Browsing by Subject "insulin resistance"

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  • Kochumon, Shihab; Arefanian, Hossein; Sindhu, Sardar; Shenouda, Steve; Thomas, Reeby; Al-Mulla, Fahd; Tuomilehto, Jaakko; Ahmad, Rasheed (2021)
    Steroid receptor RNA activator 1 (SRA1) is involved in pathophysiological responses of adipose tissue (AT) in obesity. In vitro and animal studies have elucidated its role in meta-inflammation. Since SRA1 AT expression in obesity/type 2 diabetes (T2D) and the relationship with immune-metabolic signatures remains unclear, we assessed AT SRA1 expression and its association with immune–metabolic markers in individuals with obesity/T2D. For this, 55 non-diabetic and 53 T2D individuals classified as normal weight (NW; lean), overweight, and obese were recruited and fasting blood and subcutaneous fat biopsy samples were collected. Plasma metabolic markers were assessed using commercial kits and AT expression of SRA1 and selected immune markers using RT-qPCR. SRA1 expression was significantly higher in non-diabetic obese compared with NW individuals. SRA1 expression associated with BMI, PBF, serum insulin, and HOMA-IR in the total study population and people without diabetes. SRA1 associated with waist circumference in people without diabetes and NW participants, whereas it associated inversely with HbA1c in overweight participants. In most study subgroups AT SRA1 expression associated directly with CXCL9, CXCL10, CXCL11, TNF-α, TGF-β, IL2RA, and IL18, but inversely with CCL19 and CCR2. TGF-β/IL18 independently predicted the SRA1 expression in people without diabetes and in the total study population, while TNF-α/IL-2RA predicted SRA1 only in people with diabetes. TNF-α also predicted SRA1 in both NW and obese people regardless of the diabetes status. In conclusion, AT SRA1 expression is elevated in people with obesity which associates with typical immunometabolic markers of obesity/T2D, implying that SRA1 may have potential as a biomarker of metabolic derangements.
  • Fan, Yuxin; Wang, Leishen; Liu, Huikun; Zhang, Shuang; Tian, Huiguang; Shen, Yun; Tuomilehto, Jaakko; Yu, Zhijie; Yang, Xilin; Hu, Gang; Liu, Ming (2020)
    Introduction To evaluate the single association of postpartum beta-cell dysfunction and insulin resistance (IR), as well as different combinations of postpartum beta-cell dysfunction, IR, obesity, and a history of gestational diabetes mellitus (GDM) with postpartum type 2 diabetes risk. Research design and methods The study included 1263 women with prior GDM and 705 women without GDM. Homeostatic model assessment was used to estimate homeostatic model assessment of beta-cell secretory function (HOMA-%beta) and homeostatic model assessment of insulin resistance (HOMA-IR). Results Multivariable-adjusted ORs of diabetes across quartiles of HOMA-%beta and HOMA-IR were 1.00, 1.46, 2.15, and 6.25 (p(trend) Conclusions beta-cell dysfunction or IR was significantly associated with postpartum diabetes. IR and beta-cell dysfunction, together with obesity and a history of GDM, had the highest ORs of postpartum diabetes risk.
