High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study.

BACKGROUND: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect. OBJECTIVE: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome. DESIGN: Cross-sectional comparison. SETTING: University hospital in Lausanne, Switzerland. PARTICIPANTS: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L (> or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (< or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated. MEASUREMENTS: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype. RESULTS: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene. CONCLUSION: Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Fructose Rich Diet-Induced High Plasminogen Activator Inhibitor-1 (PAI-1) Production in the Adult Female Rat: Protective Effect of Progesterone.

The effect of progesterone (P4) on fructose rich diet (FRD) intake-induced metabolic, endocrine and parametrial adipose tissue (PMAT) dysfunctions was studied in the adult female rat. Sixty day-old rats were i.m. treated with oil alone (control, CT) or containing P4 (12 mg/kg). Rats ate Purina chow-diet ad libitum throughout the entire experiment and, between 100 and 120 days of age drank ad libitum tap water alone (normal diet; CT-ND and P4-ND) or containing fructose (10% w/v; CT-FRD and P4-FRD). At age 120 days, animals were subjected to a glucose tolerance test or decapitated. Plasma concentrations of various biomarkers and PMAT gene abundance were monitored. P4-ND (vs. CT-ND) rats showed elevated circulating levels of lipids. CT-FRD rats displayed high (vs. CT-ND) plasma concentrations of lipids, leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). Lipidemia and adiponectinemia were high (vs. P4-ND) in P4-FRD rats. Although P4 failed to prevent FRD-induced hyperleptinemia, it was fully protective on FRD-enhanced plasma PAI-1 levels. PMAT leptin and adiponectin mRNAs were high in CT-FRD and P4-FRD rats. While FRD enhanced PMAT PAI-1 mRNA abundance in CT rats, this effect was absent in P4 rats. Our study supports that a preceding P4-enriched milieu prevented the enhanced prothrombotic risk induced by FRD-elicited high PAI-1 production.

PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells.

Insulin secretion from pancreatic beta cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1alpha, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1alpha pathway in the control of beta-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1alpha rescued these phenotypes, implying that they are the result of HIF1alpha activation. Together, these results identify pVHL and HIF1alpha as key regulators of insulin secretion from pancreatic beta cells. They further suggest that changes in the metabolic strategy of glucose metabolism in beta cells have profound effects on whole-body glucose homeostasis.

