Grâce à leurs propriétés antioxydantes, les phénols de l’huile d’olive sont reconnus comme les acteurs principaux de la réduction de la mortalité cardiovasculaire et du diabète de type 2 associée au régime méditerranéen. Cependant, la forte métabolisation de l’hydroxytyrosol, principal composé phénolique de l’huile d’olive, en glucuronides, remet en question son activité biologique.Un premier objectif de ce travail de thèse a été de mettre en évidence l’importance des glucuronides dans l’amélioration de la fonction vasculaire grâce à un effet antioxydant. Néanmoins et contrairement à l’hydroxytyrosol, qui peut être transporté directement par la bilitranslocase, les glucuronides doivent, dans un premier temps, être déconjugués par la β-glucuronidase afin d’exercer leur activité biologique.Un deuxième objectif de ce travail de thèse a été de mettre en évidence leurs effets chez des rats atteints de syndrome métabolique. Nous avons pu constater que ni l’hydroxytyrosol, ni ses glucuronoconjugués ne modulaient la fonction vasculaire.Enfin, un troisième objectif a été de regarder la répercussion d’une supplémentation en hydroxytyrosol, sur les facteurs de risque cardiovasculaire dans un modèle de souris atteintes de diabète de type 2. La supplémentation en hydroxytyrosol a réduit la prise de poids, les masses adipeuses et a eu des effets hypotenseurs. Ces effets hypotenseurs semblent être dus à une de la fonction des cellules musculaires lisses puisque nos travaux montrent une relaxation endothélium-indépendante améliorée. Nos travaux donnent un nouvel éclairage sur les effets de l’hydroxytyrosol et ses métabolites, tous deux contribuant, potentiellement, à la réduction de l’incidence des maladies cardiovasculaires et du diabète de type 2. / Olive oil polyphenols are well-known to lower cardiovascular mortality and type 2 diabetes incidence associated to the Mediterranean diet. However, the high metabolization rate of hydroxytyrosol, the main phenolic compound of olive oil, into glucuronides, questions its real biological effect. The first objective of this thesis was to evidence the importance of glucuronides of Hydroxytyrosol in the enhancement of vascular function through antioxidative properties. It was found that, unlike to hydroxytyrosol that can be directly transported with bilitranslocase glucuronides have to be deconjugated by β-glucuronidase to exert their biological activity. A second objective was to evidence the effects of Hydroxytyrosol and glucuronides on vascular function in diet-induced metabolic syndrome rats. Neither hydroxytyrosol nor glucuronides modulated vascular function in this pathological context. A third objective was to show the effect of a chronic Hydroxytyrosol supplementation in refined olive oil on cardiovascular risk factors in a mice model of Metabolic Syndrome. Hydroxytyrosol supplementation was able to reduce weight gain, white adipose tissues mass and to lower blood pressure. These hypotensive effects seem to be due in smooth muscle cells function. In conclusion, our works highlight the importance of Hydroxytyrosol and its glucuronoconjugated metabolites, both contributing to the reduction of the incidence of cardiovascular risk factors associated to type 2 diabetes and Metabolic syndrome.

