gastrins and Diabetes-Mellitus--Type-2

Obesity and its comorbidities, such as type 2 diabetes mellitus and cardiovascular disease, constitute growing challenges for public health and economies globally. The available treatment options for these metabolic disorders cannot reverse the disease in most individuals and have not substantially reduced disease prevalence, which underscores the unmet need for more efficacious interventions. Neurobiological resilience to energy homeostatic perturbations, combined with the heterogeneous pathophysiology of human metabolic disorders, has limited the sustainability and efficacy of current pharmacological options. Emerging insights into the molecular origins of eating behaviour, energy expenditure, dyslipidaemia and insulin resistance suggest that coordinated targeting of multiple signalling pathways is probably necessary for sizeable improvements to reverse the progression of these diseases. Accordingly, a broad set of combinatorial approaches targeting feeding circuits, energy expenditure and glucose metabolism in concert are currently being explored and developed. Notably, several classes of peptide-based multi-agonists and peptide-small molecule conjugates with superior preclinical efficacy have emerged and are currently undergoing clinical evaluation. Here, we summarize advances over the past decade in combination pharmacotherapy for the management of obesity and type 2 diabetes mellitus, exclusively focusing on large-molecule formats (notably enteroendocrine peptides and proteins) and discuss the associated therapeutic opportunities and challenges.

Topics: Animals; Body Mass Index; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Male; Metabolic Diseases; Metformin; Mice; Molecular Targeted Therapy; Obesity; Prognosis; Risk Assessment; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Personalized management of diabetes has become an imperative since majority of monotherapy fails within 3 years of its use. Identifying responders from nonresponders for a certain type of therapy would reduce a period of unsuccessful treatment and minimize health care costs. Incretin therapies, mainly glucagon-like peptide (GLP)-1 receptor agonists (GLP- 1RA) are relatively new glucose-lowering agents which increase insulin and lower glucagon response as well as slow down glucose absorption by acting on gastric emptying. However, problem with incretin- based therapy is distinguishing responders from non-responders and currently lack of specific predictors of treatment response.. Experimental data demonstrated that activation of GLP-1 and gastrin signaling induces beta cell neogenesis, leading to glucose-dependent insulin secretion. Several studies demonstrated better glycemic control in patients with type 2 diabetes (DMT2) co-treated with proton pump inhibitors (PPI) and incretin based therapy agents.. Higher gastrin levels in patients with diabetes prior to initiation of treatment with incretin mimetics could suggest a better potential for reversible human β-cell reprogramming with concomitant incretin therapy. Therefore, baseline levels of endogenous gastrin could be used as a predictor of response to GLP-1 therapy. In addition, treatment with PPI could also raise gastrin levels and in patients treated with GLP-1RA, lead to better glycemic control by initiating β-cell neogenesis and proliferation of pancreatic β-cells.

Topics: B-Lymphocytes; Biomarkers; Diabetes Mellitus, Type 2; Gastrins; Humans; Incretins; Predictive Value of Tests; Treatment Outcome

Diabetes mellitus is a complex chronic disease associated with an absolute insulin deficiency in type 1 diabetes (T1D) and a progressive deterioration of β-cell function in type 2 diabetes (T2D). T2D pathophysiology has numerous defects including incretin deficiency/resistance. Gastrin has demonstrated to be an islet growth factor (like glucagon-like peptide-1, epidermal growth factor, transforming growth factor-α,…) and be able to restore a functional β-cell mass in diabetic animals. This hormone is likely to stimulate insulin secretion during an ordinary protein-rich meal, this is, to have an incretin-like effect. Proton pump inhibitors (PPIs) can raise serum gastrin concentration significantly and therefore, affect to glucose metabolism through promoting β-cell regeneration/expansion and also enhancing insulin secretion. The present paper aims to review studies concerning the effect of PPIs on glucose metabolism. Several research groups have recently explored the potential role of this class of drugs on glycemic control, mainly in T2D. The results show antidiabetic properties for the PPIs with a global glucose-lowering power around 0.6-0.7 % points of HbA1c, but the level of evidence for the available literature is still not high. If these data start to become demonstrated in the ongoing clinical trials, PPIs could become a new antidiabetic agent with a good and safe profile for T2D and even useful for T1D, particularly in the area of islet transplantation to preserve β-cell mass.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enterochromaffin-like Cells; Gastric Emptying; Gastrin-Secreting Cells; Gastrins; Gastrointestinal Agents; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Parietal Cells, Gastric; Proton Pump Inhibitors; Somatostatin; Somatostatin-Secreting Cells

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Epidermal Growth Factor; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Agents; Glucagon-Like Peptide-1 Receptor; Humans; Insulin-Secreting Cells; Receptors, Glucagon; Thiazolidinediones

Transition Therapeutics (through its acquisition of Waratah Pharmaceuticals), in collaboration with Novo Nordisk, is developing E1-INT, an injectable islet neogenesis therapy comprising an epidermal growth factor analog and a gastrin analog, for the treatment of insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes. The compound is currently undergoing phase II clinical trials.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Industry; Epidermal Growth Factor; Gastrins; Humans; Hypoglycemic Agents; Structure-Activity Relationship