Assessment of total cardiovascular risk in hypertensive subjects

Valtimotautiriskin arviointi verenpainepotilailla Valtimotaudit ovat yleisin kuolinsyy koko maailmassa. Väestön elintapojen muuttuminen ja ikääntyminen uhkaavat edelleen lisätä valtimotautien esiintyvyyttä. Kokemäenjokilaakson valtimotautien ehkäisyprojektin tavoitteena oli löytää 45–70-vuotiaasta väestöstä henkilöt, joilla on kohonnut riski sairastua valtimotauteihin. Kaksivaiheisen seulontamenetelmän avulla voitiin terveydenhoitajan antama elintapaneuvonta kohdistaa riskihenkilöihin ja rajoittaa lääkärin vastaanoton tarve niihin potilaisiin, jotka todennäköisesti hyötyvät ennaltaehkäisevästä lääkityksestä. Suomalainen tyypin 2 diabeteksen sairastumisriskin arviointikaavake ja hoitajan toteama kohonnut verenpaine osoittautuivat käytännöllisiksi menetelmiksi seuloa väestöstä riskihenkilöitä. Valtimotautien ehkäisyprojektissa Harjavallassa ja Kokemäellä todettiin verenpainetauti 1 106 henkilöllä, jotka eivät sairastaneet valtimotautia tai aiemmin todettua diabetesta. Heidän tutkimustulostensa avulla voidaan arvioida kohonneen verenpaineen vaikutusta sokeriaineenvaihduntaan ja verenpaineen aiheuttamiin kohde-elinvaurioihin. Sokeriaineenvaihdunnan häiriöt ovat verenpainetautia sairastavilla yleisempiä kuin väestössä muutoin. Käyttämällä metabolisen oireyhtymän kriteerejä sokerirasituskokeen suorittamisen edellytyksenä voidaan tutkimusten määrää vähentää kolmanneksella ja silti löytää lähes kaikki diabetesta tai sen esiastetta sairastavat verenpainepotilaat. Verenpainepotilaista etenkin metabolista oireyhtymää sairastavilla naisilla on suurentunut munuaisten vajaatoiminnan riski. Jos verenpainepotilaan munuaisten toimintaa arvioidaan pelkästään plasman kreatiniini -arvon perusteella, kolme neljästä munuaisten vajaatoimintaa potevasta jää toteamatta verrattuna laskennallisen glomerulusten suodattumisnopeuden määritykseen seulontamenetelmänä. Joka kolmannella verenpainetautia sairastavalla voidaan todeta alaraajavaltimoiden kovettumista; useammin niillä, joiden ylä- ja alaverenpaineen erotus, pulssipaine on yli 65 mmHg. Verenpainetauti on itsenäinen perifeerisen valtimotaudin vaaratekijä. Tutkimuksessa käytetty menetelmä nilkka-olkavarsipainesuhteen määrittämiseksi soveltunee hyvin perusterveydenhuollon käyttöön riskihenkilöiden löytämiseksi. Valtimotautien kokonaisriskin arviointimenetelmät tai uuden riskitekijän, herkän C-reaktiivisen proteiinin määritys eivät voi korvata kohde-elinvaurioiden mittaamista verenpainepotilaan valtimotautiriskin huolellisessa arvioinnissa.

On Glucose Metabolism in Patients with the m.3243A>G Mutation

Background: The m.3243A>G mutation in mitochondrial DNA is the most common cause for mitochondrial diabetes. In addition, unexpected deaths related to the m.3243A>G associate with encephalopathy and cardiomyopathy. Failing mitochondrial respiratory chain in neurons, myocytes and beta cells is considered to underlie the multiorgan manifestations of the m.3243A>G. Aims: The primary aim of the study was to characterize the organ-specific glucose metabolism in patients with m.3243A>G and secondly, to study patients with or without signs of diabetes, cardiomyopathy or encephalopathy. The insulin-stimulated glucose metabolism in brain, heart, skeletal muscle, adipose tissue and liver were measured with 2-deoxy-2-[18F]fluoro-α-D-glucose in 15 patients and 14 controls. Brain oxygen metabolism was assessed with [15O]oxygen and insulin secretion was modelled based on oral glucose tolerance test. Results: The glucose oxidation in brain was globally decreased in patients with or without clinical encephalopathy. The insulin-stimulated glucose influx to skeletal muscle and adipose tissue was decreased in patients with or without diabetes as the hepatic glucose metabolism was normal. Impaired beta cell function and myocardial glucose uptake were associated with the high m.3243A>G heteroplasmy. Conclusions: This cross-sectional study suggests that: 1) The ability of insulin to stimulate glucose metabolism in skeletal muscle and adipose tissue is weakened before the beta cell failure results in mitochondrial diabetes. 2) Glucose oxidation defect is detected in otherwise unaffected cerebral regions in patients with the m.3243A>G, thus it likely precedes the clinical encephalopathy. 3) Uneconomical glucose hypometabolism during hyperinsulinemia contributes to the cardiac vulnerability in patients with high m.3243A>G heteroplasmy