  • Liimatta, Jani; Utriainen, Pauliina; Laitinen, Tomi; Voutilainen, Raimo; Jääskeläinen, Jarmo (2019)
    Context: Premature adrenarche (PA) is associated with childhood overweight and hyperinsulinemia; the long-term cardiometabolic outcome is unknown. Objective: To study cardiometabolic profile in adult women with previous PA. Design and participants: Thirty women with PA and 41 control subjects were followed from prepuberty to young adulthood. Main outcome measures: Prevalence of the metabolic syndrome (MetS) and clinical and biochemical cardiovascular risk factors. Results: There were no differences in the prevalence of MetS or in any parameters indicating dyslipidemia, hypertension, hepatosteatosis, atherosclerosis, or low-grade inflammation between the study groups. However, prevalence of insulin resistance (IR; P = 0.014) and acanthosis nigricans (P = 0.010) was higher in the PA group. Neither fasting glucose nor insulin concentrations differed between the study groups, but HbA1c [adjusted for body mass index (BMI) P = 0.011] and Homeostatic Model Assessment of Insulin Resistance (P = 0.044; BMI-adjusted P = nonsignificant) were higher in the PA group. Although BMI and fat percentage were comparable between the study groups, the PA group had higher central fat mass than the control group. In the whole study population, MetS and IR were associated with greater adult fat mass, but no prepubertal factors predicting later IR were found. Conclusion: PA does not seem to be associated with MetS, dyslipidemia, hypertension, atherosclerosis, or low-grade inflammation in young adult women. However, some women with PA may be at an increased risk of unfavorable glucose metabolism, which is associated with increased central adiposity at adult age rather than determined by prepubertal factors. Copyright (C) 2019 Endocrine Society
  • Petäjä, Elina M.; Yki-Järvinen, Hannele (2016)
    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and fibrosis. "Obese/Metabolic NAFLD" is closely associated with obesity and insulin resistance and therefore predisposes to type 2 diabetes and cardiovascular disease. NAFLD can also be caused by common genetic variants, the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2). Since NAFL, irrespective of its cause, can progress to NASH and liver fibrosis, its definition is of interest. We reviewed the literature to identify data on definition of normal liver fat using liver histology and different imaging tools, and analyzed whether NAFLD caused by the gene variants is associated with insulin resistance. Histologically, normal liver fat content in liver biopsies is most commonly defined as macroscopic steatosis in less than 5% of hepatocytes. In the population-based Dallas Heart Study, the upper 95th percentile of liver fat measured by proton magnetic spectroscopy (1H-MRS) in healthy subjects was 5.6%, which corresponds to approximately 15% histological liver fat. When measured by magnetic resonance imaging (MRI)-based techniques such as the proton density fat fraction (PDFF), 5% macroscopic steatosis corresponds to a PDFF of 6% to 6.4%. In contrast to "Obese/metabolic NAFLD", NAFLD caused by genetic variants is not associated with insulin resistance. This implies that NAFLD is heterogeneous and that "Obese/Metabolic NAFLD" but not NAFLD due to the PNPLA3 or TM6SF2 genetic variants predisposes to type 2 diabetes and cardiovascular disease.
  • Qin, Nanbing; Bayat, Ali-Reza; Trevisi, Erminio; Minuti, Andrea; Kairenius, Piia; Viitala, Sirja; Mutikainen, Mervi; Leskinen, Heidi; Elo, Kari Tapani; Kokkonen, Tuomo Juhani; Vilkki, Johanna (2018)
    To investigate the metabolic (.11, ! in the adipose tissue (AT) of dairy cows under milk fat depression (MFD), 30 cows were randomly allocated to a control diet, a conjugated linoleic acid (CLA)-supplemented diet, or a high-starch diet supplemented with a mixture of sunflower and fish oil (2:1; as HSO diet) from 1 to 112 d in milk. Performance of animals, milk yield, milk composition, energy balance, and blood metabolites were measured during lactation. Quantitative PCR analyses were conducted on the AT samples collected at wk 3 and 15 of lactation. The CLA and HSO diets considerably depressed milk fat yield and milk fat content at both wk 3 and 15 in the absence of significant changes in milk protein and lactose contents. In addition, the HSO diet lowered milk yield at wk 15 and decreased dry matter intake of cows from wk 3 to 15. Compared with the control, both CLA and HSO groups showed reduced body weight loss, improved energy balance, and decreased plasma concentrations of nonesterified fatty acids and beta-hydroxybutyrate at early lactation. The gene expression analyses reflected suppressed lipolysis in AT of the CLA and HSO groups compared with the control at wk 3, as suggested by the downregulation of hormone-sensitive lipase and fatty acid binding protein 4 and the upregulation of perilipin 2. In addition, the HSO diet promoted lipogenesis in AT at wk 15 through the upregulation of 1-acylglycerol-3-phosphate O-acyltransferase 2, mitochondria' glycerol-3-phosphate acyltransferase, perilipin 2, and peroxisome proliferator-activated receptor gamma. The CLA diet likely regulated insulin sensitivity in AT as it upregulated the transcription of various genes involved in insulin signaling, inflammatory responses, and ceramide metabolism, including protein kinase B2, nuclear factor kappa B1, toll-like receptor 4, caveolin 1, serine palmitoyltransferase long chain base subunit 1, and N-acylsphingosine amidohydrolase 1. In contrast, the HSO diet resulted in little or no change in the pathways relevant to insulin sensitivity. In conclusion, the CLA and HSO diets induced a shift in energy partitioning toward AT instead of mammary gland during lactation through the regulation of different pathways.
