gastrins and Diabetes-Mellitus--Type-1

Topics: Allylamine; Animals; Blood Glucose; Bromocriptine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Metformin; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; United States

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

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

Transgenic expression of gastrin and EGF receptor ligands stimulates islet neogenesis in adult mice, significantly increasing islet mass. The present study aimed to determine whether pharmacological treatment with gastrin and EGF can significantly stimulate beta-cell regeneration in chronic, severe insulin-dependent diabetes. Diabetes was induced by intravenous streptozotocin, resulting in >95% beta cell destruction. Four weeks later, blood glucose levels were restored to normal range by exogenous insulin therapy and rats were treated with EGF/gastrin in combination, gastrin alone, or EGF alone given subcutaneously. After 14 days treatment blood glucose was significantly lower in the EGF/gastrin group compared to the untreated diabetic controls. Along with improved glucose tolerance, EGF/gastrin treatment significantly increased plasma C peptide and pancreatic insulin content compared to diabetic controls. Histological analysis showed that EGF/gastrin treatment significantly increased beta-cell mass as determined by point counting morphometrics. The EGF/gastrin group had a significantly greater number of BrdU labelled beta-cells/section consistent with stimulation of beta-cell replication or neogenesis. An increased number of gastrin receptor positive cells were observed in the EGF/gastrin-treated groups. In contrast to the effectiveness of the EGF/gastrin combination, neither gastrin nor EGF alone improved glucose tolerance in severely streptozotocin-diabetic rats. These studies indicate that physiologically significant improvement in glucose tolerance can be achieved through stimulating beta-cell regeneration with gastrin/EGF administered systemically as conventional pharmacological therapy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Combinations; Epidermal Growth Factor; Gastrins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Rats; Receptors, Cholecystokinin

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

Progressive destruction of pancreatic islet β-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional β-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide hormone that is produced by intestinal cells and foetal islets and can increase β-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycaemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycaemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with the protection of, and/or higher frequencies of, insulin-producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gastrins; Islets of Langerhans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD

The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed.. To investigate CgA utility as a marker of endocrine autoimmunity.. CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology.. Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy participant controls (C), the odds of positive CgA measurement were up to 28 times higher in the disease groups. In detail, the odds ratios (ORs) for positive CgA levels were 27.98, 15.22, 7.32 (all P < 0.0001) and 3.89 (P = 0.0073) in patients with NET, T1D, AG, and AP, respectively. In AG, CgA and serum gastrin correlated positively (r = 0.55; P < 0.0001). The area under the receiver operating characteristic curve to predict AG was higher for parietal cell antibody (PCA) positivity than for CgA (0.84 vs 0.67; P < 0.0001). However, in combination with PCA and intrinsic factor autoantibodies, CgA independently improved prediction of AG (OR 6.5; P = 0.031). An impact of age on CgA positivity and on CgA value was detected (P < 0.0001) while current smoking significantly increased CgA serum levels by 25% (P = 0.0080).. CgA qualifies as a novel biomarker for T1D, AP, and AG.

Topics: Adolescent; Adult; Aged; Autoantibodies; Autoimmunity; Biomarkers; Chromogranin A; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Gastrins; Gastritis; Healthy Volunteers; Humans; Male; Middle Aged; Neuroendocrine Tumors; Polyendocrinopathies, Autoimmune; Predictive Value of Tests; ROC Curve; Young Adult

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9

Topics: Animals; Autoimmunity; Blood Glucose; Cell Transdifferentiation; Chimerism; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Female; Gastrins; Gene Expression Regulation; Glucagon; Glucagon-Secreting Cells; Insulin; Insulin-Secreting Cells; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Precursor Cells, B-Lymphoid; Regeneration

Topics: Adult; Diabetes Mellitus, Type 1; Female; Gastric Mucosa; Gastrins; Gastrointestinal Agents; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Incretins; Male; Postprandial Period; Research Design; Secretory Pathway; Stomach

Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT.. A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B12, anti-parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophagogastroduodenoscopy-obtained biopsies.. Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity × specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B12 levels (96.1% specificity).. Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up.

