In the present study, we determined whether expression of the messenger ribonucleic acids (mRNAs) for insulin-like growth factor-II (IGF-II), and its principal IGF type-1 receptor and IGF-binding protein-2 (IGFBP-2), as well as basic fibroblast growth factor (bFGF), was developmentally regulated in the baboon fetal adrenal gland. In the second phase of this study, fetal pituitary ACTH was suppressed by the administration of betamethasone to determine the possible effect on the mRNA levels for those factors, i.e. IGF-II and IGFBP-2, shown to be expressed at high levels in the adrenal late in fetal development. Adrenals were obtained from fetuses delivered via Cesarean section on days 60 (early), 100 (mid), and 165 (late) of gestation (term=184 days) from untreated baboons and on day 165 from baboons in which betamethasone was administered to the fetus, or to fetus and mother, every other day between days 150 and 164 of gestation. Although the mRNA levels of IGF-II in the fetal adrenal were similar at early, mid and late gestation, IGF type-1 receptor mRNA levels were approximately 2- to 3-fold greater (P<0.01) at mid than at early or late gestation. In contrast, there was an increase (P<0.001) in fetal adrenal IGFBP-2 and bFGF mRNA levels in late gestation. Although fetal adrenal weights and width of the zone of definitive/transitional cells exhibiting immunocytochemical staining for Delta(5)-3beta-hydroxysteroid dehydrogenase (3beta-HSD) were markedly suppressed (P<0.01) by the administration of betamethasone, IGF-II and IGFBP-2 mRNA expression was not decreased. In summary, very different patterns of mRNA levels for IGF-II, IGF type-1 receptor, IGFBP-2 and bFGF were exhibited in the developing baboon fetal adrenal gland, which may reflect functionally important differences in their respective cellular localization within the cortex, as well as a divergence in the functional development of the fetal, transitional and definitive zones of the baboon fetal adrenal cortex.
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- Abstract: Diabetes x
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Wang-Yang Xu, Yan Shen, Houbao Zhu, Junhui Gao, Chen Zhang, Lingyun Tang, Shun-Yuan Lu, Chun-Ling Shen, Hong-Xin Zhang, Ziwei Li, Peng Meng, Ying-Han Wan, Jian Fei, and Zhu-Gang Wang
Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1−/− mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.
R. D. G. MILNER, A. J. BARSON, and M. A. ASHWORTH
Pieces of human foetal pancreas were incubated under control conditions and in media containing different stimuli of insulin release. Insulin secretion was stimulated from the pancreases of foetuses (83–625 g body weight) which were of 16–24 weeks gestational age. Potassium (60 mmol/l), barium (2·54 mmol/l) and ouabain (10−5 mol/l) were effective stimuli in all experiments. Glucagon (5 μg/ml), theophylline (1 mmol/l) and dibutyryl 3′,5′-cyclic adenosine monophosphate (1 mmol/l) stimulated insulin secretion in media containing 0, 0·6 or 3·0 mg glucose/ml. Theophylline and dibutyryl 3′,5′-cyclic adenosine monophosphate were effective in all experients and glucagon stimulated insulin release in four out of six experiments. At all ages studied, histological examination of the pancreas after each experiment revealed islets of Langerhans containing β cells. In most cases the islets were of the mantle type but occasionally bipolar islets were seen. Cellular normality, as judged by light microscopy, was preserved after periods of incubation for up to 5½ h. Glycogen was demonstrable in the pancreatic acinar tissue but not in the islets.
The results of these experiments indicate that, between the 16th and 24th week of foetal life, the human β cell is capable of releasing insulin in vitro when stimulated appropriately.
Andréa M Caricilli, Paula H Nascimento, José R Pauli, Daniela M L Tsukumo, Lício A Velloso, José B Carvalheira, and Mário J A Saad
The aims of the present study were to investigate the expression of toll-like receptor 2 (TLR2) in muscle and white adipose tissue (WAT) of diet-induced obesity (DIO) mice, and also the effects of its inhibition, with the use of TLR2 antisense oligonucleotide (ASON), on insulin sensitivity and signaling. The expression of TLR2 was increased in muscle and WAT of DIO mice, compared with those that received standard chow. Inhibition of TLR2 in DIO mice, by TLR2 ASON, improved insulin sensitivity and signaling in muscle and WAT. In addition, data show that the inhibition of TLR2 expression prevents the activation of IKBKB, MAPK8, and serine phosphorylation of IRS1 in DIO mice, suggesting that TLR2 is a key modulator of the crosstalk between inflammatory and metabolic pathways. We, therefore, suggest that a selective interference with TLR2 presents an attractive opportunity for the treatment of insulin resistance in obesity and type 2 diabetes.
