sincalide and Diabetes-Mellitus--Type-2

There is clear evidence of a positive correlation between carbohydrate absorption, plasma concentration of glucose, and the rate of gastric emptying. This suggests that clinical manipulation of gastric emptying rates may have therapeutic potential in glycaemic control. Cholecystokinin (CCK-8) has been shown to delay gastric emptying in individuals with Type 2 diabetes, but its potential as a therapy is limited by the need to administer it intravenously. The preferred routes of administration would be intramuscular injections, an intranasal spray or the use of orally ingested CCK analogues. Alternatively, the oral administration of an agent that enhances endogenous release of CCK could represent an important approach to the treatment of Type 2 diabetes. Agents such as POT II may have a therapeutic indication in patients with recently diagnosed Type 2 diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Proteins; Gastric Emptying; Humans; Infusions, Intravenous; Intestinal Absorption; Plant Proteins; Postprandial Period; Protease Inhibitors; Reference Values; Sincalide; Solanum tuberosum

Discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes.. We performed a randomized, placebo-controlled, double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min) or saline was administered in randomized order. The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed.. CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions.. Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.

Topics: Aged; Bile Acids and Salts; Chelating Agents; Cholagogues and Choleretics; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enteroendocrine Cells; Female; Gallbladder Emptying; Gastric Emptying; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infusions, Intravenous; Male; Metformin; Middle Aged; Sevelamer; Sincalide

Cholecystokinin (CCK) is a gut hormone and a neuropeptide that has the capacity to stimulate insulin secretion. As insulin secretion is impaired in type 2 diabetes, we explored whether exogenous administration of this peptide exerts antidiabetogenic action. The C-terminal octapeptide of CCK (CCK-8) was therefore infused i.v. (24 pmol/kg x h) for 90 min in six healthy postmenopausal women and in six postmenopausal women with type 2 diabetes. At 15 min after start of infusion, a meal was served and ingested during 10 min. On a separate day, saline was infused instead of CCK-8. In both healthy subjects and subjects with type 2 diabetes, CCK-8 reduced the increase in circulating glucose after meal ingestion and potentiated the increase in circulating insulin. The ratio between the area under the curves for serum insulin and plasma glucose during the 15- to 75-min period after meal ingestion was increased by CCK-8 by 198 +/- 18% in healthy subjects (P = 0.002) and by 474 +/- 151% (P = 0.038) in subjects with type 2 diabetes. In contrast, the increase in the circulating levels of gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), or glucagon after meal ingestion was not significantly affected by CCK-8. The study therefore shows that CCK-8 exerts an antidiabetogenic action in both healthy subjects and type 2 diabetes through an insulinotropic action that most likely is exerted trough a direct islet effect. As at the same time, CCK-8 was infused without any adverse effects, the study suggests that CCK is a potential treatment for type 2 diabetes.

Topics: Aged; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Injections, Intravenous; Insulin; Pancreas; Peptide Fragments; Postprandial Period; Protein Precursors; Sincalide

Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) exert important complementary beneficial metabolic effects. This study assessed the biological actions and therapeutic utility of a novel (pGlu-Gln)-CCK-8/exendin-4 hybrid peptide compared with the stable GLP-1 and CCK mimetics exendin-4 and (pGlu-Gln)-CCK-8, respectively. All peptides significantly enhanced in vitro insulin secretion. Administration of the peptides, except (pGlu-Gln)-CCK-8 alone, in combination with glucose significantly lowered plasma glucose and increased plasma insulin in mice. All treatments elicited appetite-suppressive effects. Twice-daily administration of the novel (pGlu-Gln)-CCK-8/exendin-4 hybrid, (pGlu-Gln)-CCK-8 alone, or (pGlu-Gln)-CCK-8 in combination with exendin-4 for 21 days to high-fat-fed mice significantly decreased energy intake, body weight, and circulating plasma glucose. HbA1c was reduced in the (pGlu-Gln)-CCK-8/exendin-4 hybrid and combined parent peptide treatment groups. Glucose tolerance and insulin sensitivity also were improved by all treatment modalities. Interestingly, locomotor activity was decreased in the hybrid peptide group, and these mice also exhibited reductions in circulating triglyceride and cholesterol levels. Pancreatic islet number and area, as well β-cell area and insulinotropic responsiveness, were dramatically improved by all treatments. These studies highlight the clear potential of dual activation of GLP-1 and CCK1 receptors for the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet, High-Fat; Exenatide; Glucagon; Insulin; Mice; Obesity; Peptides; Satiation; Sincalide; Venoms