Topics: Adult; Aged; Biomarkers; Chromogranin A; Diabetes Mellitus, Type 1; Enterochromaffin-like Cells; Female; Gastrins; Hashimoto Disease; Humans; Hyperplasia; Longitudinal Studies; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Risk Factors; ROC Curve; Sensitivity and Specificity; Stomach; Stomach Diseases

Over the past decade, many immune tolerance agents have shown promise in the non-obese diabetic mouse model for prevention and reversal of type 1 diabetes but have not been successful in clinical trials among recently diagnosed type 1 patients. The trials from decades ago using Cyclosporine A in significantly lower dosages than used for organ transplantation and in similar dosages that have increased T regulatory cell populations in conditions such as atopic dermatitis, demonstrated very high initial insulin-free remission rates when administered immediately after diagnosis. Over time, all newly diagnosed type 1 patients given Cyclosporine A required insulin. Human trials with immune tolerance agents suggest that in addition to an immune tolerance agent, a beta cell regeneration agent may also be necessary to induce long-lasting remission among patients with recent onset type 1 diabetes.. A randomized, double-blind prospective trial among recent onset type 1 diabetes patients has been designed using Cyclosporine A and a proton-pump inhibitor, which increases gastrin levels and has been shown to work through the Reg receptor to transform pancreatic duct cells into islets.

Topics: Animals; Cyclosporine; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Gastrins; Humans; Immune Tolerance; Insulin-Secreting Cells; Lansoprazole; Mice; Pancreatic Ducts; Prospective Studies; Proton Pump Inhibitors; Regeneration; Species Specificity

The aim of this study was to investigate whether combined epidermal growth factor (EGF) and gastrin can correct the hyperglycemia induced by streptozotocin (STZ) in rats and to determine the involvement of the transcription factor pancreatic and duodenal homeobox 1 (PDX1) in this process.. Rat diabetes was induced by intraperitoneal injection of STZ. The mRNA and protein levels of insulin and PDX1 were determined by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Serum levels of C-peptide and insulin were analyzed using radioimmunoassay kits.. The combined administration of EGF and gastrin efficiently reversed the hyperglycemia induced by STZ. Elevated insulin concentration was detected in diabetic rats treated with EGF plus gastrin. The authors also found that both insulin and PDX1 expression were reduced in STZ-treated rats. Interestingly, the combination treatment also significantly enhanced the mRNA levels of insulin and PDX1, and that of their protein products.. Therapy with EGF plus gastrin corrected hyperglycemia and maintained insulin content in STZ-induced diabetic rats via up-regulation of PDX1 expression, suggesting that this combination treatment may provide a valuable approach for pancreatic islet neogenesis in vivo.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Combinations; Epidermal Growth Factor; Gastrins; Homeodomain Proteins; Humans; Hyperglycemia; Injections, Subcutaneous; Insulin; Islets of Langerhans; Male; Radioimmunoassay; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trans-Activators

Type 1 diabetes (T1D) results from an autoimmune destruction of insulin-producing β cells. Currently, islet transplantation is the only curative therapy for late-stage T1D, but the beneficial effect is limited in its duration, even under chronic immunosuppression, because of the chronic graft rejection mediated by both auto- and alloimmunity. Clinical islet transplantation is also restricted by a severe shortage of donor islets. Induction of mixed chimerism reverses autoimmunity, eliminates insulitis, and reverses new-onset but not late-stage disease in the nonobese diabetic (NOD) mouse model of T1D. Administration of gastrin and epidermal growth factor (EGF) also reverses new-onset but not late-stage T1D in this animal model. Here, we showed that combination therapy of induced mixed chimerism under a radiation-free nontoxic anti-CD3/CD8 conditioning regimen and administration of gastrin/EGF augments both β cell neogenesis and replication, resulting in reversal of late-stage T1D in NOD mice. If successfully translated into humans, this combination therapy could replace islet transplantation as a long-term curative therapy for T1D.