  • Luukkonen, Panu K.; Qadri, Sami; Ahlholm, Noora; Porthan, Kimmo; Mannisto, Ville; Sammalkorpi, Henna; Penttilä, Anne K.; Hakkarainen, Antti; Lehtimäki, Tiina E.; Gaggini, Melania; Gastaldelli, Amalia; Ala-Korpela, Mika; Orho-Melander, Marju; Arola, Johanna; Juuti, Anne; Pihlajamäki, Jussi; Hodson, Leanne; Yki-Järvinen, Hannele (2022)
    Background & Aims: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. Methods: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D-5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). Results: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepaticmitochondrial redox state, as determined by serum beta-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum beta-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. Conclusions: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. Lay summary: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
  • Polianskyte-Prause, Zydrune; Tolvanen, Tuomas A.; Lindfors, Sonja; Kon, Kanta; Hautala, Laura C.; Wang, Hong; Wada, Tsutomu; Tsuneki, Hiroshi; Sasaoka, Toshiyasu; Lehtonen, Sanna (2022)
    Ebselen, a multifunctional organoselenium compound, has been recognized as a potential treatment for diabetes-related disorders. However, the underlying mechanisms whereby ebselen regulates metabolic pathways remain elusive. We discovered that ebselen inhibits lipid phosphatase SHIP2 (Src homology 2 domain-containing inositol-5-phosphatase 2), an emerging drug target to ameliorate insulin resistance in diabetes. We found that ebselen directly binds to and inhibits the catalytic activity of the recombinant SHIP2 phosphatase domain and SHIP2 in cultured cells, the skeletal muscle and liver of the diabetic db/db mice, and the liver of the SHIP2 overexpressing (SHIP2-Tg) mice. Ebselen increased insulin-induced Akt phosphorylation in cultured myotubes, enhanced insulin sensitivity and protected liver tissue from lipid peroxidation and inflammation in the db/db mice, and improved glucose tolerance more efficiently than metformin in the SHIP2-Tg mice. SHIP2 overexpression abrogated the ability of ebselen to induce glucose uptake and reduce ROS production in myotubes and blunted the effect of ebselen to inhibit SHIP2 in the skeletal muscle of the SHIP2-Tg mice. Our data reveal ebselen as a potent SHIP2 inhibitor and demonstrate that the ability of ebselen to ameliorate insulin resistance and act as an antioxidant is at least in part mediated by the reduction of SHIP2 activity.
  • Luukkonen, Panu K.; Dufour, Sylvie; Lyu, Kun; Zhang, Xian-Man; Hakkarainen, Antti; Lehtimäki, Tiina E.; Cline, Gary W.; Petersen, Kitt Falk; Shulman, Gerald I.; Yki-Järvinen, Hannele (2020)
    Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D-7]glucose, [C-13(4)]beta-hydroxybutyrate and [3-C-13]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (H-1-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (-58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward keto-genesis (+232%) due to reductions in serum insulin concentrations (-53%) and hepatic citrate synthase flux (-38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (-45%) and triiodothyronine (-21%) concentrations. These data demonstrate heretofore unde-scribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.