The prevalence of type 2 diabetes is increasing dramatically worldwide. Type 2 diabetes is a major health and socio-economic burden. Genetic predisposition and the obesity epidemic, due to sedentary life style and high caloric food intake, are associated with development of type 2 diabetes. Circulating free fatty acids (FFAs), in particular saturated FFAs, are linked with insulin resistance and β cell dysfunction. Following this background we performed RNA sequencing of human pancreatic islets treated with the saturated FFA palmitate to acquire a global image of the islet response to this insult. We identified several stress pathways induced by palmitate with a major induction of the endoplasmic reticulum (ER) stress response. The ER stress response, in particular the PKR-like ER kinase (PERK) branch, has been shown to be induced by saturated FFA. It leads to increased β cell apoptosis both in fluorescence activated cell sorter (FACS) purified rat β cells and human islets. We further clarified the role of this pathway by studying the involvement of the constitutive repressor of eIF2α phosphorylation (CReP) in a monogenic form of diabetes. CReP is a repressor of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation. A direct target of PERK, eIF2α is involved in translational attenuation and induction of apoptosis. We have shown that CReP loss-of-function leads to a new syndrome of young onset diabetes, intellectual disability and microcephaly. The identified R658C mutation abrogated CReP activity leading to increased eIF2α phosphorylation and β cell apoptosis. To further demonstrate the importance of eIF2α dysregulation in β cell demise, we used guanabenz, a chemical inhibitor of growth arrest DNA damage inducible 34 (GADD34). GADD34 is an ER stress-induced repressor of eIF2α phosphorylation. Guanabenz potentiated FFA-mediated ER stress and apoptosis in clonal and primary rat β cells and in human islets through the activation of CCAAT/enhancer binding protein homologous protein (CHOP), downstream of eIF2α. Guanabenz administration in mice impaired glucose tolerance and led to β cell dysfunction. In ex vivo experiments guanabenz also induced β cell dysfunction in mouse and rat islets.In conclusion our data demonstrate that the dysregulation of signaling in the PERK/eIF2α pathway is crucial for β cell demise. Together with previously reported monogenic diabetes caused by loss-of-function mutations in PERK in man and the eIF2αS51A mutation in mice, our findings suggest that a narrow regulation of PERK/eIF2α signaling is central for proper β cell function and survival. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, which develops as a consequence of peripheral insulin resistance and defective insulin secretion from pancreatic β-cells. A high calorie diet coupled with physical inactivity are known risk factors for the development of T2DM; however, these alone fail to account for the rapid rise of the disease. Recent attention has turned to the role of environmental pollutants in the development of metabolic diseases. PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes (T2D), however, the precise mechanisms are not clear. In particular, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10 μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study suggests that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation. This can cause the β-cells to oversecrete insulin, potentially leading to hyperinsulinemia, insulin resistance, and high blood glucose. In contrast to the potential diabetogenic effects of POPs, there are several naturally-derived compounds which accomplish just the opposite, exerting sensitizing effect on the peripheral tissues and sparing effect on β-cells. TQ, a natural occurring quinone and the main bioactive component of plant Nigella sativa, undergoes intracellular redox cycling and re-oxidizes NADH to NAD+. TQ administration (20 mg/kg/bw/day) to the Diet-Induced Obesity (DIO) mice reduced their diabetic phenotype by decreasing fasting blood glucose and fasting insulin levels, and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose and insulin tolerance tests (OGTT and ITT). Furthermore, TQ decreased serum cholesterol levels and liver triglycerides, increased protein expression of phosphorylated Akt, decreased serum levels of inflammatory markers resistin and MCP-1, and decreased the NADH/NAD+ ratio. These changes were paralleled by an increase in phosphorylated SIRT-1 and AMPKα in liver and phosphorylated SIRT-1 in skeletal muscle. TQ also increased insulin sensitivity in insulin-resistant HepG2 cells via a SIRT-1-dependent mechanism These findings are consistent with the TQ-dependent re-oxidation of NADH to NAD+, which stimulates glucose and fatty acid oxidation and activation of SIRT-1-dependent pathways. Taken together, these results demonstrate that TQ ameliorates the diabetic phenotype in the DIO mouse model of type 2 diabetes.

