RESUMO
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: These data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Gastrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeos/administração & dosagem , Animais , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Gastrinas/agonistas , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Ratos , Ratos ZuckerRESUMO
Antidiabetic treatments aiming to preserve or even to increase ß-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, ß-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of ß-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in ß-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in ß-cell mass observed in the ZP3022-treated mice appeared to be driven by increased ß-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1-gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in ß-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases ß-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.
Assuntos
Gastrinas/agonistas , Peptídeo 1 Semelhante ao Glucagon/agonistas , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Dados de Sequência MolecularRESUMO
AIM: To characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice. METHODS: Blood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology. RESULTS: Total pancreatic beta cell mass increased significantly from 2.1 ± 0.3 mg in mice aged 5 weeks to a peak value of 4.84 ± 0.26 mg (P < 0.05) in 12-week-old mice, then gradually decreased to 3.27 ± 0.44 mg in mice aged 34 weeks. Analysis of islets in the 5-, 10-, and 24-week age groups showed increased beta cell proliferation in the 10-week-old animals whereas a low proliferation is seen in older animals. The expansion in beta cell mass was driven by an increase in mean islet mass as the total number of islets was unchanged in the three groups. CONCLUSIONS/INTERPRETATION: The age-dependent beta cell dynamics in male db/db mice has been described from 5-34 weeks of age and at the same time alterations in insulin/glucose homeostasis were assessed. High beta cell proliferation and increased beta cell mass occur in young animals followed by a gradual decline characterised by a low beta cell proliferation in older animals. The expansion of beta cell mass was caused by an increase in mean islet mass and not islet number.
Assuntos
Células Secretoras de Insulina/metabolismo , Fatores Etários , Animais , Apoptose , Glicemia , Peptídeo C/sangue , Proliferação de Células , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Jejum/sangue , Insulina/sangue , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , CamundongosRESUMO
Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac5c¹, Aib³, Leu8, Gln¹°, Har¹¹, Ala¹², Trp¹4, Asp¹7]PTH(1-17)-NH2), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹7 side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats. To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range.