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

Proton pump inhibitor (PPI) drugs reduce gastric acid secretion and lead to an increase in serum gastrin levels. Many preclinical and some clinical researches have established some positive effects of gastrin or PPI therapy on glucose regulation. The aim of this study was to prospectively investigate the short term effects of esomeprazole on glycaemic control in patients with type 2 diabetes mellitus. In addition, the presence of an association between this effect and gastrin levels was evaluated.. Thirty-two subjects with type 2 diabetes mellitus were enrolled and grouped as intervention (n=16) and control (n=16). The participants in the intervention group were prescribed 40 mg of esomeprazole treatment for three months. At the beginning of the study and at the 3rd month, HbA1c level (%) and gastrin levels (pmol/L) of participants were assessed. Then, the groups were compared in terms of their baseline and 3rd month values.. In the intervention group, the mean gastrin level increased significantly from 34.3±14.4 pmol/L to 87.4±43.6 pmol/L (p<0.001). The mean HbA1c level was similar to the pre-treatment level (6.3±0.7% vs. 6.4±0.9%, p=0.441). There were no statistically significant differences in all parameters of the control group. The majority of individuals were on metformin monotherapy (65.6 %). The subgroup analysis of metformin monotherapy revealed that, in intervention group, there was a significant increase in gastrin levels (39.9±12.6 vs. 95.5±52.5, p=0.026), but the HbA1c levels did not change (6.0±0.4 % vs. 5.9±0.6 %, p=0.288); and in control group, gastrin levels did not change (37.5 ± 26.7 vs. 36.1 ±23.3, p=0.367), but there was an increase in HbA1c levels (6.1 ± 0.50 vs. 6.4 ± 0.60, p=0.01).. Our study demonstrates that esomeprazole has no extra benefit for the controlled diabetic patient in three months. However, in only the metformin-treated subgroup, esomeprazole may prevent the rise in HbA1c level.

Topics: Aged; Anti-Ulcer Agents; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Esomeprazole; Female; Gastrins; Glycated Hemoglobin; Glycemic Control; Humans; Male; Metformin; Middle Aged; Proton Pump Inhibitors; Treatment Outcome; Up-Regulation

To determine if a 4-week course of 14 mg weekly GLP-1 agonist LY2428757 combined with 3 mg or 2 mg daily gastrin analogue TT223 (LY+TT223) results in long-term glycaemic changes.. Patients with in adequately-controlled type 2 diabetes mellitus ±metformin (N=151) were randomized to a 4-week course of LY+TT223 (3 mg), LY+TT223 (2 mg), LY+TT223 placebo (LY-only) or LY placebo+TT223 placebo (placebo). The primary objective was change in HbA1c from baseline to 5 month safter completion of therapy (i.e. at 6 months) and safety and tolerability with LY+TT223 versus LY-only.. LY groups showed HbA1c reductions during the active treatment phase. These did not persist during follow-up phase. Combining TT223 with LY did not result in additional glycaemic effects during treatment or follow-up. At 6 months, LSM ± SE for change in HbA1c from baseline was: LY+TT223 (3 mg): -0.1 ± 0.2%; LY+TT223 (2 mg): 0.1 ± 0.2%; LY-only: -0.2 ± 0.2%; placebo: 0.04 ± 0.2%. Secondary analyses were consistent with primary results. LY+TT223 was not superior to LY for other time points or end points, including insulin secretory response to mixed meal tolerance tests. The most common adverse events (nausea and vomiting) were more frequent with LY+TT223 versus LY-only. The safety profile was consistent with previous findings.. GLP-1+gastrin combination therapy did not improve glycaemic control versus GLP-1 alone.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gastrins; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged

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

Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c) and cardiovascular risk factors in type 2 diabetes.. Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n = 20) or placebo (n = 21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA(1c) and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements.. Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049 ± 17,659 vs 27,270 ± 32,004 pmol/l × min (p = 0.838). In the placebo group AUC for insulin decreased from 27,392 ± 14,348 pmol/l × min to 22,938 ± 11,936 pmol/l × min (p = 0.002). Esomeprazole treatment (n = 20) caused a ninefold increase in the AUC for gastrin. HbA(1c) increased from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.3 ± 0.8% (56 ± 6 mmol/mol) in the esomeprazole-treated group and from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.4 ± 0.8% (57 ± 6 mmol/mol) in the placebo group (n = 21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p > 0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p < 0.05). No change in BP was seen in the patients treated with esomeprazole.. Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Topics: Aged; Biomarkers; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Combined Modality Therapy; Denmark; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Esomeprazole; Gastrins; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Secretion; Male; Middle Aged; Placebo Effect; Proton Pump Inhibitors; Risk Factors; Yogurt

To explore the effect of Chinese herbs (CH) for cool-moistening and freeing collaterals on gastro-dynamic disturbance in patients of diabetes mellitus type 2 with gastroparesis (DM-GP).. Fifty-three patients of DM-GP were enrolled and treated with CH (n = 28) and Cisapride (n = 25) respectively for 4 weeks, the changes of gastrin and electro-gastrogram (EGG) before and after treatment were observed.. After treatment, the EGG improved significantly, showing the rhythm significantly improved, and level of serum gastrin lowered significantly, as compared with those before treatment, the difference was significant (P<0.01), but insignificant difference was found between the two groups. Fifteen patients in each group were followed-up afar stopping medication for 3 months, recurrence occurred in 1 patient of CH treated group, and 2 patients of Cisapride treated group. No adverse reaction was found in the rest patients.. CH could obviously improve the gastro-intestinal motility and hormones abnormality.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Electromyography; Electrophysiology; Female; Gastric Emptying; Gastrins; Gastrointestinal Agents; Gastrointestinal Motility; Gastroparesis; Humans; Male; Middle Aged; Phytotherapy

