this disease.

Topics: Adult; Aged; Blood Glucose; Cholecystokinin; Diabetes Mellitus, Type 2; Female; Food; Humans; Hyperglycemia; Insulin; Male; Middle Aged

Exocrine pancreatic insufficiency has been observed in some diabetics with peripheral neuropathy and diarrhea. Several mechanisms may be responsible for this insufficiency: (1) pancreatic atrophy, (2) disruption of the cholinergic enteropancreatic reflexes, or (3) elevated serum levels of peptides such as glucagon and pancreatic polypeptide which are known to inhibit pancreatic exocrine secretion. To clarify the mechanism(s) involved in this exocrine pancreatic impairment, we studied 10 diabetics with diarrhea and peripheral neuropathy. Their results were compared to those of eight normal volunteers. Each subject underwent a standardized pancreatic function study which assessed nonstimulated secretion, the response to intrajejunal infusion of a mixture of amino acids, and the output following intravenous administration of secretin and cholecystokinin (CCK). In separate studies, the effect of a background infusion of bethanechol and secretin on the pancreatic response to CCK was assessed in six patients and six normal controls. Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol. Plasma glucagon and pancreatic polypeptide levels in diabetics were not significantly higher than those in controls. We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion and possible mechanisms for this are discussed.

Topics: Adult; Amino Acids; Bethanechol; Bethanechol Compounds; Cholecystokinin; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diarrhea; Dose-Response Relationship, Drug; Humans; Intubation, Gastrointestinal; Male; Middle Aged; Pancreas; Secretin

Pancreozymin-secretin-stimulated secretion was measured for volume, bicarbonate concentration and total amylase output in 16 noninsulin-dependent patients and 23 age-, sex-, and weight-matched similar control subjects. Another group of 17 insulin-dependent patients was studied using secretin stimulation and the secretory response compared to a similar group of 37 control subjects. Pancreozymin-secretin-stimulated pancreatic function was normal in noninsulin-dependent patients. Abnormal values for at least one parameter of secretion were found in 82% of insulin-dependent patients. Amylase output was low in 35% and bicarbonate concentration was low in 30%. Hypersecretion occurred in 35%. One patient had abnormal values for all three parameters and three patients had two abnormal values. Hypersecretory response to secretin stimulation is considered to be an early finding of pancreatic exocrine dysfunction among insulin-dependent patients. Progressive secretory failure occurs as the pathological process increases, and a decrease in total amylase output becomes the most significant abnormality.

Topics: Adolescent; Adult; Aged; Amylases; Bicarbonates; Cholecystokinin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Function Tests; Secretin; Thailand

Postprandial responses of plasma cholecystokinin (CCK) in patients with non-insulin dependent diabetes mellitus (NIDDM) were studied with a CCK specific radioimmunoassay. After the ingestion of a liquid test meal, plasma CCK levels increased from the basal level of 9.8 +/- 1.1 pg/ml to a peak of 19.4 +/- 1.8 pg/ml at 20 min in healthy subjects (n = 10). The ingestion of a test meal in patients with NIDDM (n = 10) resulted in a significantly greater increase of plasma CCK than in healthy subjects and a significant increase of plasma CCK from a basal level of 14.2 +/- 4.4 pg/ml to a peak of 47.4 +/- 12.4 pg/ml at 10 min.

Topics: Adult; Cholecystokinin; Diabetes Mellitus, Type 2; Eating; Female; Food, Formulated; Humans; Kinetics; Male; Middle Aged; Radioimmunoassay; Time Factors