Transgenic mice which overexpress insulin-like growth factor binding protein-1 (IGFPB-1) demonstrate fasting hyperglycemia, hyperinsulinemia and glucose intolerance in adult life. Here we have examined the ontogeny of pancreatic endocrine dysfunction and investigated islet cell proliferation and apoptosis in this mouse model. In addition we have examined pancreatic insulin content in transgenic mice derived from blastocyst transfer into non-transgenic mice. Transgenic mice were normoglycemic at birth but had markedly elevated plasma insulin levels, 56.2 +/- 4.5 versus 25.4 +/- 1.5 pmol/l, p < 0.001, and pancreatic insulin concentration, 60.5 +/- 2.5 versus 49.0 +/- 2.6 ng/mg of tissue, P < 0.01, compared with wild-type mice. Transgenic mice derived from blastocyst transfer to wild-type foster mothers had an elevated pancreatic insulin content similar to that seen in pups from transgenic mice. There was an age-related decline in pancreatic insulin content and plasma insulin levels and an increase in fasting blood glucose concentrations, such that adult transgenic mice had significantly less pancreatic insulin than wild-type mice. Pancreatic islet number and the size of mature islets were increased in transgenic animals at birth compared with wild-type mice. Both islet cell proliferation, measured by 5-bromo-2'-deoxyuridine labeling, and apoptosis, assessed by the in situ terminal deoxynucleotidyl transferase and nick translation assay, were increased in islets of newborn transgenic mice compared with wild-type mice. In adult mice both islet cell proliferation and apoptosis were low and similar in transgenic and wild-type mice. Islets remained significantly larger and more numerous in adult transgenic mice despite a reduction in pancreatic insulin content. These data suggest that overexpression of IGFBP-1, either directly or indirectly via local or systemic mechanisms, has a positive trophic effect on islet development.
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- Abstract: Diabetes x
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- Abstract: Glucagon x
- Abstract: IGF* x
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ST Dheen, K Rajkumar, and LJ Murphy
SJ Conroy, I Green, G Dixon, PM Byrne, J Nolan, YH Abdel-Wahab, N McClenaghan, PR Flatt, and P Newsholme
We have previously reported that newly diagnosed Type-1 diabetic patient sera potently suppressed insulin secretion from a clonal rat pancreatic beta-cell line (BRIN BD11) but did not alter cell viability. Here, we report that apoptosis in BRIN BD11 cells incubated in various sera types (fetal calf serum (FCS), normal human serum and Type-1 diabetic patient) was virtually undetectable. Although low levels of necrosis were detected, these were not significantly different between cells incubated in sera from different sources. ATP levels were reduced by approximately 30% while nitrite production increased twofold from BRIN BD11 cells incubated for 24 h in the presence of Type-1 diabetic patient sera compared with normal human sera. Additionally, ATP levels were reduced by approximately 40% and DNA fragmentation increased by more than 20-fold in BRIN BD11 cells incubated in FCS in the presence of a pro-inflammatory cytokine cocktail (interleukin-1beta, tumour necrosis factor-alpha and interferon-gamma), compared with cells incubated in the absence of cytokines. Nitric oxide production from BRIN BD11 cells was markedly increased (up to 10-fold) irrespective of sera type when the cytokine cocktail was included in the incubation medium. Type-1 diabetic patient sera significantly (P<0.001) raised basal levels of intracellular free Ca(2+ )concentration ([Ca(2+)](i)) in BRIN BD11 cells after a 24-h incubation. The alteration in [Ca(2+)](i) concentration was complement dependent, as removal of the early complement components C1q and C3 resulted in a significant reduction (P<0.01) of sera-induced [Ca(2+)](i )changes. We propose that the mechanism of Type-1 diabetic patient sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement-stimulated elevation of [Ca(2+)](i) which attenuates the nutrient-induced insulin secretory process possibly by desensitizing the cell to further changes in Ca(2+).