To observe the effect of Jianpi Wenshen Decoction (JWD) on serum gastrin, plasma motilin and somatostatin in patients of diabetic diarrhea (DD).. Patients with DD were randomly divided into two groups, the JWD group and the control group treated with Loperamide (LPA). Besides, a normal control group was set up. Changes of serum gastrin, plasma motilin and somatostatin were observed.. Before treatment, the levels of gastrin and motilin in both groups were higher and somatostatin lower than those in the normal control group. After 1 month treatment, levels of the three indices were restored in both group approaching the normal range with insignificance as compared with those in the normal control group (P > 0.05). Level of plasma motilin and serum gastrin showed an increasing trend along with the therapeutic effect elevation, while level of somatostatin showed a decreasing trend.. JWD could promote the recovery of the impaired function of vegetative nerve system in DD patients. At the same time, serum gastrin, plasma motilin and somatostatin may be taken as the indexes for evaluating the efficacy in treating DD.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diarrhea; Drugs, Chinese Herbal; Female; Gastrins; Humans; Male; Middle Aged; Motilin; Phytotherapy; Somatostatin

The authors investigated the effect of a balanced meal on gastric emptying rate and gastrin plasma concentrations in patients with type II diabetes and autonomic neuropathy, in diabetic patients without autonomic neuropathy, and in healthy subjects (controls). Before food the gastrin plasma concentrations were higher in patients with diabetes with autonomic neuropathy. After food, gastric emptying rate was slower in patients with diabetes with autonomic neuropathy, whereas gastrin plasma concentrations increased in 30 minutes in all groups but to a greater extent in patients with diabetes with autonomic neuropathy. Sixty minutes after food, there was a significant decrease in gastrin plasma concentrations in patients with diabetes with autonomic neuropathy, compared with the other two groups. These data suggest that in patients with type II diabetes with autonomic neuropathy, food causes slower gastric emptying and different plasma gastrin level responses from those in patients with type II diabetes without autonomic neuropathy and controls. There are therefore differences in the responses to food ingestion between these groups because of vagal denervation induced by autonomic neuropathy. These tests should be reserved for patients with symptoms suggestive of disturbed gastric emptying, or for patients with autonomic neuropathy without symptoms of gastroparesis.

Topics: Aged; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gastric Emptying; Gastrins; Gastroparesis; Humans; Male; Middle Aged

Gastrin influences polyamine synthesis in the enterocytes, which can lead to increased DAO activity. In diabetics with autonomic neuropathy (AN), a higher than normal gastrin concentration was found. However, in diabetics with enteropathy, a low level of plasma DAO activity was discovered. The purpose of this study was to investigate gastrin secretion and to evaluate DAO activity after i.v. injection of heparin in a group of diabetics with AN. Group I consisted of 12 diabetics with AN, group II 20 patients with diabetes without any complications and group III (the control group) 20 patients without diabetes. It was discovered that basal gastrin concentrations were significantly greater in group I (147 pg/ml +/- 76.5) that in groups II (78 pg/ml +/- 55.5)(p < 0.01) and III (61.5 pg/ml +/- 42.6)(p < 0.01). DAO activity was at its lowest in group I (247.1 pmol/min/ml +/- 104.8) and it was significantly different from group II (441 pmol/min/ml +/- 225.9)(p < 0.001) and III (540.7 pmol/min/ml +/- 171.1)(p < 0.001). There were no differences in the mean values of gastrin and DAO activity between group II and III. In group I low DAO activity was accompanied by a proportionally high concentration of the basal gastrin value (r = 0.567). In conclusion, in diabetics with AN, low postheparin plasma DAO activity was accompanied by a high basal gastrin value.

Topics: Adult; Amine Oxidase (Copper-Containing); Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Gastrins; Heparin; Humans; Male; Middle Aged

Gastric abnormalities are more common in diabetics than in the normal population. They seem to be related to gastric parietal cell autoantibodies (GPCA). We have studied 168 patients affected with non-insulin-dependent diabetes mellitus (NIDDM), and assessed the GPCA in the serum and haematologic disorders. We have also assessed the endoscopic and histological findings of atrophic gastritis in patients with GPCA. GPCA were found in 15.74% of diabetic patients and in 2% of a control group of blood donors. 80% of GPCA positive patients showed signs of atrophic gastritis. Such presence of GPCA seems to be a good marker to identify patients affected by atrophic gastritis and its complications.

