Browsing by Subject "type 2 diabetes"

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  • Kauppila, T.; Laine, M.K.; Honkasalo, Mika; Raina, Marko; Eriksson, J.G. (2020)
    The aim of this study was to evaluate whether patients with type 2 diabetes (T2D) who had stopped attending their diabetes treatment system (referred to as “lost to follow-up”, LTF) but who succeeded in improving their glycaemic control after returning to the diabetes treatment system had changes in their diabetes medication when compared with similar patients who did not show improvement. “LTFs” who had baseline haemoglobin A1 c (HbA1 c) ≥53 mmol/mol and succeeded in reducing HbA1 c ≥ 6 mmol/mol during a 12–30 month follow-up period after adhering again to their diabetes treatment system were compared with “LTFs” who had an unsatisfactory change in HbA1 c or with “LTFs” who maintained good glycaemic control throughout the 12–30 month follow-up period. Unsatisfactory change in HbA1 c was determined as HbA1 c ≥ 53 mmol/mol and change <6 mmol/mol after the 12–30 month follow-up period in their diabetes treatment system or HbA1 c < 53 mmol/mol when returning to the diabetes treatment system but ≥53 mmol/mol at the end of the 12–30 month follow-up period. “LTFs” with improvement in glycaemic control used a higher number of different anti-hyperglycaemic agents (P < 0.001) and their dosages of metformin increased (P < 0.05) when compared with “LTFs” without improvement or “LTFs” with satisfactory glycaemic control. Cholesterol-, LDL-cholesterol- and triglyceride-concentrations decreased during the 12–30 month follow-up period (P < 0.05) in “LTFs” with improved glycaemic control, but not in the other groups. “LTFs” with T2D who had poor glycaemic control seemed to require an increase in their anti-diabetic medication when attempting to improve their glycaemic control. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
  • Hebbar, Prashantha; Abubaker, Jehad Ahmed; Abu-Farha, Mohamed; Tuomilehto, Jaakko; Al-Mulla, Fahd; Thanaraj, Thangavel Alphonse (2019)
    Despite dedicated nation-wide efforts to raise awareness against the harmful effects of fast-food consumption and sedentary lifestyle, the Arab population continues to struggle with an increased risk for metabolic disorders. Unlike the European population, the Arab population lacks well-established genetic risk determinants for metabolic disorders, and the transferability of established risk loci to this population has not been satisfactorily demonstrated. The most recent findings have identified over 240 genetic risk loci (with similar to 400 independent association signals) for type 2 diabetes, but thus far only 25 risk loci (ADAMTS9, ALX4, BCL11A, CDKAL1, CDKN2A/B, COL8A1, DUSP9, FTO, GCK, GNPDA2, HMG20A, HNF1A, HNF1B, HNF4A, IGF2BP2, JAZF1, KCNJ11 , KCNQ1, MC4R, PPAR gamma, SLC30A8, TCF7L2, TFAP2B, TP53INP1, and WFS1) have been replicated in Arab populations. To our knowledge, large-scale population- or family-based association studies are non-existent in this region. Recently, we conducted genome-wide association studies on Arab individuals from Kuwait to delineate the genetic determinants for quantitative traits associated with anthropometry, lipid profile, insulin resistance, and blood pressure levels. Although these studies led to the identification of novel recessive variants, they failed to reproduce the established loci. However, they provided insights into the genetic architecture of the population, the applicability of genetic models based on recessive mode of inheritance, the presence of genetic signatures of inbreeding due to the practice of consanguinity, and the pleiotropic effects of rare disorders on complex metabolic disorders. This perspective presents analysis strategies and study designs for identifying genetic risk variants associated with diabetes and related traits in Arab populations.
  • Pekkala, Timo; Hall, Anette; Mangialasche, Francesca; Kemppainen, Nina; Mecocci, Patrizia; Ngandu, Tiia; Rinne, Juha O.; Soininen, Hilkka; Tuomilehto, Jaakko; Kivipelto, Miia; Solomon, Alina (2020)
    We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE epsilon 4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.