  • Salin, S.; Vanhatalo, A.; Jaakkola, S.; Elo, K.; Taponen, J.; Boston, R. C.; Kokkonen, T. (2018)
    High energy intake in the dry period has reportedly had adverse effects on mobilization of body reserves, dry matter intake, and productivity of dairy cows. We investigated whether grass silage (GS) fed ad libitum (high energy intake, HEI; 141% of daily metabolizable energy requirements) in an 8-wk dry period affects metabolic adaptation-specifically, peripheral insulin resistance-compared with a total mixed ration consisting of GS, wheat straw, and rapeseed meal (55/40/5%; controlled energy intake, CEI; 108% of metabolizable energy/d) fed ad libitum. Multiparous Ayrshire dairy cows (n = 16) were used in a randomized complete block design until 8 wk after parturition. Commercial concentrates were fed 1 and 2 kg/d during the last 10 to 6 and 5 to 0 d before the expected calving date, respectively. Postpartum, a similar lactation diet with ad libitum access to GS and increasing concentrate allowance (maximum of 16 kg/d) was offered to all. The HEI group gained more body weight and had higher plasma insulin, glucose, and beta-hydroxybutyrate concentrations than the CEI group prepartum. Postpartal plasma glucose tended to be higher and milk yield was greater from wk 5 onward for HEI compared with CEI cows. An intravenous glucose tolerance test (IVGTT) was performed at -13 +/- 5 d and 9 +/- 1 d relative to calving. The HEI cows had greater insulin response to glucose load and smaller area under the response curve for glucose than CEI cows in prepartal IVGTT. Thus, compensatory insulin secretion adapted to changes in insulin sensitivity of the peripheral tissues, preserving glucose tolerance of HEI cows. Higher insulin levels were needed in HEI cows than in CEI cows to elicit a similar decrement of nonesterified fatty acid concentration in prepartal wurr, suggesting reduced inhibition of lipolysis by insulin in HEI cows before parturition. In conclusion, high energy intake of moderately digestible GS with low concentrate feeding in the close-up dry period did not have adverse effects on metabolic adaptation, insulin sensitivity, and body mobilization after parturition. Instead, this feeding regimen was more beneficial to early-lactation performance than GS-based total mixed ration diluted with wheat straw.
  • Sekhar, Deepa (Helsingfors universitet, 2012)
    Metabolic disorders are known to predispose dairy cows to periparturient diseases. Main components of metabolic disorder are insulin resistance and severe negative energy balance which are responsible for the reduced fertility in addition of increased risk of disease in dairy cows. The mobilization of adipose tissue in response to energy deficiency is associated with metabolic and endocrine changes during early lactation. Reduced insulin sensitivity in peripheral tissues could potentially change the relative rates of lipolysis and lipogenesis. This study focused on expression of lipogenesis and lipolysis associated genes around parturition. Samples and data sets for this study were obtained from the feeding experiments conducted from September 2010 to April 2011 in Viikki Experimental Farm at the University of Helsinki. Sixteen multiparous Ayrshire cows were divided into two groups based on energy level and fibre content of their feed: (1) grass silage group (control) and (2) silage-roughage mixture group (experiment). During experimental period average energy intake (MJ/day) in silage group was 35% higher than in silage-roughage mixture group. Subcutaneous adipose tissue samples were collected a week before, one day and a week after parturition from cows. Total RNA was extracted from tissue samples quality and quantity of total RNA was analysed using electrophoresis and spectrophotometer. Complementary DNA (cDNA) was prepared from the total RNA for quantitative PCR (qPCR). QPCR was conducted to quantitate expression of the following genes: adiponectin (ADIPOQ), leptin (LEP), peroksisome proliferator activated receptor gamma (PPAR-?), adiponectin receptor-1 (AR1), adiponectin receptor-2 (AR2), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD) and hormone-sensitive lipase (HSL). Two genes, AR2 and LEP, were downregulated in group 1. Reduced expression of AR2 in group 1 may relate to an increased insulin resistance. The glucose metabolism was reduced further leading to reduced insulin sensitivity. Lower expression of LEP after parturition indicates usage of energy for milk production. The upregulation of SCD in group 1 before and after calving as well as after calving in group 2 may be a result of the uptake of fatty acids by the mammary tissues. The expression of ADIPOQ, AR1, LPL, PPAR, and HSL did not show any significant changes.