Metformin in gestational diabetes mellitus

METFORMIININ KÄYTTÖ RASKAUSDIABETEKSESSA Raskausdiabeteksella tarkoitetaan sokeriaineenvaihdunnan häiriötä, joka todetaan ensimmäisen kerran raskauden aikana. Hoidolla voidaan vähentää raskausdiabetekseen liittyviä äidin ja vastasyntyneen haittoja. Lääkitystä tarvitaan, jos ruokavaliohoidolla ei saavuteta hyvää sokeritasapainoa. Perinteisesti lääkityksenä on käytetty insuliinia, mutta metformii¬nin käyttöä insuliinin vaihtoehtona on ehdotettu. Metformiini läpäisee istukan, mutta sen läpäisymekanismi ei ole selvillä. Tämän tutkimuskokonaisuuden pääasiallisin tarkoitus oli verrata metformiinin tehokkuutta ja turvallisuutta insuliiniin raskausdiabeteksen hoidossa selvittämällä lääkkeen vaiku¬tusta äitiin ja vastasyntyneeseen. Lisäksi haluttiin tutkia, mitkä tekijät ennustavat insulii¬nin tarvetta metformiinin lisänä, jotta saavutettaisiin hyvä sokeritasapaino. Metformiinin annoksen vaikutus äitiin ja vastasyntyneeseen arvioitiin mittaamalla metformiinin pitoisuus äidistä, ja sikiön puolelta napanuoran veressä. Tässä tutkimuksessa selvitettiin myös aktiivisen kuljetusproteiinin (OCT) merkitystä metformiinin kulkeutumiseen istukan läpi perfusiomalla istukkaa ex vivo . Ex vivo istukkaperfuusiotutkimuksen tulokset viittasivat siihen, että OCT-kuljetusproteiinilla ei ollut todennäköisesti merkittävää osuutta metformiinin kulkeutumisessa istukan läpi. Metformiinin pitoisuusmittaukset synnytyksen yhteydessä osoittivat metformiinin siirtyvän sikiöön istukan läpi suuressa määrin (96 %) kertymättä kuitenkaan sikiön verenkiertoon. Metformiinin pitoisuudella ei ollut vaikutusta vastasyntyneen hyvinvointiin. Maksi¬maalisella metformiinin annostuksella ja korkealla metformiinipitoisuudella todettiin olevan suotuisa vaikutus äidin painon nousuun raskauden aikana. Insuliiniin verrattuna metformiini ei lisännyt äidin, sikiön tai vastasyntyneen haittatapahtumia, eikä sillä ollut vaikutusta synnytystapaan. Sokeritasapaino insuliini- ja metformiinilääkityksen aikana oli yhtäläinen arvioitaessa sitä HbA1c- ja fruktosamiinimittauksilla, mutta 21 % metformiinin käyttäjistä tarvitsi lisäksi insuliinia hyvän sokeritasapainon saavuttamiseksi. Tutkimuksesssa todettiin, että mitä iäkkäämpi äiti oli, mitä varhaisemmassa raskauden vaiheessa sokerirasitus oli tehty ja lääkitys aloitettu, ja mitä korkeammat HbA1c ja fruktosamiinipitoisuudet olivat, sitä suuremmalla todennäköisyydellä metformiinin lisänä tarvittiin insuliinia.

Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake

Different levels of insulin sensitivity have been described in several animal models of obesity as well as in humans. Monosodium glutamate (MSG)-obese mice were considered not to be insulin resistant from data obtained in oral glucose tolerance tests. To reevaluate insulin resistance by the intravenous glucose tolerance test (IVGTT) and by the clamp technique, newborn male Wistar rats (N = 20) were injected 5 times, every other day, with 4 g/kg MSG (N = 10) or saline (control; N = 10) during the first 10 days of age. At 3 months, the IVGTT was performed by injecting glucose (0.75 g/kg) through the jugular vein into freely moving rats. During euglycemic clamping plasma insulin levels were increased by infusing 3 mU . kg-1 . min-1 of regular insulin until a steady-state plateau was achieved. The basal blood glucose concentration did not differ between the two experimental groups. After the glucose load, increased values of glycemia (P<0.001) in MSG-obese rats occurred at minute 4 and from minute 16 to minute 32. These results indicate impaired glucose tolerance. Basal plasma insulin levels were 39.9 ± 4 µU/ml in control and 66.4 ± 5.3 µU/ml in MSG-obese rats. The mean post-glucose area increase of insulin was 111% higher in MSG-obese than in control rats. When insulinemia was clamped at 102 or 133 µU/ml in control and MSG rats, respectively, the corresponding glucose infusion rate necessary to maintain euglycemia was 17.3 ± 0.8 mg . kg-1 . min-1 for control rats while 2.1 ± 0.3 mg . kg-1 . min-1 was sufficient for MSG-obese rats. The 2-h integrated area for total glucose metabolized, in mg . min . dl-1, was 13.7 ± 2.3 vs 3.3 ± 0.5 for control and MSG rats, respectively. These data demonstrate that MSG-obese rats develop insulin resistance to peripheral glucose uptake