Topics: Adult; Autoantibodies; Diabetes Mellitus, Type 2; Female; Ferritins; Gastrins; Gastritis, Atrophic; Humans; Iron; Islets of Langerhans; Male; Middle Aged; Parietal Cells, Gastric

A hitherto undescribed form of diabetes mellitus type 2 is reported in a Flemish family. In these patients, markedly elevated gastrin levels were observed, which could not be linked to gastrointestinal symptoms.. Gel permeation chromatography was performed for gastrin, insulin, and proinsulin. Proprotein convertase subtilisin/kexin type (PCSK1 and PCSK2)] were sequenced. Whole-exome sequencing was performed on the genomic DNA extracted from leukocytes of the proband of the family.. Gel permeation chromatography revealed that the apparent hypergastrinemia was caused by the accumulation of biologically inactive progastrin. Besides, high serum concentrations of proinsulin and intact fibroblast growth factor 23 (FGF23) were also detected. Sequencing of PCSK1 and PCSK2 genes did not reveal any mutations in these genes. Whole exome sequencing revealed a c.1150C > T (p.Pro384Ser) mutation in G protein-coupled receptor kinase 6 (GRK6), which cosegregated with the disease. Expression of the mutant enzyme in mammalian cells revealed that it was mislocalized compared to the wild-type GRK6.. In the affected patients, prohormone processing is impaired likely due to the altered function of mutant GRK6. Delayed pro-insulin processing causes hypoglycaemia episodes a couple of hours following meals. In addition, increased plasma concentrations of progastrin and intact FGF23 in the affected individuals can be explained by incomplete processing of the precursor hormones.

Topics: Animals; Base Sequence; Diabetes Mellitus, Type 2; Gastrins; Humans; Mammals; Mutation; Proinsulin

The aim: To study the gastrin level dynamics in patients with diabetes mellitus (DM) 2 type and chronic gastritis (CG) on the background of antihelicobacter therapy (AHT).. Materials and methods: 60 patients with DM type 2 and HP-associated CG underwent examination. Patients were divided into two groups of 30 patients each: group 1 included patients who received only standard AHT, group 2 - patients who in addition to standard AHT received the drug SB (Normagut, company Mega) 2 capsules 2 times/day.. Results: According to our study results yeast SB, not only increase the HP eradication rate but together with the standard AHT contribute to the serum gastrin reduction, which is a gastric acid stimulator, which in turn leads to an improvement in the CG clinical course.. Conclusions: Patients with DM type 2 and CG associated with HP should include yeast SB to standard AHT as they reduce side effects from this treatment (by an average of 20%), increase the eradication frequency (by 10%), and also lead to significant decrease in serum gastrin (up to 82.15 ± 2.47 pg/ml).A decrease in serum gastrin levels in patients with HP-associated CG and DM type 2 leads to an improvement in the clinical course of the diseases, namely a decrease in nausea, diarrhea, abdominal pain, and discomfort incidence.

Topics: Diabetes Mellitus, Type 2; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans

To evaluate the effect of proton pump inhibitors on glycaemic indices in patients with type 2 diabetes mellitus.. The case-control study was conducted at the National Diabetes Centre, Mustansiriyah University, Baghdad, Iraq, from January to April 2018, and comprised type 2 diabetes patients and non-diabetic healthy controls. The subjects were divided into three groups: Group A had controls on proton pump inhibitors; Group B had patients treated with metformin 850 g/day; and Group C had patients treated with metformin 850 g/day plus proton pump inhibitors. Gastrin serum levels, lipid profile, glycaemic indices and blood pressure changes were measured in the groups. Data was analysed using SPSS 20.. Of the 100 subjects, 60(60%) were patients with a mean age of 54.98}4.22 years, while40(40%) were controls with a mean age of 50.69}4.34 years. Group A had 40(40%) subjects, while Group B and Group C had 30(30%) each. Proton pump inhibitors improved glycaemic indices and lipid profile in the patients 9p<0.05) while increasing gastrin serum levels which were significantly correlated with reduction in glycated haemoglobin, fasting blood glucose and augmentation of β-cell function (p<0.05 each).. Proton pump inhibitors improved glycemic indices and metabolic profile in type 2 diabetes patients via augmentation of gastrin serum levels.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Gastrins; Glycated Hemoglobin; Glycemic Index; Humans; Insulin; Lipids; Middle Aged; Proton Pump Inhibitors

Recent studies suggest the possibility of the stomach playing a role in diabetes remission after bariatric surgery. In this study, we investigated whether bypassing the stomach alleviates diabetes in diabetic rodent model. Eighteen moderately obese and diabetic Sprague-Dawley rats were randomly assigned to Esophagoduodenostomy with or without gastric preservation (EDG and EDNG/total gastrectomy, respectively), and SHAM groups. Bodyweight, food intake, fasting glucose level, oral glucose tolerance test result (OGTT), and hormone levels (insulin, glucagon-like peptide-1, ghrelin, gastrin and glucagon) were measured preoperative and postoperatively. Postoperatively, bodyweight and food intake did not differ significantly between the EDG and EDNG groups. Postoperative fasting blood glucose and OGTT results declined significantly in the EDG and EDNG group when compared with the respective preoperative levels. Postoperative glucose control improvements in EDNG group was significantly inferior when compared to EDG. Compared preoperatively, postoperative plasma ghrelin and gastrin levels declined significantly in EDNG group. Preoperative and postoperative plasma GLP-1 level did not differ significantly among all the groups. Postoperatively, EDG group had significantly higher insulin and lower glucagon levels when compared with SHAM. In conclusion, bypassing and preserving the stomach resulted in superior glucose control improvements than total gastrectomy.