Compromise of gastric inhibitory polypeptide (GIP) receptor action and activation of cholecystokinin (CCK) receptors represent mechanistically different approaches to the possible treatment of obesity-related diabetes. In the present study, we have compared the individual and combined effects of (Pro(3))GIP[mPEG] and (pGlu-Gln)-CCK-8 as an enzymatically stable GIP receptor antagonist and CCK receptor agonist molecule, respectively.. Twice-daily injections of (pGlu-Gln)-CCK-8 alone and in combination with (Pro(3))GIP[mPEG] in high-fat-fed mice for 34 days significantly decreased the energy intake throughout the entire study (P<0.05 to P<0.01). Body weights were significantly depressed (P<0.05 to P<0.01) in all treatment groups from day 18 onwards. Administration of (pGlu-Gln)-CCK-8, (Pro(3))GIP[mPEG] or a combination of both peptides significantly (P<0.01 to P<0.001) decreased the overall glycaemic excursion in response to both oral and intraperitoneal glucose challenge when compared with the controls. Furthermore, oral glucose tolerance returned to lean control levels in all treatment groups. The beneficial effects on glucose homeostasis were not associated with altered insulin levels in any of the treatment groups. In keeping with this, the estimated insulin sensitivity was restored to control levels by twice-daily treatment with (pGlu-Gln)-CCK-8, (Pro(3))GIP[mPEG] or a combination of both peptides. The blood lipid profile on day 34 was not significantly different between the high-fat controls and all treated mice.. These studies highlight the potential of (pGlu-Gln)-CCK-8 and (Pro(3))GIP[mPEG] in the treatment of obesity-related diabetes, but there was no evidence of a synergistic effect of the combined treatment.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Therapy, Combination; Energy Intake; Insulin Resistance; Male; Mice; Obesity; Receptors, Cholecystokinin; Receptors, Gastrointestinal Hormone; Sincalide; Time Factors

The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.. This study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically stable forms of GLP-1, GIP and CCK, respectively.. All peptides significantly (p < 0.01-p < 0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat-fed mice significantly decreased accumulated food intake (p < 0.05-p < 0.01), body weight gain (p < 0.05-p < 0.01) and improved (p < 0.05) insulin sensitivity in high fat-fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p < 0.05) lowered circulating glucose levels and improved (p < 0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p < 0.05) lowered blood glucose levels 24 h post injection in untreated high fat-fed mice.. This study highlights the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Cell Line; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Therapy, Combination; Exenatide; Gastric Inhibitory Polypeptide; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred Strains; Obesity; Peptides; Rats; Sincalide; Time Factors; Venoms

Diabetes is associated with the reduction of beta cell mass and activity. Cholecystokinin (CCK) is known to induce growth of the exocrine pancreas and to stimulate insulin secretion.. We investigated the possible role of CCK-octapeptide (CCK-8) in generating islet cell proliferation in type 1 and type 2 diabetic rats.. Streptozotocin-induced type 1 diabetic rats, streptozotocin/nicotinamide-induced type 2 diabetic rats and non-diabetic rats were subjected to CCK-8 (1, 2 and 4 microg/kg) or saline injections (for the control group), three times daily for 8 successive days.. The islets of Langerhans were analyzed morphometrically; the beta-cell function was evaluated by an oral glucose tolerance test, and plasma basal glucose and insulin concentrations.. In type 1 diabetic rats, CCK-8 induced an increase in beta cell surface associated with a marked increase in the mitotic index; this effect appeared at a concentration of 1 microg/kg CCK-8 and was the highest at a concentration of 4 microg/kg CCK-8. In addition, pancreatic- and plasma-insulin concentrations increased while fasting blood glucose concentrations were reduced when compared to saline-treated rats but the glycemic response to an oral glucose challenge did not significantly improve. In type 2 diabetic rats and in non-diabetic rats, CCK-8 treatment did not significantly affect either the structure or the functional state of beta-cells.. CCK-8 could improve blood glucose concentrations in type 1 diabetic rats correlated with an increase in beta cell mass probably potentiated by the chronic hyperglycemic state.