  • Ritzel, Robert; Roussel, Ronan; Giaccari, Andrea; Vora, Jiten; Brulle-Wohlhueter, Claire; Yki-Järvinen, Hannele (2018)
    AimsTo investigate the efficacy and safety of insulin glargine 300U/mL (Gla-300) vs insulin glargine 100U/mL (Gla-100) over 12months in a patient-level meta-analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM). Methods EDITION 1, 2 and 3 were multicentre, randomized, open-label, 2-arm, parallel-group, treat-to-target phase IIIa studies. Similar study designs and endpoints enabled a meta-analysis to be conducted. ResultsReductions in glycated haemoglobin (HbA1c) were better sustained over 12months with Gla-300 than with Gla-100 (least squares [LS] mean difference in change from baseline: -0.10 % [95% confidence interval {CI} -0.18 to -0.02] or -1.09mmol/mol [95% CI -2.01 to -0.20]; P=.0174). Risk of confirmed (3.9mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 vs Gla-100 at night (relative risk 0.85 [95% CI 0.77-0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90-0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 vs Gla-100 at night (rate ratio 0.82 [95% CI 0.67-0.99]), but comparable at any time of day. HbA1c ConclusionsIn a broad population of people with T2DM over 12months, use of Gla-300 provided more sustained glycaemic control and significantly lower hypoglycaemia risk at night and at any time of day compared with Gla-100.
  • D'Alessio, D.; Haering, H. -U.; Charbonnel, B.; de Pablos-Velasco, P.; Candelas, C.; Dain, M. -P.; Vincent, M.; Pilorget, V.; Yki-Jarvinen, H.; EAGLE Investigators (2015)
  • Kauppila, Timo; Laine, Merja K.; Honkasalo, Mikko; Raina, Marko; Eriksson, Johan G. (2016)
    Objective: To characterize dropouts from type-2 diabetes (T2D) care in communal primary health care. Design: An observational study. Setting: In a Finnish city, patients with T2D who had not contacted the public primary health care system during the past 12 months were identified with a computer based search and contacted by a trained diabetes nurse. Subjects: Dropouts from T2D treatment. Main outcome measures: Demographic factors, laboratory parameters, examinations, medications, and comorbidities. Results: Of the patients with T2D, 10% (n=356) were dropouts and 60% of them were men. Median HbA(1c) was 6.5 (QR for 25% and 75%: 6.0, 7.7) %, (45 [42,61] mmol/mol). Of the dropouts, 14% had HbA(1c)9.0% (75mmol/mol), and these patients were younger than the other dropouts (mean age 54.4 [SD 10.8] years vs. 60.6 [9.4] years, p Conclusions: Ten percent of T2D patients were dropouts of whom those with a poor glycaemic control were younger than the other dropouts. BP and LDL cholesterol concentrations were non-optimal among the majority of the dropouts. Metformin was prescribed less frequently to the dropouts than is usual for T2D patients. The comorbidities were equally common among the dropouts as among the other T2D patients.