Topics: Animals; Bariatric Surgery; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenostomy; Eating; Esophagostomy; Gastric Bypass; Gastrins; Ghrelin; Glucose; Glucose Tolerance Test; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Streptozocin; Treatment Outcome

Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals.. Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography.. Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastrectomy; Gastrins; Hormones; Insulin-Secreting Cells; Male; Pantoprazole; Rats

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

β-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of β-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin

Topics: Aged; Aged, 80 and over; Animals; Basic Helix-Loop-Helix Transcription Factors; Case-Control Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastrins; Gene Expression Regulation, Developmental; Gerbillinae; Humans; Immunohistochemistry; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Nerve Tissue Proteins; Real-Time Polymerase Chain Reaction; Somatostatin-Secreting Cells; Stem Cells

Bariatric surgery is a highly effective treatment of type 2 diabetes in patients with morbid obesity. The weight-loss independent improvement of glycemic control observed after these procedures has led to the discussion whether bariatric surgery can be introduced as treatment for type 2 diabetes in patients with a body mass index < 35 kg/m(2). We have studied the effects of two bariatric procedures on type 2 diabetes and on gastrointestinal hormone secretion in a lean diabetic animal model.. Male Goto-Kakizaki rats, 17-18 weeks old, were randomized into three groups: duodenojejunostomy (DJ), sleeve gastrectomy (SG), or sham operation. During 36 postoperative weeks we evaluated body weight, fasting blood glucose, glucose tolerance, insulin, HbA1c, glucagon-like peptide 1, cholesterol parameters, triglycerides, total ghrelin, and gastrin.. Oral glucose tolerance was significantly improved for both DJ and SG at four weeks after surgery (p < 0.05). At the 34th postoperative week, SG had significantly lower area under the curve during oral glucose tolerance test compared to sham (p = 0.007). SG had significantly lower HbA1c compared to sham at 12 weeks; (mean ± SEM) 4.3 ± 0.1 % versus 5.2 ± 0.3 % (p < 0.05) and compared to both DJ and sham 34 weeks after surgery [median (75 %;25 %)] 5.2 (6.0; 4.3) % versus 7.0 (7.5; 6.7) % and 7.3 (7.6; 6.7) % (p = 0.009). Serum gastrin levels were markedly elevated for SG compared to DJ and sham; 188.0 (318.0; 121.0) versus 77.5 (114.0; 58.0) and 68.0 (90.0; 59.5) pmol/L (p = 0.004) at six weeks and 192.0 (587.8; 110.8) versus 65.5 (77.0; 59.0) and 69.5 (113.0; 55.5) (p = 0.001) 36 weeks after surgery.. Sleeve gastrectomy induces hypergastrinemia, lowers HbA1c, and improves glycemic control in Goto-Kakizaki rats. Sleeve gastrectomy is superior to duodenojejunostomy as treatment of type 2 diabetes mellitus in this animal model.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Body Mass Index; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenostomy; Gastrectomy; Gastrins; Gastroplasty; Jejunostomy; Male; Obesity, Morbid; Rats

Gastrin increases the growth and neogenesis of the islets of Langerhans. Oral proton pump inhibitors (PPIs) increase the circulating gastrin level in animals and humans, but the therapeutic benefit of PPIs for diabetes mellitus has not been resolved. We examined whether treatment with a PPI for ≥2 months affected the glycated hemoglobin (A1C) level in patients with type 2 diabetes.. The electronic medical records of patients treated at the Busan Paik Hospital in South Korea were examined. The primary outcome measure was the change in A1C before and after PPI treatment for ≥2 months. We also tested if the primary outcome measure was affected by sex, age, duration of diabetes, body mass index, PPI molecule, duration of treatment with PPI or concurrent therapy with other antidiabetes agents.. In total, 43 patients (17 men and 26 women) were studied (mean age 63.8 years). Patients were treated with a PPI for a mean of 180 days. The A1C levels before and after treatment were not significantly different (6.86%±1.10% and 6.77%±1.07%, respectively; p=0.406). Metformin monotherapy did not lower A1C levels as compared with a combination therapy including metformin and antidiabetes medication not including metformin.. Proton pump inhibitor treatment of patients with type 2 diabetes did not reduce A1C levels. The data of this study were obtained from a retrospective chart review and included a small number of subjects. Furthermore, large randomized controlled studies are needed to define the effect of PPIs for type 2 patients with diabetes.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Gastrins; Glycated Hemoglobin; Humans; Male; Middle Aged; Proton Pump Inhibitors; Republic of Korea; Retrospective Studies; Treatment Outcome

Combination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly diabetic Zucker Diabetic Fatty (ZDF) rats.. ZDF rats aged 11 weeks were dosed s.c., b.i.d. for 8 weeks with vehicle, ZP3022, liraglutide, exendin-4, or gastrin-17 with or without exendin-4. Glycemic control was assessed by measurements of HbA1c and blood glucose levels, as well as glucose tolerance during an oral glucose tolerance test (OGTT). Beta cell dynamics were examined by morphometric analyses of beta and alpha cell fractions.. ZP3022 improved glycemic control as measured by terminal HbA1c levels (6.2±0.12 (high dose) vs. 7.9±0.07% (vehicle), P<0.001), as did all treatments, except gastrin-17 monotherapy. In contrast, only ZP3022, exendin-4 and combination treatment with exendin-4 and gastrin-17 significantly improved glucose tolerance and increased insulin levels during an OGTT. Moreover, only ZP3022 significantly enhanced the beta cell fraction in ZDF rats, a difference of 41%, when compared to the vehicle group (0.31±0.03 vs. 0.22±0.02%, respectively, P<0.05).. These data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Insulin-Secreting Cells; Mice; Peptides; Rats; Rats, Zucker