Topics: Animals; Blood Glucose; Cell Division; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Glucose Tolerance Test; Insulin; Insulin Secretion; Islets of Langerhans; Male; Niacinamide; Rats; Rats, Wistar; Sincalide; Streptozocin

We investigated the effects of increasing concentrations of cholecystokinin octapeptide (CCK-8) on the exocrine pancreas of a new model of type 2 diabetic rats due to the partial protection exerted by nicotinamide against the beta-cytotoxic effect of streptozotocin. CCK-8, administered for 8 successive days, exerted a biphasic action on the growth of the pancreas in non-diabetic and type 2 diabetic rats; however, the latter were less sensitive to CCK-8. Similar results were obtained in vitro by measuring the uptake of 5-bromo-2'-deoxyuridine (BrdU) in cultured isolated acinar cells. This effect was completely blocked by 3S(-)(N'-2,3-dihydro-1-methyl-2-oxo5-phenyl-1H-1,4-benzo-diazepin-3-yl)-1H-indole-2-carboxamide (L 364,718; a CCK(1) receptor antagonist) but not by (3R)-3[N'-(3-methylphenyl)ureido]-1,3-dihydro-1-methyl-5-phenyl-2H1,4-benzo-diazepin-2-one (L 365,260; a CCK(2) receptor antagonist), suggesting a direct effect via CCK(1) receptors. Binding studies showed that these effects were mediated by a single class of low-affinity CCK(1) receptors in diabetic rats and two classes of CCK-8 binding sites (with high and low affinity) in non-diabetic rats. Thus, in our new type 2 diabetes model, the loss of sensitivity of the pancreas to CCK-8 could be attributed to the loss of CCK(1) receptors of high affinity.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Organ Size; Pancreas; Rats; Rats, Wistar; Receptors, Cholecystokinin; Sincalide

Insulin resistance is followed by an islet adaptation resulting in a compensating increase in insulin secretion and hyperinsulinemia. The mechanism underlying this increased insulin secretion is not established. We studied whether islet phospholipase A(2) (PLA(2)) contributes by using C57BL/6J mice fed a high-fat diet, since we previously showed that the insulin responses to the two PLA(2)-activating insulin secretagogues carbachol and cholecystokinin (CCK) are enhanced in this model. CCK (100 nM) and carbachol (100 microM) stimulated [(3)H]AA efflux, reflecting PLA(2) activation, both in islets from mice after 12 weeks on high-fat diet and in controls. The efflux increase was more pronounced in islets from high-fat diet-fed mice during both CCK (by 93 +/- 46%; P = 0. 034) and carbachol (by 64 +/- 22%; P = 0.009) stimulation. Also a direct PLA(2) activation by mellitin (2 microg/ml) elicited a potentiated efflux in islets from the insulin-resistant mice (by 361 +/- 107%; P = 0.002). The results suggest that exaggerated non-glucose-induced PLA(2) activation contributes to the islet compensation in insulin resistance.

Topics: Animals; Arachidonic Acid; Blood Glucose; Body Weight; Carbachol; Diabetes Mellitus, Type 2; Dietary Fats; Enzyme Activation; Fatty Acids, Nonesterified; Female; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Melitten; Mice; Mice, Inbred C57BL; Phospholipases A; Sincalide; Time Factors