Abstract Exercise promotes health, work ability, well-being and prevents diseases, such as type 2 diabetes. This study looks at the factors affecting exercise motivation in adults. Factors affecting exercise motivation refers to factors that either motivate people to exercise or restrict them. The study material was gathered from four different sets of subjects: women attending gymnastics classes arranged by the sports association Oulun Voimisteluseura, parents with young children and persons at high risk of type 2 diabetes taking part in the follow-up of the Finnish Diabetes Prevention Study in Oulu or the Elvira Counseling project. The survey targeted at female gymnasts (n=76) included open-ended questions and 56 statements which were studied using factor analysis. The survey aimed at parents with young children (n=37) consisted of five open-ended questions. The high-risk persons (n=74) who took part in group counseling in the Elvira Counseling project completed questionnaires at the beginning and at the end of the counseling. Twenty-two of them were interviewed. Group counseling sessions (82 h) were videotaped. The surveys yielded information on issues such as exercise activity and pedometer use and respondents’ assessments of how their exercise volume had been affected by pedometer use. Exercise activity was reported as the means of metabolic equivalent (MET) hours and its 95% confidence intervals. The statistical significance of changes in MET hours was measured using pairwise t-test, and differences in MET hours between groups were tested with variance analysis. Surveys targeted at persons from Oulu taking part in the Finnish Diabetes Prevention Study were conducted in 2003 (n=63) and 2008 (n=71). The survey comprised five open-ended questions. Qualitative data were analyzed using inductive content analysis. Exercise motivation consisted of exercise capital, which comprises four sub-areas: exercise activity, exercise as a habit, exercise as a resource and perceiving life situation as conducive to exercise. Factors motivating and restricting exercise came out as physical, mental and social factors. The concept of exercise capital provides a tool for exercise counseling in different life situations. Exercise motivation can be supported by looking at the factors restricting by focusing on their own exercise activity and motivation, by strengthening factors that promote motivation to exercise and by supporting family exercise and the social aspects of exercise. / Tiivistelmä Liikunta edistää terveyttä, työkykyä, hyvinvointia ja ehkäisee sairauksia, kuten tyypin 2 diabetesta. Tässä tutkimuksessa selvitetään, millaisia ovat aikuisten liikuntamotivaatioon vaikuttavat tekijät. Liikuntamotivaatioon vaikuttavilla tekijöillä tarkoitetaan liikkumiseen motivoivia ja liikkumista rajoittavia tekijöitä. Tutkimusaineisto kerättiin neljästä osa-aineistosta: Oulun Voimisteluseuran liikuntaryhmissä käyviltä naisilta, pienten lasten vanhemmilta ja tyypin 2 diabeteksen korkean riskin henkilöiltä, jotka osallistuivat Suomalaisen diabeteksen ehkäisytutkimuksen seurantaan Oulussa tai Elvira counseling -hankkeeseen. Kysely naisvoimistelijoille (n=76) sisälsi avoimia kysymyksiä sekä 56 väittämää, joita tarkasteltiin faktorianalyysillä. Pienten lasten vanhempien (n=37) kysely sisälsi viisi avointa kysymystä. Elvira counseling –hankkeessa toteutettuun ryhmäohjaukseen osallistuneet henkilöt (n=74) vastasivat kyselyyn ohjauksen alussa ja lopussa, heistä 22 haastateltiin, ja kaikki ryhmäohjauskerrat videoitiin (82 h). Kyselyt tuottivat tietoa muun muassa liikunta-aktiivisuudesta ja askelmittarin käytöstä sekä vastaajien arvioita askelmittarin käytön vaikutuksesta heidän liikkumisensa määrään. Liikunta-aktiivisuus raportoitiin metabolic equivalent (MET) -tuntien keskiarvoina ja sen 95 % luottamusväleinä. MET-tunneissa tapahtuneiden muutosten tilastollista merkitsevyyttä mitattiin parittaista T-testiä käyttäen, ja ryhmien välisiä MET-tuntieroja testattiin varianssianalyysilla. Suomalaiseen diabeteksen ehkäisytutkimukseen osallistuneille oululaisille toteutettiin kyselytutkimukset vuosina 2003 (n=63) ja 2008 (n=71). Kysely sisälsi viisi avointa kysymystä. Laadulliset aineistot analysoitiin aineistolähtöisellä sisällönanalyysilla. Liikuntamotivaatio muodostui liikunnallisesta pääomasta, jossa on neljä toisiinsa vaikuttavaa osa-aluetta: liikunta-aktiivisuus, liikunta tottumuksena, liikunta voimavarana sekä elämäntilanteen kokeminen liikkumiselle suotuisana. Liikkumiseen motivoivat tekijät ja liikkumista rajoittavat tekijät ilmenivät fyysisinä, psyykkisinä ja sosiaalisina tekijöinä. Liikunnallisen pääoman käsite tarjoaa työvälineen erilaisissa elämäntilanteissa. Liikuntamotivaatiota voidaan tukea pohtimalla liikkumista rajoittavia tekijöitä oman liikunta-aktiivisuuden ja liikuntamotivaation tarkastelun ja ongelmanratkaisun avulla, vahvistamalla liikkumista motivoivia tekijöitä sekä tukemalla perheliikuntaa ja liikunnan sosiaalisia merkityksiä.