In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes.. The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity.. Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content.. Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastrins; Glucagon; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Omeprazole; Peptides; Venoms

Diabetes is characterized by β-cell deficiency, and therefore restoration of β-cell function has been suggested as a potential therapy. We hypothesized that a novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist, ZP3022, improves glycaemic control via improvement of β-cell status in db/db mice.. Diabetic mice were studied following short- or long-term treatment with either the GLP-1-gastrin dual agonist or the commercially available GLP-1 agonists (exendin-4 and liraglutide). The effects on glycaemic control were addressed by repeated glucose tolerance tests and/or measurements of HbA1c levels, and pancreatic islet and β-cell masses were determined by stereology.. ZP3022 and the pure GLP-1 agonists improved glycaemic control after both short- and long-term treatment compared with vehicle. Interestingly, the effect was sustainable only in mice treated with ZP3022. Stereology data displayed a dose-dependent increase of β-cell mass (p < 0.05) following treatment with ZP3022, whereas no significant effect of liraglutide was observed (β-cell mass: vehicle 3.7 ± 0.2 mg; liraglutide (30 nmol/kg) 3.4 ± 0.5 mg; ZP3022 (30 nmol/kg) 4.3 ± 0.4 mg and ZP3022 (100 nmol/kg) 5.2 ± 0.4 mg).. The novel GLP-1-gastrin dual agonist, ZP3022, improved glycaemic control in db/db mice, and pancreatic islet and β-cell mass increased significantly following treatment with ZP3022 compared with vehicle.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Gastrins; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Inbred C57BL; Peptides; Venoms

Gastrin has been implicated in islet growth/neogenesis, and proton pump inhibitors (PPIs) have been shown to increase endogenous gastrin levels in animals and humans. Therefore, we investigated the effect of PPIs in a model of type 2 diabetes, Psammomys obesus.. P. obesus (morning blood glucose [mBG] 16.9 +/- 0.6 mmol/l) were treated with vehicle or different doses (1-15 mg/kg) of lansoprazole for 17 days.. Treatment with lansoprazole resulted in up to ninefold dose-dependent increases in endogenous gastrin levels (p < 0.05 for 10 mg/kg lansoprazole vs vehicle). There was a significant reduction in mBG levels in all animals in the high-dose lansoprazole groups during the 17 day treatment period, whereas there was no significant improvement in mBG in animals in the vehicle groups. The mBG at end of study was 18.2 +/- 2.1, 8.7 +/- 2.2 (p < 0.01), and 6.1 +/- 2.3 (p < 0.001) mmol/l for vehicle and lansoprazole 10 and 15 mg/kg, respectively. The animals treated with 15 mg/kg lansoprazole, compared with vehicle, had a 2.3-fold increase in the intensity of insulin staining in beta cells (p=0.0002) and 50% higher beta cell mass (p=0.04).. The PPI lansoprazole had significant glucose-lowering effects in an animal model of type 2 diabetes, an effect that is most likely mediated through an increase in endogenous gastrin levels.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Analysis of Variance; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gastrins; Gerbillinae; Hyperglycemia; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Lansoprazole; Male; Proton Pump Inhibitors

Type 1 and type 2 diabetes are characterised by a beta cell deficit. Islet hyperplasia has been described in patients with Zollinger-Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta cell formation (beta cell replication and islet neogenesis) increased and beta cell apoptosis decreased in pancreas specimens from gastrinoma cases?. Pancreas was obtained at surgery from four patients with Zollinger-Ellison syndrome caused by pancreatic gastrinomas and 15 control subjects at autopsy.. Islet fractional beta cell area (p<0.001), islet size (p<0.001) and beta cell replication (Ki67 staining) (p<0.05) were increased in islets adjacent to the tumours, but not in tumour-distant pancreas, compared with control subjects. We did not observe any differences in beta cell apoptosis or in the number of insulin-positive cells in ducts either adjacent to or distant from the tumour.. One or more factors released by human gastrinomas increase beta cell replication in islets immediately adjacent to the tumour, but not in tumour-distant islets. While these findings demonstrate that adult human beta cells can be driven into the cell cycle, they caution against the therapeutic usefulness of gastrin, since islets located >1 cm away from the gastrinomas did not exhibit changes in beta cell turnover, despite markedly elevated systemic gastrin levels sufficient to cause severe gastrointestinal symptoms.

Topics: Body Mass Index; Cell Division; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gastrinoma; Gastrins; Humans; Insulin-Secreting Cells; Islets of Langerhans; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