  • Honkala, Sanna Maria; Motiani, Piryanka; Kivelä, Riikka; Hemanthakumar, Karthik Amudhala; Tolvanen, Erik; Motiani, Kumail Kumar; Eskelinen, Jari-Joonas; Virtanen, Kirsi A.; Kemppainen, Jukka; Heiskanen, Marja Anneli; Loyttyniemi, Eliisa; Nuutila, Pirjo; Kalliokoski, Kari K.; Hannukainen, Jarna Christina (2020)
    Introduction We investigated the effects of a supervised progressive sprint interval training (SIT) and moderate-intensity continuous training (MICT) on adipocyte morphology and adipose tissue metabolism and function; we also tested whether the responses were similar regardless of baseline glucose tolerance and sex. Research design and methods 26 insulin-resistant (IR) and 28 healthy participants were randomized into 2-week-long SIT (4-6x30 s at maximum effort) and MICT (40-60 min at 60% of maximal aerobic capacity (VO2peak)). Insulin-stimulated glucose uptake and fasting-free fatty acid uptake in visceral adipose tissue (VAT), abdominal and femoral subcutaneous adipose tissues (SATs) were quantified with positron emission tomography. Abdominal SAT biopsies were collected to determine adipocyte morphology, gene expression markers of lipolysis, glucose and lipid metabolism and inflammation. Results Training increased glucose uptake in VAT (p
  • Seppa, Satu; Tenhola, Sirpa; Voutilainen, Raimo (2019)
    Context: Among cytokines, fibroblast growth factor 21 (FGF21), adiponectin (Adn), and irisin have been considered potential biomarkers for insulin sensitivity (IS). Objective: We evaluated whether serum FGF21, Adn, and irisin associate with markers of IS and serum lipids in 12-year-old children. Design, Participants, and Main Outcome Measures: This cohort study included 192 12-year-old children (109 girls). Seventy-eight of them had been born appropriate for gestational age (AGA), 70 small for gestational age (SGA), and 44 from preeclamptic pregnancies (PREs) as AGA. Fasting serum FGF21, Adn, irisin, lipids, inflammatory markers, and IS markers were measured. Quantitative insulin sensitivity check index (QUICKI) was calculated. Results: The means of serum FGF21, high molecular weight (HMW) Adn, and irisin did not differ between the sexes or between the SGA, AGA, and PRE children. In the whole study population, FGF21 associated positively with irisin and uric acid and negatively with leptin and high-density lipoprotein cholesterol (HDL-C). HMW Adn associated positively with total Adn, HDL-C, leptin, and SHBG. Apart from FGF21, irisin associated positively with insulin, high-sensitivity C-reactive protein, y-glutamyltransferase, and triglycerides, and negatively with QUICKI, SHBG, and IGF binding protein-1. In multivariate regression analyses, irisin predicted lower IS and HMW Adn predicted higher HDL-C body mass index-independently, whereas FGF21 had no independent contribution to IS or lipid variables. Conclusion: In 12-year-old children, serum irisin was associated with markers reflecting reduced IS. HMW Adn predicted HDL-C, whereas FGF21 did not contribute to IS or lipid parameters in multivariate regression analyses. Copyright (C) 2019 Endocrine Society
  • Wasik, Anita A.; Lehtonen, Sanna (2018)
    Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a common cause of end-stage renal disease worldwide. DKD manifests as an increased urinary protein excretion (albuminuria). Multiple studies have shown that insulin resistance correlates with the development of albuminuria in non-diabetic and diabetic patients. There is also accumulating evidence that glomerular epithelial cells or podocytes are insulin sensitive and that insulin signaling in podocytes is essential for maintaining normal kidney function. At the cellular level, the mechanisms leading to the development of insulin resistance include mutations in the insulin receptor gene, impairments in the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, or perturbations in the trafficking of glucose transporters (GLUTs), which mediate the uptake of glucose into cells. Podocytes express several GLUTs, including GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8. Of these, the most studied ones are GLUT1 and GLUT4, both shown to be insulin responsive in podocytes. In the basal state, GLUT4 is preferentially located in perinuclear and cytosolic vesicular structures and to a lesser extent at the plasma membrane. After insulin stimulation, GLUT4 is sorted into GLUT4-containing vesicles (GCVs) that translocate to the plasma membrane. GCV trafficking consists of several steps, including approaching of the GCVs to the plasma membrane, tethering, and docking, after which the lipid bilayers of the GCVs and the plasma membrane fuse, delivering GLUT4 to the cell surface for glucose uptake into the cell. Studies have revealed novel molecular regulators of the GLUT trafficking in podocytes and unraveled unexpected roles for GLUT1 and GLUT4 in the development of DKD, summarized in this review. These findings pave the way for better understanding of the mechanistic pathways associated with the development and progression of DKD and aid in the development of new treatments for this devastating disease.