Viscosity of gums in vitro and their ability to reduce postprandial hyperglycemia in normal subjects

Experiments were carried out in vitro with three viscous polysaccharides (guar gum, pectin, and carboxymethylcellulose (CMC)) of similar initial viscosity submitted to conditions that mimic events occurring in the stomach and duodenum, and their viscosity in these situations was compared to their actions on postprandial hyperglycemia in normal human subjects. Guar gum showed greater viscosity than the other gums during acidification and/or alkalinization and also showed larger effects on plasma glucose levels (35% reduction in maximum rise in plasma glucose) and on the total area under the curve of plasma glucose (control: 20,314 ± 1007 mg dl-1 180 min-1 vs guar gum: 18,277 ± 699 mg dl-1 180 min-1, P<0.01). Pectin, which showed a marked reduction in viscosity at 37oC and after events mimicking those that occur in the stomach and duodenum, did not have a significant effect on postprandial hyperglycemia. The performance of viscosity and the glycemia response to CMC were at an intermediate level between guar gum and pectin. In conclusion, these data suggest that temperature, the process of acidification, alkalinization and exposure to intestinal ions induce different viscosity changes in gums having similar initial viscosity, establishing a direct relationship between a minor decrease of gum viscosity in vitro and a reduction of postprandial hyperglycemia

Low levels of sex hormone-binding globulin and hyperproinsulinemia as markers of increased pancreatic ß-cell demand in men

Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic ß-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic ß-cell secretion in men with different body compositions. Eighteen young men (30.0 ± 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P<0.05), proinsulin (r = -0.47, P<0.05), C-peptide (r = -0.55, P<0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P<0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P<0.05). When subjects were divided into obese (BMI >28 kg/m2, N = 8) and nonobese (BMI £25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic ß-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic ß-cell demand.

Specific insulin and proinsulin in normal glucose tolerant first-degree relatives of NIDDM patients

In order to identify early abnormalities in non-insulin-dependent diabetes mellitus (NIDDM) we determined insulin (using an assay that does not cross-react with proinsulin) and proinsulin concentrations. The proinsulin/insulin ratio was used as an indicator of abnormal ß-cell function. The ratio of the first 30-min increase in insulin to glucose concentrations following the oral glucose tolerance test (OGTT; I30-0/G30-0) was taken as an indicator of insulin secretion. Insulin resistance (R) was evaluated by the homeostasis model assessment (HOMA) method. True insulin and proinsulin were measured during a 75-g OGTT in 35 individuals: 20 with normal glucose tolerance (NGT) and without diabetes among their first-degree relatives (FDR) served as controls, and 15 with NGT who were FDR of patients with NIDDM. The FDR group presented higher insulin (414 pmol/l vs 195 pmol/l; P = 0.04) and proinsulin levels (19.6 pmol/l vs 12.3 pmol/l; P = 0.03) post-glucose load than the control group. When these groups were stratified according to BMI, the obese FDR (N = 8) showed higher fasting and post-glucose insulin levels than the obese NGT (N = 9) (fasting: 64.8 pmol/l vs 7.8 pmol/l; P = 0.04, and 60 min post-glucose: 480.6 pmol/l vs 192 pmol/l; P = 0.01). Also, values for HOMA (R) were higher in the obese FDR compared to obese NGT (2.53 vs 0.30; P = 0.075). These results show that FDR of NIDDM patients have true hyperinsulinemia (which is not a consequence of cross-reactivity with proinsulin) and hyperproinsulinemia and no dysfunction of a qualitative nature in ß-cells.

