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Diabetologia
Journal Prestige (SJR): 3.228
Citation Impact (citeScore): 5
Number of Followers: 276  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1432-0428 - ISSN (Online) 0012-186X
Published by Springer-Verlag Homepage  [2350 journals]
  • 54 th EASD Annual Meeting of the European Association for the Study of
           Diabetes
    • Pages: 1 - 620
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4693-0
      Issue No: Vol. 61, No. S1 (2018)
       
  • Up front
    • Pages: 2073 - 2074
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4721-0
      Issue No: Vol. 61, No. 10 (2018)
       
  • The bark giving diabetes therapy some bite: the SGLT inhibitors
    • Authors: Sally M. Marshall
      Pages: 2075 - 2078
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4673-4
      Issue No: Vol. 61, No. 10 (2018)
       
  • Development of SGLT1 and SGLT2 inhibitors
    • Authors: Timo Rieg; Volker Vallon
      Pages: 2079 - 2086
      Abstract: Abstract Sodium–glucose cotransporters SGLT1 (encoded by SGLT1, also known as SLC5A1) and SGLT2 (encoded by SGLT2, also known as SLC5A2) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4654-7
      Issue No: Vol. 61, No. 10 (2018)
       
  • Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2
    • Authors: Chiara Ghezzi; Donald D. F. Loo; Ernest M. Wright
      Pages: 2087 - 2097
      Abstract: Abstract The concentration of glucose in plasma is held within narrow limits (4–10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium−glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. ‘Knockout’ of these transporters in mice and men results in the excretion of filtered glucose in the urine. In humans, intravenous injection of the plant glucoside phlorizin also results in excretion of the full filtered glucose load. This outcome and the finding that, in an animal model, phlorizin reversed the symptoms of diabetes, has stimulated the development and successful introduction of SGLT2 inhibitors, gliflozins, in the treatment of type 2 diabetes mellitus. Here we summarise the current state of our knowledge about the physiology of renal glucose handling and provide background to the development of SGLT2 inhibitors for type 2 diabetes treatment.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4656-5
      Issue No: Vol. 61, No. 10 (2018)
       
  • The actions of SGLT2 inhibitors on metabolism, renal function and blood
           pressure
    • Authors: Merlin C. Thomas; David Z. I. Cherney
      Pages: 2098 - 2107
      Abstract: Abstract Inhibition of the sodium–glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA1c of 7–10 mmol/mol (0.6–0.9%) when compared with placebo. This glucose-lowering activity is proportional to the ambient glucose concentration and glomerular filtration of this glucose, so may be greater in those with poor glycaemic control and/or hyperfiltration at baseline. Equally, the glucose-lowering effects of SGLT2 inhibitors are attenuated in individuals without diabetes and those with a reduced eGFR. However, unlike the glucose-lowering effects of SGLT2 inhibitors, the spill-over of sodium and glucose beyond the proximal nephron following SGLT2 inhibition triggers dynamic and reversible realignment of energy metabolism, renal filtration and plasma volume without relying on losses into the urine. In addition, these processes are observed in the absence of significant glucosuria or ongoing natriuresis. In the long term, the resetting of energy/salt/water physiology following SGLT2 inhibition has an impact, not only on adiposity, renal function and blood pressure control, but also on the health and survival of patients with type 2 diabetes. A better understanding of the precise biology underlying the acute actions of SGLT2 inhibitors in the kidney and how they are communicated to the rest of the body will likely lead to improved therapeutics that augment similar pathways in individuals with, or even without, diabetes to achieve additional benefits.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4669-0
      Issue No: Vol. 61, No. 10 (2018)
       
  • SGLT2 inhibitors and mechanisms of cardiovascular benefit: a
           state-of-the-art review
    • Authors: Subodh Verma; John J. V. McMurray
      Pages: 2108 - 2117
      Abstract: Abstract Sodium–glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit. Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without diabetes.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4670-7
      Issue No: Vol. 61, No. 10 (2018)
       
  • Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and
           benefits
    • Authors: Beatrice C. Lupsa; Silvio E. Inzucchi
      Pages: 2118 - 2125
      Abstract: Abstract Sodium–glucose cotransporter 2 (SGLT2) inhibitors belong to a novel class of glucose-lowering medications that reduce plasma glucose concentrations by inhibiting glucose reabsorption by the kidney, inducing glucosuria. Their actions encompass reductions in HbA1c, fasting and postprandial blood glucose levels, body weight and BP. To date, empagliflozin and canagliflozin have additionally been shown to improve cardiovascular outcomes in high-risk individuals and to slow the progression of diabetic kidney disease. Adverse effects associated with this class include urinary frequency, dehydration, genitourinary tract infections and, rarely, euglycaemic diabetic ketoacidosis. Of the SGLT2 inhibitors, only canagliflozin has been linked to a higher risk of lower-extremity amputations and bone fractures compared with placebo. Optimal prescribing of agents within this relatively new drug category requires a full understanding of their risks in addition to their benefits.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4663-6
      Issue No: Vol. 61, No. 10 (2018)
       
  • SGLT inhibitor adjunct therapy in type 1 diabetes
    • Authors: Rory J. McCrimmon; Robert R. Henry
      Pages: 2126 - 2133
      Abstract: Abstract Non-insulin adjunct therapies in type 1 diabetes have been proposed as a means of improving glycaemic control and reducing risk of hypoglycaemia. Evidence to support this approach is, however, scant and few pharmacological agents have proved effective enough to become part of routine clinical care. Recent short-term Phase II trials and 24 week Phase III trials provide initial support for the use of sodium–glucose cotransporter (SGLT) inhibitors in type 1 diabetes. Two international, multicentre, randomised, controlled clinical trials, Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-1) and inTandem3, have reported that SGLT inhibition with dapagliflozin and sotagliflozin, respectively, confer additional benefits in terms of a 5–6 mmol/mol (0.4–0.5%) reduction in HbA1c accompanied by weight loss and reductions in total daily insulin doses. The reduction in HbA1c does not come with a significantly increased risk of hypoglycaemia but does carry an increased risk of diabetic ketoacidosis and mycotic infections. These results suggest that SGLT inhibition will have a place in the management of type 1 diabetes. Longer-term clinical trials (≥52 weeks) and observational cohort studies are needed to determine any additional benefits or adverse effects of this adjunct therapy and to determine which group of patients may benefit most from this approach. In addition, use of SGLT inhibitors in routine type 1 diabetes care will require specific patient and healthcare professional educational packages to ensure patient safety and to minimise risk.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4671-6
      Issue No: Vol. 61, No. 10 (2018)
       
  • SGLT2 inhibitors: the future for treatment of type 2 diabetes mellitus and
           other chronic diseases
    • Authors: Christoph Wanner; Nikolaus Marx
      Pages: 2134 - 2139
      Abstract: Abstract Individuals with diabetes mellitus exhibit an increased propensity to develop cardiovascular disorders such as coronary artery disease, stroke and heart failure. Over recent decades, numerous cardiovascular outcome trials in individuals with type 2 diabetes have been published, with data showing a reduction of cardiovascular morbidity and mortality by sodium–glucose cotransporter 2 (SGLT2) inhibitors. These results not only provide novel therapeutic options for this high-risk population but also advance our current understanding of cardiovascular risk reduction in diabetes. The current overview article summarises these aspects and discusses future treatment strategies with SGLT2 inhibitors in diabetic and non-diabetic individuals with chronic kidney disease, liver disease and heart failure.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4678-z
      Issue No: Vol. 61, No. 10 (2018)
       
  • Sex differences in the association between diabetes and cancer: a
           systematic review and meta-analysis of 121 cohorts including 20 million
           individuals and one million events
    • Authors: Toshiaki Ohkuma; Sanne A. E. Peters; Mark Woodward
      Pages: 2140 - 2154
      Abstract: Aims/hypothesis Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown. Methods A systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex-specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratios of RRs (RRRs) for all-site and site-specific cancers. Results Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer. Conclusions/interpretation Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4664-5
      Issue No: Vol. 61, No. 10 (2018)
       
