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Donna e diabete in Regione Lombardia
Palazzo della Regione, Grattacielo Pirelli (Milano), 9 Marzo 2016
Bruno Solerte
Dip. Medicina Interna, Università degli Studi di
Pavia
[email protected]
Donna e la forza della Fragilità
Donna e la forza della Fragilità
la forza della Fragilità
Qual’è la forza della
Fragilità nella donna
la sua forza è nella sua
biologia
ESTROGENI /
glicemia
INSULINA
GLP-1
GLUCAGONE
HOMA-IR
ESTROGENI /
DECADIMENTO COGNITIVO
ESTROGENI / OSSO
ESTROGENI / MUSCOLO
Sci Rep. 2015 May 13;5:10211. doi: 10.1038/srep10211.
Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin
sensitivity and glucose homeostasis.
Tiano JP1, Tate CR2, Yang BS3, DiMarchi R3, Mauvais-Jarvis F4.
•1Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine,
Chicago, IL 60611.
•2Division of Endocrinology &Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New
Orleans, LA 70112.
•3Department of Chemistry, Indiana University, Bloomington, IN, 47405.
•41] Division of Endocrinology &Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New
Orleans, LA 70112 [2] Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University
School of Medicine, Chicago, IL 60611.
Abstract
The female estrogen 17β-estradiol (E2) enhances pancreatic β-cell function via estrogen receptors (ERs).
However, the risk of hormone dependent cancer precludes the use of general estrogen therapy as a chronic treatment for diabetes. To
target E2 to β-cells without the undesirable effects of general estrogen therapy, we created fusion peptides combining
active or inactive glucagon-like peptide-1 (GLP-1) and E2 in a single molecule (aGLP1-E2 and iGLP1-E2
respectively). By combining the activities of GLP-1 and E2, we envisioned synergistic insulinotropic activities of these molecules on β-cells.
In cultured human islets and in C57BL/6 mice, both aGLP1 and aGLP1-E2 enhanced glucose-stimulated insulin secretion (GSIS) compared
to vehicle and iGLP1-E2 without superior efficacy of aGLP1-E2 compared to GLP-1 alone. However, aGLP1-E2 decreased fasting and fed
blood glucose to a greater extent than aGLP1 and iGLP1-E2 alone. Further, aGLP1-E2 exhibited improved insulin sensitivity
compared to aGLP1 and iGLP1-E2 alone (HOMA-IR and insulin tolerance test). In conclusion, targeted estrogen delivery to non-diabetic
islets in the presence of GLP-1 does not enhance GSIS. However, combining GLP-1 to estrogen delivers additional efficacy relative to GLP-1
alone on insulin sensitivity and glucose homeostasis in non-diabetic mice.
Sci Rep. 2015 May 13;5:10211. doi: 10.1038/srep10211.
Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin
sensitivity and glucose homeostasis.
Tiano JP1, Tate CR2, Yang BS3, DiMarchi R3, Mauvais-Jarvis F4.
•1Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine,
Chicago, IL 60611.
•2Division of Endocrinology &Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New
Orleans, LA 70112.
•3Department of Chemistry, Indiana University, Bloomington, IN, 47405.
•41] Division of Endocrinology &Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New
Orleans, LA 70112 [2] Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University
School of Medicine, Chicago, IL 60611.
Abstract
The female estrogen 17β-estradiol (E2) enhances pancreatic β-cell function via estrogen receptors (ERs).
However, the risk of hormone dependent cancer precludes the use of general estrogen therapy as a chronic treatment for diabetes. To target
E2 to β-cells without the undesirable effects of general estrogen therapy, we created fusion peptides combining active or
inactive glucagon-like peptide-1 (GLP-1) and E2 in a single molecule (aGLP1-E2 and iGLP1-E2 respectively). By
combining the activities of GLP-1 and E2, we envisioned synergistic insulinotropic activities of these molecules on β-cells. In cultured human
islets and in C57BL/6 mice, both aGLP1 and aGLP1-E2 enhanced glucose-stimulated insulin secretion (GSIS) compared to vehicle and iGLP1E2 without superior efficacy of aGLP1-E2 compared to GLP-1 alone. However, aGLP1-E2 decreased fasting and fed blood glucose to a
greater extent than aGLP1 and iGLP1-E2 alone. Further, aGLP1-E2 exhibited improved insulin sensitivity compared to aGLP1 and
iGLP1-E2 alone (HOMA-IR and insulin tolerance test). In conclusion, targeted estrogen delivery to non-diabetic islets in the presence of GLP1 does not enhance GSIS. However, combining GLP-1 to estrogen delivers additional efficacy relative to GLP-1 alone on insulin sensitivity
and glucose homeostasis in non-diabetic mice.
Diabetologia. 2015 Mar;58(3):604-14. doi: 10.1007/s00125-014-3478-3.
GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New
Zealand obese (NZO) mice.
Schwenk RW1, Baumeier C, Finan B, Kluth O, Brauer C, Joost HG, DiMarchi RD, Tschöp MH, Schürmann A.
•1Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116,
14558, Nuthetal, Germany, [email protected].
AIMS/ HYPOTHESIS:
Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent
development of a glucagon-like peptide-1 (GLP-1)-oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors,
offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the
effects of GLP-1 and GLP-1-oestrogen during beta cell failure under glucolipotoxic conditions.