Specific insulin and proinsulin secretion in glucokinase-deficient individuals

Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose levels within a narrow range. Mutations in the glucokinase gene cause a rare form of diabetes called maturity-onset diabetes of the young (MODY). An early onset (less than 25 years), autosomal dominant inheritance and low insulin secretion stimulated by glucose characterize MODY patients. Specific insulin and proinsulin were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared to non-diabetic unrelated individuals (control group 1) matched for age and body mass index (BMI). In one kindred, some of these subjects were also obese (BMI >26 kg/m2), and other family members also presented with obesity and/or late-onset NIDDM. The MODY patients were also compared to a group of five of their first-degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was different in members of the two MODY kindreds. Fasting proinsulin and the proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects from control group 1, but were significantly lower than in MODY members of kindred SA (P<0.02 and P<0.01, for proinsulin and proinsulin/insulin ratio, respectively). Moreover, MODY members of family SA had higher levels of proinsulin and proinsulin/insulin ratio, although not significantly different, when compared to their first-degree relatives and to subjects from control group 2. In conclusion, we observed variable degrees of proinsulin levels and proinsulin/insulin ratio in MODY members of two different kindreds. The higher values of these parameters found in MODY and non-MODY members of kindred SA is probably related to the obesity and late-onset NIDDM background present in this family.

Multiple sclerosis and pregnancy: clinical and immunological aspects

Background: Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system that affects most commonly young women in their childbearing age. Previous studies have shown that MS relapse rate usually reduces during pregnancy and increases again after delivery. Patients with MS and their treating physicians are interested to know more about the risks the disease can cause to pregnancy and how pregnancy affects the disease. The reasons for increased relapse rate after delivery are not entirely clear, but loss of pregnancy related immune tolerance and changes in the hormonal status at the time of delivery seem to be of relevance. Aims and methods: The aims of this study were to follow the natural course of MS during and after pregnancy, evaluate pregnancy related risks among MS patients, follow the inflammatory response of MS patients during and after pregnancy and clarify the risk of relevant co-morbidities known to affect other autoimmune diseases after pregnancy and compare these results to healthy controls. This study was a part of a prospective nation-wide follow-up study of 60 Finnish MS patients. All eligible MS patients were enrolled in the study during the years 2003-2005. A prospective followup continued from early pregnancy until six months postpartum. MS relapses, EDSS scores and obstetric details were recorded. Blood samples were obtained from the patients at early, middle, and late pregnancy, after delivery and one month, three months and six months postpartum. Results: MS patients were no more likely to experience pregnancy or delivery complications than the Finnish mothers in general. The need of instrumental assistance, however, was higher among mothers with MS. Disease activity followed the course seen in previous studies. The majority of mothers (90.2%) breastfed their babies. Contrary to previous results, breastfeeding did not protect MS patients from disease worsening after delivery in present study. Mothers with active pre-pregnancy disease chose to breastfeed less frequently and started medication instead. MS patients presented with higher prevalence of elevated thyroid autoantibodies postpartum than healthy controls, but the rate of thyroid hormonal dysfunction was similar as that of healthy controls. The mode of delivery nor the higher rate of tissue damage assessed with C-reactive protein concentration were not predictive of postpartum relapses. The prevalence of gestational diabetes was slightly higher among mothers with MS compared to Finnish mothers in general, but postpartum depression was observed in similar rates. MS patients presented with significantly lower serum concentrations of vitamin D during pregnancy and postpartum than healthy controls. Conclusions: Childbearing can be regarded as safe for mothers with MS as it is for healthy mothers in general. Breastfeeding can be recommended, but it should be done only after careful evaluation of the individual risk for postpartum disease activation. Considering MS patients tend to develop thyroid antibody positivity after delivery more often than healthy controls and that certain treatments can predispose MS patients to thyroid hormonal dysfunction, we recommend MS mothers to be screened for thyroid abnormalities during pregnancy and after delivery. Increased risk for gestational diabetes should be kept in mind when following MS mothers and glucose tolerance test in early pregnancy should be considered. Adequate vitamin D supplementation is essential for MS mothers also during pregnancy and postpartum period.