Topics: Animals; Combined Modality Therapy; Diabetes Mellitus, Type 1; Disease Models, Animal; Epidermal Growth Factor; Female; Gastrins; Humans; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Regeneration; Translational Research, Biomedical; Transplantation Chimera; Transplantation Conditioning

Parietal cell antibodies (PCA) are markers of autoimmune gastritis (AG). AG can lead to hypergastrinemia and iron-deficiency anaemia (IDA). Compared to healthy controls, adults with type 1 diabetes mellitus (T1DM) show a higher prevalence of PCA (1% vs 20%). The aim of the present study was to evaluate the frequency of PCA in children and adolescents with T1DM compared to healthy controls and the clinical and biochemical markers.. We studied 170 patients (87 boys) with T1DM (mean age 12.9 years) and 101 healthy controls (49 boys; mean age 13.0 years). PCA, free T4, free T3, thyroid-stimulating hormone (TSH), and thyroid antibodies were measured in all of the patients. In addition, gastrin, pepsinogen I, iron, ferritin, vitamin B12, and folate were measured in patients with T1DM only. Gastroscopy was carried out in patients with T1DM having high (>100 U/mL) PCA levels.. The frequency of PCA in patients with T1DM was 5.29% compared to 1.98% in healthy controls (not significant). PCA was strongly correlated to both thyroid peroxidase antibodies (TPOAb) and gastrin levels (P = 0.001). IDA was present in 4 of 9 patients from the PCA-positive group compared to 4 of 160 patients from the PCA-negative group. Hypergastrinemia was found in 2 PCA-positive patients. Histopathologically, 1 of 4 patients showed early symptoms of AG.. Children and adolescents with T1DM have a lower frequency of PCA than is reported for adults. Compared to healthy controls, they seem to be at increased risk for developing PCA, in particular if positive for TPOAb, but overt clinical disease is rare in children with T1DM.

Topics: Adolescent; Anemia, Iron-Deficiency; Autoantibodies; Biomarkers; Diabetes Mellitus, Type 1; Female; Gastrins; Gastritis; Humans; Iodide Peroxidase; Male; Parietal Cells, Gastric; Prevalence; Reference Values

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Female; Gastrins; Mice; Mice, Inbred NOD

Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic beta-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the beta-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.. Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and beta-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.. Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, beta-cell mass, and insulin-positive cells in pancreatic ducts, and beta-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1- and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1 -and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-gamma to transforming growth factor-beta1, and beta-cells were protected from apoptosis.. Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic beta-cell mass and downregulating the autoimmune response.

Topics: Animals; Apoptosis; Autoantibodies; Blood Glucose; Cell Division; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Gastrins; Glucagon-Like Peptide 1; Injections, Intraperitoneal; Insulin Antibodies; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Reference Values

The precise fate of beta cells and the presence of islet infiltrates after onset of type 1 diabetes have not yet been fully characterized. Recently we showed that in newly diabetic NOD mice an appreciable number of beta cells remain. This was also observed during the first 2 weeks of diabetes in NOD mice without treatment with insulin. However, the mean number of beta cells per unit islet cross-sectional area decreased with increasing duration of disease. In contrast, glucagon and somatostatin cell numbers showed an increase. The persistence of insulitis in several islets until 4 weeks of diabetes suggests ongoing beta cell autoimmunity over a protracted phase. Combined daily treatment of newly diabetic NOD mice with epidermal growth factor (EGF) and gastrin for the first 14 days of diabetes resulted in temporary restoration of normoglycemia in 7 of 15 mice. We speculate that the residual beta cells present soon after onset of diabetes may respond to experimental regeneration. Treatment of newly diabetic NOD mice with the bioactive peptides EGF and gastrin resulted in partial and temporary reversal of diabetes. We propose that peptide therapies combined with other benign immunomodulatory approaches to rescue and preserve beta cells in the long term and to prevent recurring autoimmunity may be more effective than peptide therapy alone in reversing diabetes in NOD mice.