Magister Public Health - MPH / Background: Optimal management of Type 2 diabetes requires that patients have a convenient method of collecting chronic medication. In the Western Cape Province, Type 2 diabetes patients can collect chronic medication from primary health care facilities including community health centres. The Chronic Dispensing Unit (CDU) was established to facilitate the dispensing of chronic medication by making medication collection more convenient for patients and was expected to improve medication collection. However, it has been observed that some Type 2 diabetes patients fail to collect pre-packed CDU parcels on the prescribed date and time which could result in poor treatment outcomes and secondary complications. This study therefore aims to explore the factors that influence collection of CDU chronic medication parcels by Type 2 diabetes patients from the Elsies River Community Health Centre (CHC), a primary health care facility in the Western Cape Province. Methodology: An exploratory qualitative research design was used to explore the personal-, social-, health system-related factors that affect collection of pre-packed CDU parcels. Semistructured interviews were conducted in English or Afrikaans with 18 purposefully selected Type 2 diabetes patients who are registered to collect pre-packed CDU parcels from the Elsies River CHC, and three key-informants from the Elsies River CHC. Data was recorded using a digital recorder. Interviews were transcribed and analysed using inductive content analysis. Results: The main factors that facilitate collection of pre-packed CDU parcels were support from family and social support. On the other hand, social factors that were reported as barriers to collection were the safety of the patients and collectors failing to collect on behalf of the patient. Patients' recognition of the value of their treatment and value of the service were the main personal factors which facilitated collection. Personal factors that were reported as a barrier to collection included forgetfulness, laziness and tiredness. Other personal factors that were reported by participants as barriers to collection were illness, transport problems, financial constraints and anticipating non-collection. Health service related factors reported as facilitating factors were reduced waiting time and mistrust of the off-site collection system. In addition, participation in the diabetes chronic club and pharmacy support were also reported as facilitating factors. Negative staff attitude and a limited collection time for pre-packed CDU parcels were reported as barriers to collection by Conclusion: Various personal-, social and health service related factors affect the collection of pre-packed CDU parcels by Type 2 diabetes patients from the Elsies River CHC. To improve collection among patients who fail to collect on their appointment date, the factors that have been found to facilitate collection should be extended to more patients. Recommendations: It is recommended that patients surround themselves with support structures including family, friends and community organisations to assist and motivate them in displaying adherent behaviour. Patients who make use of independent collectors should ensure that these individuals are reliable to avoid an undersupply of medication. Counselling and health promotion should be provided to patients by health service staff as a means of encouragement and empowerment. The diabetes club which serves as a source of information and support should be accessed by more patients. Open communications channels between health service staff and patients should be constructed to ensure that staff are aware of the barriers patients face.

Le diabète de type 2 (DT2) est une pathologie largement associée à l'obésité dont la prévalence est en constante augmentation dans le monde. L'inflammation et le stress du réticulum endoplasmique (RE) ont été largement décrits pour leur rôle dans la pathogénèse du DT2 en favorisant une insulinorésistance des tissus périphériques et une altération de la sécrétion d'insuline par le pancréas. La protéine Thioredoxine Interacting Protein (TXNIP) est activée lors d'un stress RE et joue un rôle important dans la mise en place de la réponse inflammatoire en activant l'inflammasome NLRP3 (Nod-Like Receptor 3). Nous nous sommes donc intéressés au rôle de cette protéine dans les monocytes des patients DT2. Nous montrons que la composition lipidique du plasma des patients DT2 pourrait être impliquée dans la mise en place d'un stress RE et d'une réponse UPR (Unfolded Protein Response) augmentée dans les monocytes de ces patients. Cette augmentation est associée à une activation de l'expression de TXNIP et des marqueurs de l'inflammation dans ces cellules qui pourrait participer à la mise en place d'une inflammation systémique chez ces patients. / Type 2 diabetes (T2D) is a pathology largely associated with obesity, which is rising constantly around the world. Inflammation and endoplasmic reticulum (ER) stress have been largely associated with the pathogenesis of DT2, promoting insulin resistance in peripheral tissues and a defect in insulin secretion from the pancreas. During ER stress the Thioredoxin Interacting Protein (TXNIP) is activated and plays an important role in the onset of inflammatory responses by activating the NLRP3 (Nod-Like Receptor 3) inflammasome. Hence we studied the role of TXNIP in monocytes from T2D patients. We have shown that the plasmatic lipid composition from T2D patients could be implicated in the onset of ER stress and an increase in the UPR (Unfolded Protein Response) in monocytes from T2D patients. This increase is associated with an activation of TXNIP expression and inflammatory markers in these cells, which could participate to the onset of systemic inflammation seen in T2D.