Psammomys obesus fed a high-calorie diet develops a NIDDM-like syndrome. The use of reverse-phase high-performance liquid chromatography (HPLC) to study Psammomys insulin biosynthesis and release revealed a very delayed elution time for the Psammomys insulin peak appearing near the position of human proinsulin. This unusual peak was initially thought to represent partially processed insulin on the basis of its molecular size and susceptibility to trimming by carboxypeptidase B (CpB). However, the findings of an active carboxypeptidase E (CpE) enzyme and the normal amidated forms of gastrin and cholecystokinin octapeptide (CCK-8) in Psammomys tissues were inconsistent with CpE-related aberrant processing of insulin. Moreover, amino acid sequencing of the delayed peak of Psammomys insulin revealed fully processed insulin with amino acid sequence as predicted by the cDNA. The unique presence of a B-30 phenylalanine residue, resulting in an increased hydrophobicity of the insulin molecule, probably underlies the marked delay in elution time on HPLC. The unusual structure of Psammomys insulin does not appear to contribute to the proinsulinemia observed in diabetic Psammomys since the HPLC-purified molecule did not inhibit PC1 and PC2 convertase activities in an in vitro assay.

Topics: Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Carboxypeptidases; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; DNA Primers; Furin; Gastrins; Gerbillinae; Humans; Insulin; Islets of Langerhans; Molecular Sequence Data; Pituitary Gland; Polymerase Chain Reaction; Proinsulin; Protein Precursors; Rats; Rats, Sprague-Dawley; Sincalide; Subtilisins

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

In a previous study we demonstrated that patients with recently diagnosed non-insulin-dependent diabetes mellitus (NIDDM) had significantly increased gastric emptying rates of glucose solutions compared with those of nondiabetic sex- and age-matched controls. This finding of rapid gastric emptying contrasts with the delayed gastric emptying often exhibited as a late manifestation of diabetes mellitus that is attributed to autonomic neuropathy. The purpose of this study was to determine, in seven of the patients previously studied, whether (1) an intravenous infusion of cholecystokinin-8 (CCK-8) would delay the gastric emptying of a liquid glucose meal and, if so, (2) whether the delay in gastric emptying would result in reduced postprandial blood glucose concentrations due to prolongation of the absorption of the glucose in the liquid meal. Each patient underwent two separate gastric emptying studies, one during a saline infusion and one during a CCK-8 infusion. Blood samples were obtained at 15-min intervals for measurement of glucose, insulin, CCK-8, and gastric inhibitory polypeptide (GIP) concentrations. The average gastric half-emptying time was 41 min with the saline infusion and 94 min with the CCK-8 infusion (P = 0.0042). The average glucose concentration over the 2-hr period following glucose ingestion was 17.1 mmol/liter with the saline infusion and 14.0 mmol/liter with the CCK-8 infusion (P = 0.0073). The average glucose excursion value over the 2-hr period was reduced from 5.6 mmol/liter to 3.7 mmol/liter with the CCK-8 infusion (P = 0.0550).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Humans; Insulin; Male; Middle Aged; Sincalide

Secrepan (Eisai Co. Tokyo, Japan) was administered to 9 healthy volunteers and 36 patients with non-insulin dependent diabetes mellitus (NIDDM) to clarify the effect of secretin on the pancreatic B-cell, by determining the changes in blood of insulin (IRI). Whereas IRI in healthy subjects showed a monophasic change, reaching a peak (delta IRI = 43 +/- 7.3 microunits/ml, M +/- SE) 5 min after secretin loading and returning to the basal level in 15 min, NIDDM patients on diet therapy (delta IRI = 40.2 +/- 7.6 microunits/ml) showed no significant difference from the control group, but NIDDM patients on sulfonylurea (SU) (15.5 +/- 2.4 microunits/ml) and those on insulin therapy (5.3 +/- 1.4 microunits/ml), both showed a significant depression in responsiveness. Further, the changes in insulin secretion after atropine administration in healthy subjects and the changes in IRI response to Secrepan in vagotomized patients were also determined. As a result, data which preclude the possibility of association of the vagus nerve and cholinergic nerve with the stimulation of insulin secretion by secretin were obtained, and a direct action of secretin on the cell of islets of Langerhans was suggested. The maximum IRI response after a secretin load had a significant positive correlation with the IRI response after a 75-gm GTT and the content of C-peptide immunoreactivity in 24-hour urine. Therefore, insulin response to a secretin load can be useful in assessing endogenous insulin secretion and provides a pertinent clinical guide for the selection of an appropriate therapy for diabetes mellitus.

Topics: Adult; Atropine; C-Peptide; Ceruletide; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged; Secretin; Sincalide; Vagotomy