Topics: Age Factors; Age of Onset; Animals; Autoimmunity; Diabetes Mellitus, Type 1; Disease Progression; Drug Evaluation, Preclinical; Epidermal Growth Factor; Female; Gastrins; Hypoglycemic Agents; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Inbred NOD; Peptides; Remission Induction; Time Factors

In a previous study, we observed that combination therapy of nonobese diabetic (NOD) mice with epidermal growth factor (EGF) and gastrin partially restored pancreatic islet beta-cell mass and reversed hyperglycemia without the use of immunotherapy. Herein we have studied the effects of EGF plus gastrin on recurrent autoimmune responses in diabetic NOD mice transplanted with syngeneic islets. EGF (10 microg/kg) plus gastrin (30 microg/kg) given intraperitoneally (i.p.) once daily to diabetic NOD mice (blood glucose, 23 +/- 2 mmol/L) significantly prolonged the median survival time of NOD islet grafts to 60 days (n = 10 mice) measured as the days until hyperglycemia recurrence (blood glucose > or =12 mmol/L; versus EGF alone to 36 days (n = 10), or gastrin alone, 19 days (n = 10), or vehicle, 11 days (n = 9). At 7-14 days after transplantation insulin-stained beta-cells were much more numerous in islet grafts of EGF plus gastrin-treated mice (13.0 +/- 0.9 x 10(5) cells) versus grafts in vehicle-treated mice (1.0 +/- 0.3 x 10(5) cells). CD45+ leukocytes were significantly reduced in number and surrounded but did not destroy the beta cells in the islets of EGF plus gastrin-treated mice (29 +/- 2 x 10(5) cells) versus those in vehicle-treated mice (57 +/- 3 x 10(5) cells). We concluded that the EGF plus gastrin combination therapy inhibited the recurrent autoimmune response and delayed rejection of syngeneic islet grafts, suggesting a therapeutic role for these peptides in islet transplantation.

Topics: Animals; Combined Modality Therapy; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Epidermal Growth Factor; Female; Gastrins; Immunohistochemistry; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Leukocyte Count; Mice; Mice, Inbred NOD; Subrenal Capsule Assay; Transplantation, Isogeneic

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

Combination therapy with epidermal growth factor (EGF) and gastrin induces beta-cell regeneration in rodents with chemically induced diabetes. We investigated whether EGF plus gastrin could correct hyperglycemia in NOD mice with autoimmune diabetes. Combined treatment with EGF (1 mug/kg) and gastrin (3 mug/kg) for 2 weeks restored normoglycemia after diabetes onset in NOD mice, whereas EGF or gastrin alone did not. Fasting blood glucose remained normal (3.5-6.5 mmol/l) or mildly elevated (<11 mmol/l) in five of six mice (83%) for 10 weeks after EGF plus gastrin treatment was stopped, whereas all mice treated with vehicle or EGF or gastrin alone became severely hyperglycemic (12-35 mmol/l). Pancreatic beta-cell mass was increased threefold and insulin content was increased eightfold in mice treated with EGF plus gastrin compared with pretreatment values. The correction of hyperglycemia correlated significantly with increases in pancreatic beta-cell mass and insulin content. In addition, splenic cells from mice treated with EGF plus gastrin delayed diabetes induction by adoptive transfer of diabetogenic cells into immunodeficient NOD-scid mice, suggesting the induction of immunoregulatory cells in NOD mice treated with EGF plus gastrin. We conclude that a short course of combined EGF and gastrin therapy increases pancreatic beta-cell mass and reverses hyperglycemia in acutely diabetic NOD mice; the impact of this combined therapy may result from the effects of EGF and gastrin on beta-cells, immune cells, or both.