Helena A Walz, Linda Härndahl, Nils Wierup, Emilia Zmuda-Trzebiatowska, Fredrik Svennelid, Vincent C Manganiello, Thorkil Ploug, Frank Sundler, Eva Degerman, Bo Ahrén, and Lena Stenson Holst
Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether β-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a β-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located α-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of β-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.
Joshua A Kulas, Kendra L Puig, and Colin K Combs
The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP−/− and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.
K Fosgerau, P Galle, T Hansen, A Albrechtsen, C de Lemos Rieper, B Klarlund Pedersen, L Kongskov Larsen, A Randrup Thomsen, O Pedersen, M Bagge Hansen, and A Steensberg
Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2.5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2.5, 95% confidence interval 1.2–4.9, P=0.01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure. Mice with plasma levels of aAb-IL6 similar to the 2.5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056±62 vs 1793±62, P=0.05) as compared with sham-vaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4.8±0.4 vs 3.3±0.1, P<0.001) and impaired glucose tolerance (AUC glucose, 1340±38 vs 916±25, P<0.001) as compared with sham-control mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2.5-fold in people with type 2 diabetes. In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.
EG Siegel, A Seidenstucker, B Gallwitz, F Schmitz, A Reinecke-Luthge, G Kloppel, UR Folsch, and WE Schmidt
Liver cirrhosis is often accompanied by a disturbed carbohydrate metabolism similar to type 2 diabetes. To investigate the severity of the defect in insulin secretion in this form of diabetes, we measured insulin release from isolated pancreatic islets of rats with CCl(4)-phenobarbital-induced liver cirrhosis. Cirrhosis was confirmed by clinical signs, elevated liver enzymes and histology. Fasting venous plasma glucose concentrations were equal in rats with liver cirrhosis and in controls. Plasma insulin and glucagon concentrations were significantly greater (P<0.01) in cirrhotic rats than in control animals. Glucose (16.7 mM)-induced stimulation of insulin release from pancreatic islets revealed a twofold increase in control and cirrhotic rats. Basal and stimulated insulin secretion, however, were significantly lower in cirrhotic animals. The incretin hormone, glucagon-like peptide-1 (GLP-1), has therapeutic potential for the treatment of type 2 diabetes. Therefore, islets from control and cirrhotic animals were incubated with GLP-1 in concentrations from 10(-)(11) to 10(-)(6) M. GLP-1 stimulated insulin release in a concentration-dependent manner. In islets from cirrhotic rats, basal and stimulated insulin secretion was blunted compared with controls. These data show that the hyperinsulinemia observed in liver cirrhosis is not due to an increase of insulin secretion from islets, but could be explained by decreased hepatic clearance of insulin. GLP-1 may ameliorate diabetes in patients with liver cirrhosis.
Rhonda D Prisby, Joshua M Swift, Susan A Bloomfield, Harry A Hogan, and Michael D Delp
Osteopenia and an enhanced risk of fracture often accompany type 1 diabetes. However, the association between type 2 diabetes and bone mass has been ambiguous with reports of enhanced, reduced, or similar bone mineral densities (BMDs) when compared with healthy individuals. Recently, studies have also associated type 2 diabetes with increased fracture risk even in the presence of higher BMDs. To determine the temporal relationship between type 2 diabetes and bone remodeling structural and mechanical properties at various bone sites were analyzed during pre-diabetes (7 weeks), short-term (13 weeks), and long-term (20 weeks) type 2 diabetes. BMDs and bone strength were measured in the femora and tibiae of Zucker diabetic fatty rats, a model of human type 2 diabetes. Increased BMDs (9–10%) were observed in the distal femora, proximal tibiae, and tibial mid- shafts in the pre-diabetic condition that corresponded with higher plasma insulin levels. During short- and long-term type 2 diabetes, various parameters of bone strength and BMDs were lower (9–26%) in the femoral neck, distal femora, proximal tibiae, and femoral and tibial mid-shafts. Correspondingly, blood glucose levels increased by 125% and 153% during short- and long-term diabetes respectively. These data indicate that alterations in BMDs and bone mechanical properties are closely associated with the onset of hyperinsulinemia and hyperglycemia, which may have direct adverse effects on skeletal tissue. Consequently, disparities in the human literature regarding the effects of type 2 diabetes on skeletal properties may be associated with the bone sites studied and the severity or duration of the disease in the patient population studied.