  • Hasan, Amal; Kochumon, Shihab; Al-Ozairi, Ebaa; Tuomilehto, Jaakko; Al-Mulla, Fahd; Ahmad, Rasheed (2020)
    Purpose: The suppression of tumorigenicity 2 (ST2) has two main splice variants including a membrane bound (ST2) form, which activates the myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-kappa B) signaling pathway, and a secreted soluble form (sST2), which acts as a decoy receptor for ST2 ligand, interleukin (IL)-33. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D). In humans, adipose tissue IL-33 displays distinct correlation profiles with glycated hemoglobin, ST2, and other immunometabolic mediators, depending on the glycemic health of the individuals. We determined whether adipose tissue ST2 displays distinct correlation profiles with immunometabolic mediators and whether ST2 and/or IL-33 are correlated with intracellular signaling molecules. Patients and Methods: A total of 91 adults with normal glycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissues were isolated and mRNA expression of biomarkers was measured. Results: In individuals with normal glycemia, adipose tissue ST2 was directly correlated with chemokine (C-C motif) ligand (CCL)-2, CCL5, IL-12, fibrinogen-like protein 2 (FGL2) and interferon regulatory factor (IRF)-4, but inversely correlated with cytochrome C oxidase subunit 7A1. IL-33 and ST2 were directly correlated with tumor necrosis factor receptorassociated factor 6 (TRAF6), NF-kappa B, and nuclear factor of activated T-cells 5 (NFAT5). In individuals with prediabetes, ST2 was inversely correlated with IL-5, whereas IL-33 but not ST2 was directly correlated with MyD88 and NF-kappa B. In individuals with T2D, ST2 was directly correlated with CCL2, IL-1 beta, and IRF5. IL-33 and ST2 were directly correlated with MyD88, TRAF6, and NF-kappa B. Conclusion: Adipose tissue ST2 and IL-33 show different correlation profiles with various immunometabolic biomarkers depending on the metabolic state of the individuals. Therefore, targeting the IL-33/ST2 axis might form the basis for novel therapies to combat metabolic disorders.
  • Lehtisalo, Jenni; Lindstrom, Jaana; Ngandu, Tiia; Kivipelto, Miia; Ahtiluoto, Satu; Ilanne-Parikka, Pirjo; Keinanen-Kiukaanniemi, Sirkka; Eriksson, Johan G.; Uusitupa, Matti; Tuomilehto, Jaakko; Luchsinger, Jose A.; Finnish Diabet Prevention Study DP (2016)
    BackgroundType 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies, but these observations are limited by lack of data on the exact timing of diabetes onset. We investigated diabetes, dysglycaemia, and cognition in the Finnish Diabetes Prevention Study, in which the timing and duration of diabetes are well documented. MethodsThe Finnish Diabetes Prevention Study comprised middle-aged, overweight participants with impaired glucose tolerance but no diabetes at baseline (n=522), randomized to lifestyle intervention or a control group. After an intervention period (mean duration 4years) and follow-up (additional 9years), cognitive assessment with the CERAD test battery and Trail Making Test A (TMT) was executed twice within a 2-year interval. Of the 364 (70%) participants with cognitive assessments, 171 (47%) had developed diabetes. ResultsCognitive function did not differ between those who developed diabetes and those who did not. Lower mean 2-h glucose at an oral glucose tolerance test (OGTT) and HbA(1C) during the intervention period predicted better performance in the TMT (p=0.012 and 0.024, respectively). Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessments (p=0.001) whereas those with long duration of diabetes did not (p=0.844). ConclusionsBetter glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9years later in this secondary analysis of the Finnish Diabetes Prevention Study population. In addition, learning effects in cognitive testing were not evident in people with long diabetes duration. Copyright (c) 2015 John Wiley & Sons, Ltd.
  • Dayeh, Tasnim; Tuomi, Tiinamaija; Almgren, Peter; Perfilyev, Alexander; Jansson, Per-Anders; de Mello, Vanessa D.; Pihlajamaki, Jussi; Vaag, Allan; Groop, Leif; Nilsson, Emma; Ling, Charlotte (2016)
    Identification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1 locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02-1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1 locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75-0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1 locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.
  • Mustonen, Erja; Horhammer, Iiris; Absetz, Pilvikki; Patja, Kristiina; Lammintakanen, Johanna; Talja, Martti; Kuronen, Risto; Linna, Miika (2020)
    Objective To evaluate the long-term effect of telephone health coaching on health care and long-term care (LTC) costs in type 2 diabetes (T2D) and coronary artery disease (CAD) patients. Data Sources/Study Setting Randomized controlled trial (RCT) data were linked to Finnish national health and social care registries and electronic health records (EHR). Post-trial eight-year economic evaluation was conducted. Study Design A total of 1,535 patients (>= 45 years) were randomized to the intervention (n = 1034) and control groups (n = 501). The intervention group received monthly telephone health coaching for 12 months. Usual health care and LTC were provided for both groups. Principal Findings Intention-to-treat analysis showed no significant change in total health and long-term care costs (intervention effect euro1248 [3 percent relative reduction], CI -6347 to 2217) in the intervention compared to the control group. There were also no significant changes among subgroups of patients with T2D or CAD. Conclusions Health coaching had a nonsignificant effect on health care and long-term care costs in the 8-year follow-up among patients with T2D or CAD. More research is needed to study, which patient groups, at which state of the disease trajectory of T2D and cardiovascular disease, would best benefit from health coaching.