  • Tuorila, Katri; Ollila, Meri-Maija; Järvelin, Marjo-Riitta; Tapanainen, Juha S.; Franks, Stephen; Puukka, Katri; Piltonen, Terhi T.; Morin-Papunen, Laure (2021)
    Context: The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. Objective: To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 years is associated with insulin resistance, insulin secretion and AGM by age 46. Design: Prospective study including 5889 females followed at ages 31 and 46 years. Setting: General community. Participants: Women with HA were compared with normoandrogenic women at ages 31 and 46 years. Intervention: None. Main outcome measurements: AGM, including prediabetes and type 2 diabetes mellitus, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic beta-cell function (HOMA-B). Results: At age 31 years, HA women displayed increased HOMA-IR (P = 0.002), HOMA-B (P = 0.007), and higher fasting insulin (P = 0.03) than normoandrogenic women after adjusting for body mass index (BMI). At age 46 years, there was a nonsignificant trend toward higher fasting glucose (P = 0.07) and glycated hemoglobin A1 (P = 0.07) levels in HA women. Women in the highest T quartile (odds ratio [OR] = 1.80; 95%CI, 1.15-2.82) at age 31 years and in the 2 highest FAI quartiles at ages 31 (Q4: OR = 3.76; 95% CI, 2.24-6.32) and 46 (Q4: OR = 2.79; 95% CI, 1.74-4.46) years had increased risk for AGM, independently of BMI, when compared with women in Q1. SHBG was inversely associated with AGM (at age 31 years: Q4: OR = 0.37; 95% CI, 0.23-0.60, at age 46 years: Q4: OR = 0.28; 95% CI, 0.17-0.44). Conclusion: Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.
  • Poessel, Maria; Freiherr, Jessica; Wiencke, Kathleen; Villringer, Arno; Horstmann, Annette (2020)
    The worldwide obesity epidemic is a major health problem driven by the modern food environment. Recently, it has been shown that smell perception plays a key role in eating behavior and is altered in obesity. However, the underlying mechanisms of this phenomenon are not well understood yet. Since the olfactory system is closely linked to the endocrine system, we hypothesized that hormonal shifts in obesity might explain this relationship. In a within-subject, repeated-measures design, we investigated sensitivity to a food and a non-food odor in the hungry and sated state in 75 young healthy (26 normal weight, 25 overweight, and 24 obese) participants (37 women). To determine metabolic health status and hormonal reactivity in response to food intake, we assessed pre- and postprandial levels of insulin, leptin, glucose, and ghrelin. Odor sensitivity did not directly depend on body weight status/body mass index (BMI) or hunger state. However, we could establish a strong negative mediating effect of insulin resistance on the relationship between BMI/waist-hip ratio and olfactory sensitivity for the food odor. These findings indicate an impact of metabolic health status on sensitivity to food odors. Our results contribute to a better understanding of the mechanisms behind altered smell perception in obesity.
  • Polianskyte-Prause, Zydrune; Tolvanen, Tuomas A.; Lindfors, Sonja; Dumont, Vincent; Van, Mervi; Wang, Hong; Dash, Surjya N.; Berg, Mika; Naams, Jette-Britt; Hautala, Laura C.; Nisen, Harry; Mirtti, Tuomas; Groop, Per-Henrik; Wähälä, Kristiina; Tienari, Jukka; Lehtonen, Sanna (2019)
    Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wahala, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.
  • Arora, G. P.; Åkerlund, M.; Brons, C.; Moen, G-H; Wasenius, N. S.; Sommer, C.; Jenum, A. K.; Almgren, P.; Thaman, R. G.; Orho-Melander, M.; Eriksson, J.; Qvigstad, E.; Birkeland, K.; Berntorp, K.; Vaag, A. A.; Groop, L.; Prasad, R. B. (2019)
    Objective Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. Methods Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). Results Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. Conclusions Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.