Topics: Animals; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Epidermal Growth Factor; Female; Gastrins; Hyperglycemia; Islets of Langerhans; Mice; Mice, Inbred NOD

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Gastrins; Growth Substances; Humans; Islets of Langerhans; Mice; Regeneration

Topics: Abdominal Pain; Adrenal Gland Neoplasms; Diabetes Mellitus, Type 1; Esophageal Stenosis; Gastrins; Humans; Hypercalcemia; Male; Middle Aged; Zollinger-Ellison Syndrome

Previous studies have shown a high prevalence of gastric parietal cell antibodies (PCA) in type 1 diabetes, which can be accompanied by (sub)clinical autoimmune gastric disease. This study aimed to determine the grade of associated autoimmunity and to assess the pattern of prevalence of PCA by gender, age, duration of disease, age at onset of diabetes, and human leukocyte antigen (HLA) type in an adult type 1 diabetic population. Furthermore, to examine the clinical significance of being PCA positive, manifestations of gastric autoimmune disease were studied in PCA-positive and PCA-negative patients. The population studied consisted of 497 type 1 diabetics (men/women, 252/245; mean age, 40.8 +/- 12.1 yr; mean duration of disease, 16.4 +/- 10.4 yr; mean age at onset, 26.9 +/- 13.5 yr; mean hemoglobin A1c, 8.1 +/- 1.6%). Associated autoantibodies were present in 39% and PCA were present in 20.9% of the subjects, particularly in older patients. Gender, duration, and age at onset of diabetes did not influence the appearance of PCA. Antithyroid peroxidase antibodies (aTPO) were more frequent in PCA-positive patients than in those without PCA (33.6% vs. 22.4%; P = 0.025), suggesting an association between gastric and thyroid autoimmunity. We could demonstrate an association between PCA and the HLA DR5 haplotype (P = 0.001) as well, but not with HLA DR3 and/or DR4. In the PCA-positive group, iron deficiency anemia was detected in 15.4%, and pernicious anemia was found in 10.5% of subjects. These autoimmune gastric manifestations were significantly more prevalent in PCA-positive diabetics than in PCA-negative subjects, in whom the percentages were 6.9% and 0.5%, respectively (P = 0.01 and P < 0.0001). PCA were prevalent in 84.6% of patients with pernicious anemia. A gastroscopic and anatomopathological examination performed in a subgroup of 30 patients with gastric symptoms revealed atrophic gastritis in 13 of 14 PCA-positive patients and in 9 of 16 PCA-negative subjects (P = 0.04). PCA were present in 59.1% of patients with atrophic gastritis. In conclusion, a high prevalence of parietal cell antibodies and associated autoimmune gastric disease is present in PCA-positive type 1 diabetics, recommending its screening. Early detection of PCA and iron deficiency anemia, pernicious anemia, and atrophic gastritis and the subsequent care could reduce the morbidity of type 1 diabetes.

Topics: Adult; Aging; Anemia, Pernicious; Autoantibodies; Autoimmune Diseases; Diabetes Mellitus, Type 1; Female; Gastrins; Gastritis, Atrophic; Glycated Hemoglobin; HLA-DR1 Antigen; Humans; Iron; Male; Middle Aged; Parietal Cells, Gastric; Risk Factors; Sex Characteristics

Overt diabetic gastroparesis is a rare long-term complication of diabetes, probably resulting from autonomic neuropathy of vagus nerve. It is now clear that neural damage plays a pivotal role in the pathogenesis of the disease. Some studies showed high basal gastrin levels in patients with diabetic gastroparesis, but the clinical meaning of this observation is still unclear. We report the case of a young woman with Insulin Dependent Diabetes Mellitus (IDDM) who was referred to evaluate nausea and vomiting associated to ketoacidosis. Our hypothesis of autonomic neuropathy with gastroparesis was confirmed. We observed a progressive increase in fasting gastrin concentration (20-fold normal values) in the absence of any clinical and laboratory signs of Zollinger-Ellison (ZE) syndrome. The increasing vomiting induced a severe state of cachexia, which required total parenteral nutrition for a long period. All therapeutic approaches were unsuccessful, and the patient rapidly died, suggesting a possible link between the severity of the clinical picture and the gastrin plasma levels.