  • Cuthbertson, Daniel J.; Koskinen, Juha; Brown, Emily; Magnussen, Costan G.; Hutri-Kahonen, Nina; Sabin, Matthew; Tossavainen, Paivi; Jokinen, Eero; Laitinen, Tomi; Viikari, Jorma; Raitakari, Olli T.; Juonala, Markus (2021)
    Aims To investigate the association between overweight/obesity and fatty liver index (FLI) on the odds of incident prediabetes/type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in 2020 participants after 10 years follow up. Methods At baseline (in 2001) 2020 participants, males and females, aged 24-39 years, were stratified according to body mass index (BMI), normal weight (= 25-= 30 kg/m(2)) and FLI (as high FLI >= 60 or low FLI
  • Sarin, Heikki V.; Taba, Nele; Fischer, Krista; Esko, Tonu; Kanerva, Noora; Moilanen, Leena; Saltevo, Juha; Joensuu, Anni; Borodulin, Katja; Männistö, Satu; Kristiansson, Kati; Perola, Markus (2019)
    Background: Food neophobia is considered a behavioral trait closely linked to adverse eating patterns and reduced dietary quality, which have been associated with increased risk of obesity and noncommunicable diseases. Objectives: In a cross-sectional and prospective study, we examined how food neophobia is associated with dietary quality, health-related biomarkers, and disease outcome incidence in Finnish and Estonian adult populations. Methods: The study was conducted based on subsamples of the Finnish DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) cohort (n = 2982; age range: 25-74 y) and the Estonian Biobank cohort (n = 1109; age range: 18-83 y). The level of food neophobia was assessed using the Food Neophobia Scale, dietary quality was evaluated using the Baltic Sea Diet Score (BSDS), and biomarker profiles were determined using an NMR metabolomics platform. Disease outcome information was gathered from national health registries. Follow-up data on the NMR-based metabolomic profiles and disease outcomes were available in both populations. Results: Food neophobia associated significantly (adjusted P <0.05) with health-related biomarkers [e.g., omega-3 (n-3) fatty acids, citrate, alpha(1)-acid glycoprotein, HDL, and MUFA] in the Finnish DILGOM cohort. The significant negative association between the severity of food neophobia and omega-3 fatty acids was replicated in all cross-sectional analyses in the Finnish DILGOM and Estonian Biobank cohorts. Furthermore, food neophobia was associated with reduced dietary quality (BSDS: beta: -0.03 +/- 0.006; P = 8.04 x 10(-5)), increased fasting serum insulin (beta: 0.004 +/- 0.0013; P = 5.83 x 10(-3)), and increased risk of type 2 diabetes during the similar to 8-y follow-up (HR: 1.018 +/- 0.007; P = 0.01) in the DILGOM cohort. Conclusions: In the Finnish and Estonian adult populations, food neophobia was associated with adverse alteration of health-related biomarkers and risk factors that have been associated with an increased risk of noncommunicable diseases. We also found that food neophobia associations with omega-3 fatty acids and associated metabolites are mediated through dietary quality independent of body weight.
  • 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.
  • Kettunen, Jarno L. T.; Tuomi, Tiinamaija (2020)
    The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study. (C) 2020 The Authors. Published by Elsevier Ltd.