Diabetes mellitus is a growing threat to human health. Current pharmacological agents cause undesirable side-effects. Herbal remedies offer the potential for alternative treatment strategies that may prove more cost-effective and devoid of the undesirable side-effects. The purpose of this study was to evaluate the in vitro anti-diabetic activity of aqueous and methanol extracts of Sclerocarya birrea (A. Rich.) Hochst. (Anacardiaceae) and Ziziphus mucronata Willd. (Rhamnaceae), which are traditionally used for the treatment of diabetes mellitus in southern Africa. Polyphenolic contents of extracts were quantified using the aluminium trichloride and Folin-Ciocalteau methods. The capacity of individual extracts to scavenge both the 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl radicals was used as a measure of antioxidant activity. The inhibitory activities of the crude extracts of both plants on the enzymes, α-amylase and α-glucosidase, were determined using colorimetric assays. The effects of the crude extracts on cell viability was assessed in C2C12 myotubes, HepG2 hepatocarcinoma cells, 3T3-L1 adipocytes and RIN-m5F pancreatic β-islet cells, using the Sulforhodamine B assay. Fluorescence detection was used to investigate the effects of the crude extracts on glucose uptake in C2C12, HepG2 and 3T3-L1 cells. Insulin secretion was assessed in RIN-m5F cells, using ELISA. Crude extracts of both plants contained flavonoids and phenols, but flavonoid content was predominantly higher. All the extracts displayed antioxidant activity, with the methanol extract of S. birrea possessing the most potent free radical scavenging ability (IC50 = 2.16 μg/ml). Aqueous and methanol extracts of S. birrea displayed significantly (p < 0.05) greater inhibition of α-amylase, than the positive control, acarbose. Only the methanol extract of Z. mucronata inhibited α-amylase activity. Furthermore, crude extracts of both plants also displayed potent α-glucosidase inhibitory activity. Most of the crude extracts had low toxicity, where concentrations of 100 μg/ml of crude extract of the plants did not induce 50% cell death. iv Although no significant increase in insulin secretion from cultured RIN-m5F cells was noted, the crude extracts of both plants significantly (p < 0.05) increased glucose uptake in C2C12, HepG2 and 3T3-L1 cells, with efficacy significantly (p < 0.05) higher than the positive control, insulin. From the results, the plant extracts appear to exert their hypoglycaemic effects independently of insulin, via an extra-pancreatic mechanism, possibly involving interactions with the different receptors. An additive hypoglycaemic effect originates from the inhibition of both α-amylase and α-glucosidase. The findings of the present study provide evidence that S. birrea and Z. mucronata possess in vitro anti-diabetic activity. Further investigations are required to elucidate the mechanism(s) of action of the crude extracts using more targeted in vitro assays. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted

>Magister Scientiae - MSc / About 180 million people have been estimated to suffer from type 2 diabetes (T2DM) in 2006 and the annual death rate due to this disease was 3 million by that time. More than 400 medicinal plants used for the treatment of diabetes mellitus have been recorded, but only a small number of these plants have received scientific and medical evaluation to assess their efficacy. The most common plant used to treat diabetes mellitus is Hypoxis hemerocallidea (HH). The present study was undertaken to investigate the effects of Hypoxis hemerocallidea (HH) on T2DM in rats. Male Wistar rats weighing 200-250 g were used in this experiment. Hypoxis hemerocallidea (HH) corm was used as plant material in the experiment. The study was based on three parts, an acute diabetes study, chronic diabetes study and insulin secretion study. In the acute study, the rats were randomly divided into 2 groups (control and diabetes). The saline solution was added to different concentrations of HH corm to produce concentration of (50, 200, 400, 800 mg/ml). Diabetes was induced by intraperitoneal injections of STZ (65mg/kg). Two weeks after the injection (STZ 65 mg/kg), different concentrations of HHS was administered intraperitoneally after an overnight fast. The blood glucose levels were monitored in the diabetic and control rats at, 30, 60, 120, 180 and 240 