Benjamin J Lamont and Sofianos Andrikopoulos
Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet β-cells and an increase in β-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase β-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic β-cells, but may be useful for preserving any remaining β-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.
P. F. Terranova, J. Th. J. Uilenbroek, L. Saville, D. Horst, and Y. Nakamura
Preovulatory follicles from adult hamsters on the morning of pro-oestrus were used in this study. Serotonin stimulated oestradiol production by preovulatory follicles during a 5-h incubation in 1 ml Krebs–Ringer bicarbonate glucose medium containing isobutylmethylxanthine (0.1 mmol/l; IBMX) and androstenedione (1 μmol/l). The enhanced oestradiol production by serotonin was dependent on the dose of IBMX and androstenedione. Mianserin, a serotonin type-1 and serotonin type-2 receptor antagonists, prevented the serotonin-enhanced oestradiol production in a dose-dependent manner. Ketanserin, a specific serotonin type-2 receptor antagonist, was ineffective in blocking the action of serotonin, indicating that the effect of serotonin was mediated by the serotonin type-1 receptor. In the presence of androstenedione (1 μmol/l), serotonin was unable to enhance oestradiol production in isolated granulosa cells. It was also unable to enhance oestradiol production in early atretic follicles; atresia was induced experimentally by an injection of phenobarbital in order to prevent ovulation.
The data indicate that serotonin stimulates oestradiol production by hamster preovulatory follicles in vitro. The mechanism of action of serotonin involves an intact healthy follicle, a serotonin type-1 receptor and possibly cyclic AMP. The increased oestradiol secretion might be related to increased androgen production by the follicle and increased permeability (leakiness) of the follicle to androstenedione which serves as substrate for aromatization to oestradiol by the granulosa cell.
Journal of Endocrinology (1990) 125, 433–438
Sachiko Kitanaka, Utako Sato, and Takashi Igarashi
Mutations in hepatocyte nuclear factor-1β (HNF-1β) lead to type 5 maturity-onset diabetes of the young (MODY5). Moreover, mutations in the HNF-1β gene might cause multiorgan abnormalities including renal diseases, genital malformations, and abnormal liver function. The objective of this study was to investigate the molecular mechanism of diabetes mellitus, intrauterine growth retardation, and cholestasis observed in MODY5 patients. We analyzed the transactivity of wild-type and three mutant HNF-1β on native human insulin, IGF-I, and multidrug resistance protein 2 (MRP2) promoters in combination with HNF-1α, using a reporter-assay system in transiently transfected mammalian cells. In the human insulin gene promoter, we found that the cooperation of HNF-1α and HNF-1β is prominent. Absence of this cooperation was observed in all of the HNF-1β mutants. In the human IGF-I and MRP2 promoters, we found that the HNF-1β His153Asn (H153N) mutant had a mutant-specific repressive effect on both HNF-1α and wild-type HNF-1β transactivity. Absence of the cooperation of HNF-1β mutants with HNF-1α in the human insulin gene promoter might be one cause of defective insulin secretion. The H153N mutant-specific repression of HNF-1α and HNF-1β transactivity in human IGF-I and MRP2 promoters might explain the case-specific clinical features of growth retardation and cholestasis observed only in early infancy. We found differential property of HNF-1α/HNF-1β activity and the effect of HNF-1β mutants by the promoters. We consider that analyses of HNF-1β mutants on the intended human native promoters in combination with HNF-1α may be useful in investigating the molecular mechanisms of the various features in MODY5.