  • Wang, Haining; Liu, Ye; Tian, Qing; Yang, Jin; Lu, Ran; Zhan, Siyan; Haukka, Jari; Hong, Tianpei (2018)
    Aims: To perform a meta-analysis of randomized controlled trials (RCTs), including 6 recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with type 2 diabetes (T2DM). Materials and Methods: For the period January 1, 2007 to May 1, 2017, the PubMed, Embase, Cochrane Central Register and databases were searched for RCTs in people with T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of >= 52 weeks. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate. Results: A total of 33 studies (n = 79971), including the 6 CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered incretin drugs compared with controls (Peto odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44-1.02). In the 6 CVOTs, 79 pancreatic cancer events were identified in 55248 participants. Pooled estimates of the 6 CVOTs showed an identical tendency (Peto OR 0.65, 95% CI 0.42-1.01). Notably, in the subgroup of participants who received treatment and follow-up for >= 104 weeks, 84 pancreatic cancer events were identified in 59919 participants, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62, 95% CI 0.41-0.95). Conclusions: Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for 104 weeks.
  • Koponen, Anne; Vahtera, Jussi; Pitkäniemi, Janne Mikael; Virtanen, Marianna; Pentti, Jaana; Simonsen-Rehn, Nina; Kivimäki, Mika; Suominen, Sakari (2013)
  • Christiansen, Jens Sandahl; Niskanen, Leo; Rasmussen, Soeren; Johansen, Thue; Fulcher, Greg (2016)
    BackgroundInsulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the basal analog insulin degludec and the rapid-acting prandial insulin aspart in a single injection. The present combined analysis of two Phase 3a trials compared the incidence of hypoglycemia in participants treated twice daily with IDegAsp or biphasic insulin aspart 30 (BIAsp 30). MethodsHypoglycemia data were analyzed from two similarly designed randomized controlled open-label treat-to-target Phase 3a clinical trials of adults with type 2 diabetes (T2D). Participants were treated twice daily with IDegAsp or BIAsp 30, with breakfast and their main evening meal. ResultsOver 26 weeks, the rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events were 19%, 57%, and 39% lower, respectively, with IDegAsp (n = 504) than BIAsp 30 (n = 364); estimated rate ratios were 0.81 (95% confidence interval [CI] 0.67, 0.98; P = 0.0341), 0.43 (95% CI 0.31, 0.59; P = 0.0001), and 0.61 (95% CI 0.26, 1.45; P = NS). The between-treatment differences were more pronounced during the maintenance period (16 weeks); compared with BIAsp 30, rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events with IDegAsp were 0.69 (95% CI 0.55, 0.87; -31%; P = 0.0015); 0.38 (95% CI 0.25, 0.58; -62%; P <0.0001), and 0.16 (95% CI 0.04, 0.59; -84%; P = 0.0061), respectively. ConclusionsCompared with BIAsp 30 twice daily, IDegAsp twice daily provided similar improvements in glycemic control with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, in subjects with T2D previously treated with insulin.
  • Urpilainen, Elina; Arima, Reetta; Karihtala, Peeter; Puistola, Ulla; Ahtikoski, Anne (2021)
    Background/Aim: Preclinical studies on metformin use and endometrial cancer have been promising but epidemiological studies have reported variable results. This study aimed to assess if metformin use is associated with endometrial cancer aggressiveness and survival in women with type 2 diabetes (T2D). Patients and Methods: This retrospective hospital-based cohort consisted of women with T2D who were treated for endometrial cancer at the Oulu University Hospital, Finland, between 2007 and 2014. Results: The sample size was 121 patients: 58 metformin users and 63 metformin non-users. Intriguingly,type 2 histology, deep myometrial invasion and the presence of lymphovascular invasion were more common in the metformin user group. However, metformin use showed no association with overall survival and progression-free survival. Conclusion: Metformin use was associated with poorer prognostic factors in endometrial cancer patients with T2D.
  • 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.
  • Urpilainen, Elina; Ahtikoski, Anne; Arima, Reetta; Puistola, Ulla; Karihtala, Peeter (2021)
    Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient's age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.