minutes post injection. In the chronic study, the rats were randomly divided into 6 different groups (control, HFD, DM, DM-HH, DM-PTHH, and HH). Diabetes mellitus was then induced in the groups of diabetic rats by intraperitoneal injections of STZ (40 mg/kg) and rats were fed a high fat diet (HFD). The body weight of the rats were measured weekly for 7 weeks. An intraperitoneal glucose tolerance test (IPGTT) was performed at the end of week 6. At the end of week 7, rats were killed and serum sample were collected for determination of fatty acid and insulin. Liver and pancreatic tissue was collected for histological evaluation. In the insulin secretion study, Hypoxis hemerocallidea was tested for its effects on insulin secretion by pancreatic islet cells exposed to low (3mM) and high (20mM) glucose medium. Results of the acute study indicated that HHS at a dose 800 mg/ml decreased blood glucose levels fastest in both normal and diabetic rats reaching significance after 30 minutes and 60 minutes respectively and remained below the baseline value until 240 minutes. In the chronic study, it was illustrated that HH had no effect in normal rats on any of the parameters evaluated. Animals in the DM group gained weight the first two weeks, but thereafter began to lose weight. At the end of seven weeks the animals gained significantly less weight than the rest. Animals fed a HFD have more visceral fat compared to the control group. The visceral fat gain occurred in the absence of a significant increase in body weight. We found a markedly lower fasting glucose level in HH treated diabetic animals compared to untreated DM animals. At time zero the blood glucose level of the HFD group (5.8±0.5mmol/l) and the HH group (4.9±0.7mmol/l) were in the normal range, and were not significantly different (P > 0.05) from the control group (5.0±0.2mmol/l). After glucose load peak blood glucose levels was measured after 30 minutes in the control group (9.0±0.6mmol/l), the HFD group (9.8±0.4 mmol/l), the DM-HH group (21±5.7 mmol/l) and the DM-HHPT group (27.8±5.3 mmol/l). In the HH group the blood glucose level reached a peak at 60 minutes (7.6±0.6 mmol/l). In the DM group two peaks were recorded one after 10 minutes (27.2±7.1mmol/l) and another after 60 minutes (31±5.2 mmol/l). In the groups control, HFD, DMHH, DM-HHPT and HH groups the blood glucose level after 120 minutes were not significantly different from the time zero value. The blood glucose level after 120 minutes in the DM group (28.2±7.1 mmol/L) was significantly higher (P ≤ 0.01) than from the time zero value. Serum fatty acid levels were increased in all groups fed a high fat diet. The serum insulin levels in the HFD group (6.2 ± 0.76 μUI/ml protein; P ≤ 0.05 ), the DM group (2.0 ± 0.9 μUI/ml protein; P ≤ 0.001), the DMHH group (3.4 ± 0.7 μUI/ml protein; P ≤ 0.001) and the DM-HHPT group (3.0 ± 1.1 μUI/ml protein; P ≤ 0.001) were significantly lower than the control group. The β-cell function in the HFD group (62 ± 8 %; P ≤ 0.001), the DM group (3 ± 1 %; P ≤ 0.001), the DM-HH (11 ± 9 %; P ≤ 0.001) group and the DM-HHPT group (4 ± 2 %; P ≤ 0.001) were significantly lower than the control group. The histological observation of the liver and the pancreas in rats after 7 weeks on different dietary regimes showed some morphological changes within the liver and pancreas parenchyma of some rats. In the insulin secretion study, glucose stimulated insulin secretion in low (3mM) and high (2mM) glucose concentration. Furthermore, insulin secretion was significantly higher when the glucose concentration was increased from 3mM to 20 mM (1.10 ± 0.13 μUI/ml protein and 1.5 ± 0.17 mIU/mg protein respectively P≤ 0.01). In the presence of low HH (100 µg/ml), there was a marked increase in insulin secretion when exposure to high glucose compared to low glucose concentration, while in the presence of high HH (500 µg/ml), there was no significant different in insulin secretion in the presence of low or high glucose. In conclusion, the results of this experimental study indicate that a concentration 800 mg/kg of HHS produces maximal hypoglycaemic effect in fasted normal and diabetic rats. HH has an antidiabetic activity as it lowers serum glucose levels in T2DM rats and significantly increases glucose tolerance. It also increases body weight of diabetic rats. HH treatment was found to improve insulin secretion in pancreatic islet cells.