We explored the hypothesis that meal-regulated release of insulin from gastric G cells can be used for gene therapy for diabetes. We generated transgenic mice in which the coding sequence of human insulin has been knocked into the mouse gastrin gene. Insulin was localized specifically to antral G cells of G-InsKi mice by double immunofluorescence staining using antibodies against insulin and gastrin. Insulin extracted from antral stomach of G-InsKi mice decreased blood glucose upon injection into streptozotocin-diabetic mice. Intragastric administration of peptone, a known potent luminal stimulant of gastrin secretion, induced an increase in circulating levels of transgenic human insulin from 10.7 +/- 2 to 23.3 +/- 4 pm in G-InsKi mice. Although G cell-produced insulin decreased blood glucose in G-InsKi mice, it did not cause toxic hypoglycemia. Proton pump inhibitors, pharmacological agents that increase gastrin output, caused a further increase in the circulating levels of gastric insulin (41.5 +/- 2 pm). G cell-produced insulin was released into circulation in response to the same meal-associated stimuli that control release of gastrin. The most striking aspect of the results presented here is that in the presence of the G-InsKi allele, Ins2(Akita/+) mice exhibited a marked prolongation of life span. These results imply that G cell-derived transgenic insulin is beneficial in the amelioration of diabetes. We suggest that an efficient G cells-based insulin gene therapy can relieve diabetic patients from daily insulin injections and protect them from complications of insulin insufficiency while avoiding episodes of toxic hypoglycemia.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Gastric Mucosa; Gastrin-Secreting Cells; Gastrins; Genetic Therapy; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Mice; Mice, Inbred C57BL; Mice, Transgenic

Cholecystokinin (CCK) and gastrin (G) and their receptors (CCK1 and CCK2) are involved in multiple physiological functions. Notably, CCK1R plays a role in the regulation of food intake whereas both CCK1R and CCK2R play a role in the regulation of pancreatic endocrine function. CCK1R and CCK2R may therefore serve as pharmacological targets in diabetes and obesity and genes encoding these receptors may be candidate genes in the pathogenesis of the diseases. In this study, we used single nucleotide polymorphism analysis and allele specific amplification for mutation screening of the CCK2 receptor gene and family linkage study. Mutated receptors were constructed, expressed in COS-7 cells for analysis of their binding and functional properties. V125I-CCK2 receptor variant was found in 2 out of 18 type 2 diabetes mellitus families tested. V125I mutation co-segregated in those 2 initial families, but further association studies showed that this mutation was not associated with diabetes or early age at diagnosis of the disease. V125I-CCK2 receptor high affinity sites exhibited a 2-fold enhanced binding affinity for CCK which was correlated to a slightly increased potency in coupling to inositol phosphate production. Since CCK2 receptor is expressed in pancreatic glucagon-producing cells in humans and is involved in secretion of glucagon, an increase of binding affinity of the mutated CCK2 receptor could enhance glucagon secretion in patients bearing V125I mutation. We also characterized a mutant of the CCK1 receptor which was previously identified in an obese patient. This mutant, V365I-CCK1, demonstrated a decreased level of expression (26%) and efficacy (25%) to stimulate inositol phosphates. It can therefore be expected that in humans bearing V365I mutation, decreases in CCK1 receptor expression and coupling efficiency may affect CCK-induced regulation of satiety. Polymorphism or mutations in the CCK receptors may be involved in type 2 diabetes mellitus and obesity. However, further studies are necessary to precisely evaluate this role in humans.

Topics: Amino Acid Sequence; Binding Sites; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA Primers; Gastrins; Gene Frequency; Genetic Linkage; Genotype; Humans; Inositol Phosphates; Middle Aged; Molecular Sequence Data; Mutagenesis, Site-Directed; Obesity; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

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

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastrins; Glucagon; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Reference Values; Tryptophan

Serum levels of gastrin, somatostatin and vasoactive intestinal polypeptide were evaluated in 105 noninsulin dependent diabetics (25 of them had a pyloric dysfunction). The serum levels were determined by RIA and blood was taken before and after the test meal. The basal gastrin level was significantly higher in patients with the pyloric dysfunction (p < 0.001). 45 minutes later the serum levels of vasoactive intestinal polypeptide and somatostatin were significantly higher in diabetics with the pyloric dysfunction (p < 0.001). The serum levels of gastrin, somatostatin and vasoactive intestinal polypeptide were impaired in diabetics with the pyloric dysfunction and might be associated with its pathogenesis.

Topics: Diabetes Mellitus, Type 2; Eating; Female; Gastric Emptying; Gastrins; Gastrointestinal Motility; Humans; Male; Middle Aged; Pylorus; Somatostatin; Vasoactive Intestinal Peptide

A 48-year-old woman with type II diabetes developed fatigue, arthralgia and myalgia. A few weeks later she was found to have hepatomegaly. The erythrocyte sedimentation rate was raised (53/93 mm), as were liver enzyme activities (GOT 186 U/l; GPT 240 U/l; gamma-GT 199 U/l), the gamma-globulin levels (40.7%;IgG 4470 mg/dl, IgA 698 mg/dl, IgM 245 mg/dl), antinuclear antibodies and antibodies against double-strand DNA, smooth muscles and actin. Laparoscopy revealed small-nodular liver cirrhosis. The autoimmune hepatitis was treated with prednisolone (initially 60 mg daily, then reduced to 10 mg daily) and azathioprine (initially 100 mg daily, reduced to 50 mg daily). The symptoms markedly improved. But one year later, during follow-up examination, gastric polyps were found, excised and histologically found to be carcinoid. The gastrin level was raised to 765 pg/ml. Another year later the liver cirrhosis had advanced further and the type A gastritis was still present, but there was no sign of carcinoid recurrence.