Xin-gang Yao, Xin Xu, Gai-hong Wang, Min Lei, Ling-ling Quan, Yan-hua Cheng, Ping Wan, Jin-pei Zhou, Jing Chen, Li-hong Hu, and Xu Shen
Impaired glucose-stimulated insulin secretion (GSIS) and increasing β-cell death are two typical dysfunctions of pancreatic β-cells in individuals that are destined to develop type 2 diabetes, and improvement of β-cell function through GSIS enhancement and/or inhibition of β-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting β-cells from cytokine- or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca2 + channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on β-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored β-cell functions as indicated by the increased plasma insulin level and decrease in the β-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.
Tao Xie, Min Chen, and Lee S Weinstein
The ubiquitously expressed G protein α-subunit Gsα mediates the intracellular cAMP response to glucagon-like peptide 1 (GLP1) and other incretin hormones in pancreatic islet cells. We have shown previously that mice with β-cell-specific Gsα deficiency (βGsKO) develop severe early-onset insulin-deficient diabetes with a severe defect in β-cell proliferation. We have now generated mice with Gsα deficiency throughout the whole pancreas by mating Gsα-floxed mice with Pdx1-cre transgenic mice (PGsKO). PGsKO mice also developed severe insulin-deficient diabetes at a young age, confirming the important role of Gsα signaling in β-cell growth and function. Unlike in βGsKO mice, islets in PGsKO mice had a relatively greater proportion of α-cells, which were spread throughout the interior of the islet. Similar findings were observed in mice with pancreatic islet cell-specific Gsα deficiency using a neurogenin 3 promoter-cre recombinase transgenic mouse line. Studies in the α-cell line αTC1 confirmed that reduced cAMP signaling increased cell proliferation while increasing cAMP produced the opposite effect. Therefore, it appears that Gsα/cAMP signaling has opposite effects on pancreatic α- and β-cell proliferation, and that impaired GLP1 action in α- and β-cells via Gsα signaling may be an important contributor to the reciprocal effects on insulin and glucagon observed in type 2 diabetics. In addition, PGsKO mice show morphological changes in exocrine pancreas and evidence for malnutrition and dehydration, indicating an important role for Gsα in the exocrine pancreas as well.
TY Tai, JY Lu, CL Chen, MY Lai, PJ Chen, JH Kao, CZ Lee, HS Lee, LM Chuang, and YM Jeng
This study aimed at elucidating the effects of interferon (IFN)-alpha on glucose metabolism in patients with chronic hepatitis B and C infections. Twenty-eight biopsy-proven patients with chronic hepatitis B (ten cases) and hepatitis C (18 cases) were given IFN-alpha for a total of 24 weeks. The patients received a 75 g oral glucose tolerance test (OGTT), glucagon stimulation test, tests for type 1 diabetes-related autoantibodies and an insulin suppression test before and after IFN-alpha therapy. Ten of the 28 patients responded to IFN-alpha therapy. Steady-state plasma glucose of the insulin suppression test decreased significantly in responders (13.32+/-1.48 (S.E.M.) vs 11.33+/-1.19 mmol/l, P=0.0501) but not in non-responders (12.29+/-1.24 vs 11.11+/-0.99 mmol/l, P=0.2110) immediately after completion of IFN-alpha treatment. In the oral glucose tolerance test, no significant difference was observed in plasma glucose in either responders (10.17+/-0.23 vs 10.03+/-0.22 mmol/l) or non-responders (10.11+/-0.22 vs 9.97+/-0.21 mmol/l) 3 Months after completion of IFN-alpha treatment. However, significant differences were noted in C-peptide in both responders (2.90+/-0.13 vs 2.20+/-0.09 nmol/l, P=0.0040) and non-responders (2.45+/-0.11 vs 2.22+/-0.08 nmol/l, P=0.0287) before vs after treatment. The changes of C-peptide in an OGTT between responders and non-responders were also significantly different (P=0.0028), with responders reporting a greater reduction in C-peptide. No case developed autoantibodies during the treatment. In patients who were successfully treated with IFN-alpha, insulin sensitivity improved and their plasma glucose stayed at the same level without secreting as much insulin from islet beta-cells.