The adipose tissue lipid chaperones aP2 and mal1, also known as fatty acid binding proteins (FABPs), are significant molecules contributing to metabolic homeostasis, whereby their absence promotes physiological changes that improve systemic metabolism. Identification of palmitoleate as a lipokine generated in aP2-mal1 deficiency--originating from adipose and directing the lipogenic program in liver, established a role for these chaperones in linking adipocyte and hepatic function. We have recently demonstrated a functional role for secreted aP2 in the activation of gluconeogenesis and hepatic glucose output, further designating this molecule as an adipocyte-derived regulatory factor that influences liver metabolism. Key molecules linking the metabolism of nutrients in energy generating pathways are the nucleotide cofactors NAD and NADH. Together, these molecules function to coordinate the maintenance of redox reactions during normal cellular metabolism and act as required substrates for enzymes such as sirtuins and poly ADP-ribose polymerases. Using global metabolite profiling, we show that combined deficiency of the adipose tissue lipid chaperones aP2 and mal1 leads to a hepatic nucleotide imbalance resulting from metabolic reprogramming in liver. We demonstrate that this reprogramming of metabolite flux is accompanied by significant alterations in liver NAD metabolism and establish a role for aP2 in directing substrate utilization through inhibition of the rate-limiting enzyme for NAD synthesis, nicotinamide phosphoribosyltransferase. Several models for the proposed regulatory pathways that link nutrient metabolism to aging include mechanisms that are NAD dependent. Accordingly, we found that long-term FABP deficiency confers a strong resistance to aging related metabolic deterioration. Together, the findings presented in this thesis support a considerable role for FABPs in the regulation of NAD metabolism and healthspan.

L’influence de l’état métabolique sur l’olfaction a été particulièrement étudiée ces dernières années. Le statut nutritionnel et les hormones impliquées dans la prise alimentaire sont capables de moduler le système olfactif, du neurone individuel jusqu’au comportement. Il semble donc logique que les pathologies liées à l’alimentation puissent induire des dysfonctionnements olfactifs. De fait, les patients atteints de diabète de type 2 (DT2) présentent des capacités olfactives réduites bien que les effets du DT2 en lui-même soient toujours inconnus. Dans cette étude, nous nous sommes intéressés à la modulation de l’olfaction chez des souris rendues diabétiques après consommation d’un régime enrichi en fructose (HFruD). Les animaux présentent un DT2 précoce après 8 semaines de régime. De plus, ils montrent une baisse de leurs capacités olfactives globales. Les réponses électrophysiologiques aux odorants de la muqueuse olfactive et des neurones sensoriels olfactifs (OSN) sont diminuées après 8 semaines de HFruD. Une augmentation du nombre d’OSN ainsi qu’une diminution de l’apoptose ont lieu dans la muqueuse olfactive, indiquant que le HFruD induit un changement de la dynamique cellulaire dans ce tissu. Nos résultats démontrent que, chez le rongeur, l’olfaction est modulée par un régime diabétogène enrichi en fructose. Des changements fonctionnels, anatomiques et comportementaux surviennent au sein du système olfactif à un stage précoce de la pathologie, indiquant que le DT2 en lui-même est suffisant pour perturber l’olfaction. Les changements métaboliques ayant lieu durant la mise en place du DT2 pourraient être à l’origine des dysfonctionnements olfactifs. / The influence of metabolic status on olfactory processes has been thoroughly investigated over the last few years. Both nutritional status and hormones implicated in food metabolism can effectively modulate the olfactory system from the single neuron to the behavior. Thus, it seems likely that metabolic disorders such as type 2 diabetes (T2D) can induce olfactory dysfunctions. In fact T2D patients display poor olfactory performances however the effects of diabetes in itself (as well as underlying mechanisms) are still unknown. In this study, we investigated the modulation of olfaction in young adult male mice caused by a high-fructose diet (HFruD) inducing T2D in rodents. Animals displayed early diabetic state after only 4 weeks of HFruD. In addition, animals exhibited a decrease in olfactory capacities for both neutral and food odors. These behavioral effects persisted and were amplified after 8 weeks of HFruD. Electrophysiological responses to odorants of both olfactory mucosa and olfactory sensory neurons were reduced in HFruD animals after 8 weeks of diet. Immunohistochemistry experiments then revealed an increase in the number of olfactory sensory neurons and a reduction of apoptosis in the OM indicating that HFruD modifies cell dynamics. Our results demonstrate that, in rodents, olfaction is modified by HFruD-induced diabetes. Functional, anatomical and behavioral changes occurred in the olfactory system even at a very early stage of the disease, indicating that T2D in itself can disrupt olfaction. Metabolic changes taking place during the onset of T2D may trigger olfactory dysfunctions.