Topics: Adult; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 1; Female; Gastrins; Gastroparesis; Hormones; Humans; Hydrogen-Ion Concentration; Radiography; Stomach

The dynamic study of somatostatin secretion was performed in patients with insulin-dependent diabetes mellitus and age- and sex matched volunteers. The basal levels of immunoreactive somatostatin, as well as its response to i.v. Glucagon (1 mg) at 10 and 20 min with consequent hyperglycemia were increased in most of diabetic patients as compared with the healthy controls. Our results suggest that the glucagon test could be used for estimating the somatostatin secretion in diabetes mellitus. This would reveal some impaired interactions between the endocrine function of the pancreas in diabetes mellitus.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cross Reactions; Diabetes Mellitus, Type 1; Female; Gastrins; Glucagon; Humans; Insulin; Radioimmunoassay; Somatostatin

Tolbutamide significantly decreased fasting plasma gastrin after 5 min of intravenous infusion in patients with atrophic gastritis, duodenal ulcer, or insulin-dependent diabetes mellitus (IDDM) as well as in healthy volunteers. Increased plasma insulin and decreased blood glucose were observed in patients with atrophic gastritis, duodenal ulcer and healthy volunteers, but not in patients with IDDM. Suppression of plasma gastrin in healthy volunteers was also observed following oral administration of tolbutamide. Despite the observed decrease in plasma gastrin, neither basal nor tetragastrin-stimulated acid output was changed for 30 min following tolbutamide infusion in healthy volunteers. Thus, our data suggest that tolbutamide inhibits gastrin release in man via mechanisms independent of changes in plasma insulin, blood glucose or acid secretion.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Drug Administration Routes; Female; Gastric Acid; Gastrins; Gastrointestinal Diseases; Humans; Insulin; Male; Middle Aged; Tolbutamide

In 40 patients with insulin-dependent diabetes mellitus, the number of gastrin cells in the mucous membrane of the antrum of the stomach was measured by immunohistochemistry according to the method of L. Sternberger. The number of the cells depended on the gravity of antral gastritis, namely their number decreased as the lesion was aggravated. The basal level of serum gastrin was determined by radioimmunoassay in 144 patients with insulin-dependent diabetes mellitus. The high basal level of gastrin was recorded in patients with achlorhydria. However, no correlation was established between the gravity of antral gastritis and the basal level of serum gastrin. If the basal gastrin level is too high, the possibility of asymptomatic paresis of the stomach should be taken into account together with the other factors.

Topics: Achlorhydria; Adult; Biopsy; Cell Count; Diabetes Mellitus, Type 1; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Immunoenzyme Techniques; Male; Middle Aged

Topics: Adolescent; Autoantibodies; Child; Diabetes Mellitus, Type 1; Female; Gastrins; Humans; Male; Pepsinogens; Stomach; Thyroid Gland

Circulating parietal cell antibodies (PCA) were fund in 8 (5.4%) out of 147 diabetic children screened. Both sexes were equally represented, but the titres were higher in the girls. No clear relationship between the presence of these antibodies and age or the duration of diabetes was observed. Gastric studies were performed on 8 children with PCA (group A) and 41 without PCA (group B). Both basal (BAO) and maximal acid output (MAO) were significantly (p < 0.05) lower and fasting serum gastrin elevated (p < 0.01) in group A as compared with the control group. Two patients were achlorhydric. In group B, 17 patients out of the 41 studied had hyposecretion and one achlorhydria. The result became most obvious in the group with a duration and diabetes over 10 years, where MAO was significantly diminished (p < 0.05). Gastric morphology revealed atrophic gastritis in 3 patients from seven biopsies in group A and one out five biopsies for severe hyposecretion in group B. Two other children in group A had superficial gastritis. Serum ferritin levels decreased along with the duration of diabetes. Those with gastric mucosa had the lowest values.

Topics: Adolescent; Autoantibodies; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Ferritins; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Male; Time Factors; Vitamin B 12