WW Lin and AM Oberbauer
IGF-I acts as a local proliferation and maturation factor for chondrocytes in the growth plate. However, the expression of different alternative IGF-I mRNA classes in the growth plate has not been characterized. Using quantitative reverse transcription PCR, the abundance of each alternative IGF-I mRNA class in resting, proliferative and hypertrophic chondrocytes was measured in rat costochondral growth plates. Class 1Ea mRNA was the most abundant IGF-I transcript overall and was highly expressed in proliferative chondrocytes at 2 and 4 weeks of age; by 6 weeks, the majority of 1Ea mRNA expression had shifted to hypertrophic chondrocytes. Class 1Eb mRNA was the second most abundant transcript and its distribution was uniform across all the cell types at 2 weeks of age. The expression pattern changed with increasing age such that at 6 weeks a gradient existed with hypertrophic chondrocytes expressing higher levels of 1Eb than resting chondrocytes. Class 2Ea mRNA was constitutively expressed at low levels across the growth plate at all ages, while class 2Eb mRNA expression was negligible. The distribution of total IGF-I mRNA also shifted across growth plate cell types as the animals aged from 2 to 6 weeks. These findings suggest that IGF-I class 1 mRNA plays the predominant role in the maturation of the growth plate.
M G Cavallo, F Dotta, L Monetini, S Dionisi, M Previti, L Valente, A Toto, U Di Mario, and P Pozzilli
In the present study we have evaluated the expression of different beta-cell markers, islet molecules and autoantigens relevant in diabetes autoimmunity by a human insulinoma cell line (CM) in order to define its similarities with native beta cells and to discover whether it could be considered as a model for studies on immunological aspects of Type 1 diabetes.
First, the positivity of the CM cell line for known markers of neuroendocrine derivation was determined by means of immunocytochemical analysis using different anti-islet monoclonal antibodies including A2B5 and 3G5 reacting with islet gangliosides, and HISL19 binding to an islet glycoprotein. Secondly, the expression and characteristics of glutamic acid decarboxylase (GAD) and of GM2-1 ganglioside, both known to be islet autoantigens in diabetes autoimmunity and expressed by human native beta cells, were investigated in the CM cell line. The pattern of ganglioside expression in comparison to that of native beta cells was also evaluated. Thirdly, the binding of diabetic sera to CM cells reacting with islet cytoplasmic antigens (ICA) was studied by immunohistochemistry. The results of this study showed that beta cell markers identified by anti-islet monoclonal antibodies A2B5, 3G5 and HISL-19 are expressed by CM cells; similarly, islet molecules such as GAD and GM2-1 ganglioside are present and possess similar characteristics to those found in native beta cells; the pattern of expression of other gangliosides by CM cells is also identical to human pancreatic islets; beta cell autoantigen(s) reacting with antibodies present in islet cell antibodies (ICA) positive diabetic sera identified by ICA binding are also detectable in this insulinoma cell line.
We conclude that CM cells show close similarities to native beta cells with respect to the expression of neuroendocrine markers, relevant beta cell autoantigens in Type 1 diabetes (GAD, GM2-1, ICA antigen), and other gangliosides. Therefore, this insulinoma cell line may be considered as an ideal model for studies aimed at investigating autoimmune phenomena occurring in Type 1 diabetes.
Journal of Endocrinology (1996) 150, 113–120
D. Janjic and M. Asfari
To investigate further the role of cytokines in the pathogenesis of type I insulin-dependent diabetes mellitus, the effects of interleukin-1β (IL-1), tumour necrosis factor-α (TNF) and γ-interferon (IFN) were tested on rat insulinoma INS-1 cells. Whereas TNF and IFN had, respectively, a minor or no effect on insulin production, IL-1 caused a time- and dose-dependent decrease in insulin release and lowered the insulin content as well as the preproinsulin mRNA content of INS-1 cells. Both IL-1 and TNF exerted a cytostatic effect, estimated by a decrease in [3H]thymidine incorporation, while only IL-1 decreased cell viability as measured by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test.
The glutathione content of INS-1 cells was shown to be modulated by the presence of 2-mercaptoethanol in the culture medium, but was not affected by IL-1 or TNF.
In conclusion, INS-1 cell culture is considered to be a useful model for studying the effect of cytokines on insulin-producing cells. The differentiated features of these cells will permit several questions to be addressed regarding the mechanism of action of IL-1 and eventually other cytokines, both at the level of gene expression and of intracellular signalling.
Journal of Endocrinology (1992) 132, 67–76