  • Vara, Katariina (Helsingfors universitet, 2012)
    The main objective of this thesis was to analyse the impact of dry period energy intake on the intensity of metabolic stress and insulin resistance through changes in gene expression in dairy cows. Calving and beginning of lactation cause a negative energy balance which increases fat mobilization, metabolic stress and insulin resistance. These are intensified by high milk yield and excess energy intake from feed during the dry period. 14 genes were selected for the analysis. These genes encode proteins that are linked to lipogenesis, lipolysis and insulin signaling. The changes in the gene expression of subcutaneous adipose tissue were compared between two groups of eight cows. The control group was fed according to the energy requirements while the test group was fed ad libitum. The biopsies were taken -8d, +1d and +9d from parturition, cDNA was synthesized from them and they were analysed by quantitative PCR and 2-??CT-method. There Expression differences were observed in seven genes within the whole data between biopsy dates. During the period from before to after parturition, differences were identified in the expression of 11 genes within the whole data and the control group, and one gene in the test group. The most significant differences were observed in LEP and SCD genes. Between the groups there was a difference in the gene expression of IRS1 before parturition. This refers to the test group being more insulin resistant. After parturition there were no significant differences found in the gene expressions. The most significant changes observed in this study were as expected in early lactation. In the period between before and after parturition there were bigger changes in the gene expression observed in the control group than in the test group. The results indicate that cows getting more energy from their feed during the dry period are more insulin resistant before parturition.
  • Hovi, Marianne (Helsingfors universitet, 2012)
    The burden of diabetes is increasing globally as the number of people with diabetes reaches over 220 million. Over 90 per cent of these people are suffering from type 2 diabetes. This condition is primarily defined by the chronic increase in blood glucose level or hyperglycemia. Type 2 diabetes is characterized by insulin resistance and is usually associated with abnormal insulin secretion. Insulin resistance is a state where normal amount of blood insulin is inadequate to increase glucose uptake in the most important target tissues of insulin. Numerous reports demonstrate that oversupply of lipids leads to loss of insulin activity and the formation of type 2 diabetes. Protein kinase C (PKC) isozymes comprise a family of serine/threoninekinases, which have a regulatory role in a multiple cellular processes. PKC!-isozyme activity is known to play a role in insulin resistance and therefore in type 2 diabetes. Free fatty acid (FFA) induced insulin gene function inhibition is associated with phosphoinositide dependent kinase1 (PDK1) independent phosphorylation of PKC!-isozyme in the most important insulin target tissues. Phosphorylated PKC!-isozyme causes insulinreceptor gene expression inhibition. Present study is part of a VHH-antibodies related research where the goal is to characterize these antibodies and to find out their effects on protein kinase C. VHH-antibodies are Ilama derived antibodies which contain a single heavy-chain variable domain, that is fully capable of antigen binding. In this work, we studied VHH-antibodies binding to PKC!-isozyme and its functional domains. PKC!-isozyme and its domains were produced in Sf9-insect cells. The binding was studied using Western blot and immunoprecipitation assays. In addition, the binding of 368 VHHantibodies to PKCε-isozyme's domain 2 were studied. With Western blot, it was discovered that E7-VHH-antibody binds to PKCε-isozyme full length and to domain 3. Other VHHantibodies tested in Western blot did not bind to PKCε-isozyme. Seven VHH-antibodies bound to PKCε-isozyme in immunoprecipitation. All of these VHH-antibodies bound to the full length and to domain 3, but not to other domains. In radioligand binding assays none of the VHH-antibodies bound to domain 2 that is the binding site to the endogenous PKCε-isozyme activator diacylglycerol (DAG). The results gathered with these three different methods were in line with each other. As the results gained from Western blot and immunoprecipitation show, all the VHH-antibodies, that bind to PKCε-isozyme, bind to its domain 3. With this study, we succeeded to gather new information about the binding of VHH-antibodies to PKCε-isozyme and its domains. The exact binding site has not been studied with so many VHH-antibodies before this study. Moreover, we also exploited methods that have not been used in this context before.
  • Lehtonen, Sanna (2020)
    SHIP2 (Src homology 2 domain-containing inositol 5 '-phosphatase 2) belongs to the family of 5 '-phosphatases. It regulates the phosphoinositide 3-kinase (PI3K)-mediated insulin signalling cascade by dephosphorylating the 5 '-position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first-line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.