METHODS:
Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1-oestrogen, respectively. Subsequently, the
effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1-oestrogen, transcription
analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed.
RESULTS:
In contrast to GLP-1, GLP-1-oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved
normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed
elevated expression of Pomc and Leprb. In livers from GLP-1-oestrogen-treated mice, expression of lipogenic genes was attenuated and
hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1-oestrogen altered the mRNA expression to a pattern that was
similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather
indirect protection of pancreatic beta cells.
CONCLUSIONS/INTERPRETATION:
GLP-1-oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of
hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic
capacity of GLP-1 alone.
Diabetologia. 2015 Mar;58(3):604-14. doi: 10.1007/s00125-014-3478-3.
GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New
Zealand obese (NZO) mice.
Schwenk RW1, Baumeier C, Finan B, Kluth O, Brauer C, Joost HG, DiMarchi RD, Tschöp MH, Schürmann A.
•1Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116,
14558, Nuthetal, Germany, [email protected].
AIMS/ HYPOTHESIS:
Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent
development of a glucagon-like peptide-1 (GLP-1)-oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors,
offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the
effects of GLP-1 and GLP-1-oestrogen during beta cell failure under glucolipotoxic conditions.
METHODS:
Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1-oestrogen, respectively. Subsequently, the
effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1-oestrogen, transcription
analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed.
RESULTS:
In contrast to GLP-1, GLP-1-oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved
normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed
elevated expression of Pomc and Leprb. In livers from GLP-1-oestrogen-treated mice, expression of lipogenic genes was attenuated and
hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1-oestrogen altered the mRNA expression to a pattern that was
similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather
indirect protection of pancreatic beta cells.
CONCLUSIONS/INTERPRETATION:
GLP-1-oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of
hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic
capacity of GLP-1 alone.
Biol Sex Differ. 2016 Jan 16;7:6. doi: 10.1186/s13293-016-0059-9.
Sex and estrogens alter the action of glucagon-like peptide-1 on reward.
Richard JE1, Anderberg RH1, López-Ferreras L1, Olandersson K1, Skibicka KP1.
•1Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of
Gothenburg, Medicinaregatan 11, PO Box 434, SE-405 30 Gothenburg, Sweden.
BACKGROUND:
Feeding behavior is regulated through an intricate array of anorexic and orexigenic hormones acting on the central nervous system (CNS).
Some of these hormones may have differential effects in males and females, effects potentially attributed to actions of gonadal steroids,
especially estrogens. Central stimulation of the glucagon-like peptide-1 (GLP-1) receptors reduces feeding and food-reward behavior by
acting on CNS regions important for the anorexic actions of estrogens. Thus, we propose that the action of GLP-1 on food intake and reward
may differ between sexes.
METHODS:
Male and female rats were centrally injected with the GLP-1 analog exendin-4 (Ex4) in a non-deprived or food-restricted state; reward
behavior was measured in a progressive ratio operant conditioning task. Intake of chow and palatable food were also measured. To
determine if sex differences in the actions of Ex4 are due to interactions with estrogens, Ex4 treatment was preceded by treatment with a
nonselective estrogen receptor-α (ERα) and ERβ or ERα-selective antagonist.
RESULTS:
Central injection of Ex4 revealed increased reward behavior suppression in females, compared to males, in the operant conditioning task.
This increase was present in both non-deprived and food-restricted animals with larger differences in the fed state. Intake of chow and
palatable food, after Ex4, were similar in males and females. Food reward, but not food intake, effect of Ex4 was attenuated by pretreatment
with ER antagonist in both sexes, suggesting that estrogens may modulate effects of Ex4 in both sexes. Furthermore, central pretreatment
with ERα-selective antagonist was sufficient to attenuate effects of Ex4 on reward.
CONCLUSIONS:
Collectively, these data reveal that females display much higher sensitivity to the food reward impact
of central GLP-1 receptor activation. Surprisingly, they also demonstrate that central ERα signaling is
necessary for the actions of GLP-1 on food-reward behavior in both sexes.
KEYWORDS:
Estrogens; Exendin-4; GLP-1; Glucagon-like peptide-1; Obesity; Reward; Sex
Nat Med. 2012 Dec;18(12):1847-56. doi: 10.1038/nm.3009.
Targeted estrogen delivery reverses the metabolic syndrome.
Finan B1, Yang B, Ottaway N, Stemmer K, Müller TD, Yi CX, Habegger K, Schriever SC, García-Cáceres C, Kabra DG, Hembree
J, Holland J, Raver C, Seeley RJ, Hans W, Irmler M, Beckers J, de Angelis MH, Tiano JP, Mauvais-Jarvis F, Perez-Tilve D, Pfluger
P, Zhang L, Gelfanov V, DiMarchi RD, Tschöp MH.
•1Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health
(GmbH), Neuherberg, Germany.
Abstract
We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of
nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development
of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the
individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven
by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models
and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen
in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of
estrogen receptors in GLP-1-targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1
agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that
enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations
with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible
combinations of peptides and small molecules may offer equal promise for other diseases.
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