Topics: Autoimmune Diseases; Azathioprine; Carcinoid Tumor; Cholangiopancreatography, Endoscopic Retrograde; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Endoscopy, Digestive System; Female; Follow-Up Studies; Gastrins; Gastritis; Hepatitis; Humans; Liver Cirrhosis; Middle Aged; Prednisolone; Stomach Neoplasms

Basal and postprandial levels of gastrin, somatostatin, vasoactive intestinal polypeptide (VIP) and pancreatic polypeptide (PP) were followed up in 105 patients with non insulin dependent diabetes mellitus (20 with autonomic neuropathy only, 35 with peripheric neuropathy only, 30 with autonomic and peripheric neuropathy simultaneously and 20 without any sign of neuropathy) and in the control group of 40 individuals. Serum levels of gastrin, somatostatin, VIP and PP are determined by a RIA (used kits of Prof. SR Bloom, Hammersmith Hospital, London). The results of investigation showed significantly higher basal and postprandial levels of gastrin and VIP in patients with autonomic neuropathy in comparison with the group without neuropathy and with the control group (p < 0.001). The serum levels of somatostatin did not differ significantly between the groups of diabetics with and without neuropathy. Basal level of PP was significantly lower and postprandial PP levels remained low in patients with autonomic neuropathy in comparison with the group without neuropathy (p < 0.001). We postulate that basal and postprandial gastrin and VIP levels raised secondary to partial vagotomy in diabetics with autonomic neuropathy. Measuring PP serum levels in diabetics after a protein rich meal can be useful to check vagus nerve function in the gastrointestinal tract in order to detect autonomic neuropathy.

Topics: Adult; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Gastrins; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide

Relationship of the lipoprotein(a) [Lp(a)] concentration as a risk factor independent of other factors with the severity of diabetic retinopathy were evaluated by multiple regression analysis. The subjects were 158 patients with non-insulin-dependent diabetes mellitus (NIDDM). Multiple regression analysis was carried with the severity of diabetic retinopathy as the dependent variable and 13 independent variables, namely the Lp(a) concentration, sex, age, body mass index, duration of diabetes, ischemic heart disease, fasting plasma glucose, glycosylated hemoglobin A1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, anti-diabetic treatments, and diabetic nephropathy. The analysis was performed separately in all subjects, males only, and females only. The standard partial regression coefficient of Lp(a) was significant (0.293, p < 0.01), and the multiple correlation coefficient was 0.611 in the males. However, the standard partial correlation coefficient of Lp(a) was not significant in all patients and in females only. The rank of contribution of Lp(a) to retinopathy was the third in males, following triglyceride and nephropathy and followed by anti-diabetic treatments. These results suggest that Lp(a) might be an independent risk factor for diabetic retinopathy in male patients with NIDDM.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Gastrins; Humans; Lipoprotein(a); Male; Middle Aged; Regression Analysis; Risk Factors; Sex Characteristics

Gastric emptying time was measured by ultrasonography in 18 NIDDM patients with and without autonomic neuropathy, evaluated by cardiovascular autonomic tests and in 10 controls before and after a physiologic test meal. Six neuropathic subjects showed gastrointestinal symptoms such as fullness and early satiety. Blood glucose, gastrin and pancreatic polypeptide were evaluated before and up to 200 min after the test meal. The gastric emptying rate was similar in controls (275 +/- 45 min) and in diabetic patients without (260 +/- 49 min) and with autonomic neuropathy (257 +/- 48 min) (p = ns), while diabetic symptomatics showed a significant reduction of gastric emptying rate (420 +/- 19.7 min) (p less than 0.001). Basal serum glucose concentration was similar in all diabetic patients (132 +/- 18 mg/dl, 166 +/- 52 mg/dl, 161 +/- 61 mg/dl, p = ns). A basal value of serum gastrin was similar in all groups while the test meal produced a rise with a peak at 40' significantly higher only in symptomatics (195 +/- 58 pg/ml vs control 107 +/- 88 pg/ml, diabetics without and with autonomic neuropathy: 98 +/- 12 pg/ml and 88 +/- 22 pg/ml respectively; p less than 0.01). Basal and stimulated PP values were similar in all groups. In conclusion ultrasonography is a simple, reliable method to evaluate gastric emptying rate without any interference in the mechanism of digestion and absorption of nutrients. The presence of non specific symptoms, such as nausea and gastric fullness, may indicate an early gastric involvement as supported by sonographic evidence of impaired emptying.

Topics: Adult; Analysis of Variance; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Eating; Gastric Emptying; Gastrins; Heart Rate; Humans; Kinetics; Middle Aged; Pancreatic Polypeptide; Reference Values; Time Factors

Xanthan gum (12 g/day) was fed in muffins during either the first or second half of a 12-wk period of muffin feeding, to free-living subjects. Nine subjects were diabetic, having moderately elevated serum glucose but managing without insulin or hypoglycemic drugs, and four were nondiabetic controls. Before the study and at the end of the xanthan and xanthan-free periods, bloods were taken before and 2 h after an oral glucose load. The feeding of xanthan gum lowered fasting and postload serum glucose and reduced fasting levels of total plasma cholesterol in diabetic subjects. Xanthan gum also tended to lower fasting and postload levels of gastrin and gastric inhibitory polypeptide (GIP) and fasting levels of total and VLDL triglyceride and cholesterol in VLDL and LDL fractions. Subjects reported a sense of fullness after consuming xanthan muffins but no severe digestive symptoms.

Topics: Adult; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Fasting; Female; Food Additives; Gastric Inhibitory Polypeptide; Gastrins; Humans; Lipoproteins; Male; Middle Aged; Polysaccharides, Bacterial; Triglycerides