A high-fructose diet induces changes in pp185 phosphorylation in muscle and liver of rats

Insulin stimulates the tyrosine kinase activity of its receptor resulting in the tyrosine phosphorylation of pp185, which contains insulin receptor substrates IRS-1 and IRS-2. These early steps in insulin action are essential for the metabolic effects of insulin. Feeding animals a high-fructose diet results in insulin resistance. However, the exact molecular mechanism underlying this effect is unknown. In the present study, we determined the levels and phosphorylation status of the insulin receptor and pp185 (IRS-1/2) in liver and muscle of rats submitted to a high-fructose diet evaluated by immunoblotting with specific antibodies. Feeding fructose (28 days) induced a discrete insulin resistance, as demonstrated by the insulin tolerance test. Plasma glucose and serum insulin and cholesterol levels of the two groups of rats, fructose-fed and control, were similar, whereas plasma triacylglycerol concentration was significantly increased in the rats submitted to the fructose diet (P<0.05). There were no changes in insulin receptor concentration in the liver or muscle of either group. However, insulin-stimulated receptor autophosphorylation was reduced to 72 ± 4% (P<0.05) in the liver of high-fructose rats. The IRS-1 protein levels were similar in both liver and muscle of the two groups of rats. In contrast, there was a significant decrease in insulin-induced pp185 (IRS-1/2) phosphorylation, to 83 ± 5% (P<0.05) in liver and to 77 ± 4% (P<0.05) in muscle of the high-fructose rats. These data suggest that changes in the early steps of insulin signal transduction may have an important role in the insulin resistance induced by high-fructose feeding.

A high-fructose diet induces insulin resistance but not blood pressure changes in normotensive rats

Rats fed a high-fructose diet represent an animal model for insulin resistance and hypertension. We recently showed that a high-fructose diet containing vegetable oil but a normal sodium/potassium ratio induced mild insulin resistance with decreased insulin receptor substrate-1 tyrosine phosphorylation in the liver and muscle of normal rats. In the present study, we examined the mean blood pressure, serum lipid levels and insulin sensitivity by estimating in vivo insulin activity using the 15-min intravenous insulin tolerance test (ITT, 0.5 ml of 6 µg insulin, iv) followed by calculation of the rate constant for plasma glucose disappearance (Kitt) in male Wistar-Hannover rats (110-130 g) randomly divided into four diet groups: control, 1:3 sodium/potassium ratio (R Na:K) diet (C 1:3 R Na:K); control, 1:1 sodium/potassium ratio diet (CNa 1:1 R Na:K); high-fructose, 1:3 sodium/potassium ratio diet (F 1:3 R Na:K), and high-fructose, 1:1 sodium/potassium ratio diet (FNa 1:1 R Na:K) for 28 days. The change in R Na:K for the control and high-fructose diets had no effect on insulin sensitivity measured by ITT. In contrast, the 1:1 R Na:K increased blood pressure in rats receiving the control and high-fructose diets from 117 ± 3 and 118 ± 3 mmHg to 141 ± 4 and 132 ± 4 mmHg (P<0.05), respectively. Triacylglycerol levels were higher in both groups treated with a high-fructose diet when compared to controls (C 1:3 R Na:K: 1.2 ± 0.1 mmol/l vs F 1:3 R Na:K: 2.3 ± 0.4 mmol/l and CNa 1:1 R Na:K: 1.2 ± 0.2 mmol/l vs FNa 1:1 R Na:K: 2.6 ± 0.4 mmol/l, P<0.05). These data suggest that fructose alone does not induce hyperinsulinemia or hypertension in rats fed a normal R Na:K diet, whereas an elevation of sodium in the diet may contribute to the elevated blood pressure in this animal model.