  • Empagliflozin is associated with improvements in liver enzymes potentially
           consistent with reductions in liver fat: results from randomised trials
           including the EMPA-REG OUTCOME® trial
    • Authors: Naveed Sattar; David Fitchett; Stefan Hantel; Jyothis T. George; Bernard Zinman
      Pages: 2155 - 2163
      Abstract: Aims/hypothesis In addition to beneficial effects on glycaemia and cardiovascular death, empagliflozin improves adiposity indices. We investigated the effect of empagliflozin on aminotransferases (correlates of liver fat) in individuals with type 2 diabetes. Methods Changes from baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in the EMPA-REG OUTCOME® trial (n = 7020), pooled data from four 24-week placebo-controlled trials (n = 2477) and a trial of empagliflozin vs glimepiride over 104 weeks (n = 1545). Analyses were performed using data from all participants and by tertiles of baseline aminotransferases. Results In the EMPA-REG OUTCOME® trial, mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo, respectively (adjusted mean difference: −2.22 [95% CI −2.83, −1.62]; p < 0.0001). Reductions in ALT were greatest in the highest ALT tertile (placebo-adjusted mean difference at week 28: −4.36 U/l [95% CI −5.51, −3.21]; p < 0.0001). The adjusted mean difference in change in ALT was −3.15 U/l (95% CI −4.11, −2.18) with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l (95% CI −6.68, −3.09) with empagliflozin vs glimepiride at week 28. ALT reductions were largely independent of changes in weight or HbA1c. AST changes showed similar patterns to ALT, but the reductions were considerably lower. Conclusions/interpretation These highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern (reductions in ALT>AST) that is potentially consistent with a reduction in liver fat, especially when ALT levels are high.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4702-3
      Issue No: Vol. 61, No. 10 (2018)
       
  • Gluten intake and risk of type 2 diabetes in three large prospective
           cohort studies of US men and women
    • Authors: Geng Zong; Benjamin Lebwohl; Frank B. Hu; Laura Sampson; Lauren W. Dougherty; Walter C. Willett; Andrew T. Chan; Qi Sun
      Pages: 2164 - 2173
      Abstract: Aims/hypothesis We investigated the association between gluten intake and long-term type 2 diabetes risk among Americans. Methods We followed women from the Nurses’ Health Study (NHS, n = 71,602, 1984–2012) and NHS II (n = 88,604, 1991–2013) and men from the Health Professionals Follow-Up Study (HPFS, n = 41,908, 1986–2012). Gluten intake was estimated using a validated food frequency questionnaire every 2–4 years. Incident type 2 diabetes was defined as self-reported physician-diagnosed diabetes confirmed using a supplementary questionnaire. Result Gluten intake was strongly correlated with intakes of carbohydrate components, especially refined grains, starch and cereal fibre (Spearman correlation coefficients >0.6). During 4.24 million years of follow-up, 15,947 people were confirmed to have type 2 diabetes. After multivariate adjustment, pooled HRs and 95% CIs for type 2 diabetes, from low to high gluten quintiles, were (ptrend < 0.001): 1 (reference); 0.89 (0.85, 0.93); 0.84 (0.80, 0.88); 0.78 (0.74, 0.82) and 0.80 (0.76, 0.84). The association was slightly weakened after further adjusting for cereal fibre, with pooled HRs (95% CIs) of (ptrend < 0.001): 1 (reference); 0.91 (0.87, 0.96); 0.88 (0.83, 0.93); 0.83 (0.78, 0.88) and 0.87 (0.81, 0.93). Dose–response analysis supported a largely linear inverse relationship between gluten intake up to 12 g/day and type 2 diabetes. The association between gluten intake and type 2 diabetes was stronger when intake of added bran was also higher (pinteraction = 0.02). Conclusions/interpretation Gluten intake is inversely associated with type 2 diabetes risk among largely healthy US men and women. Limiting gluten in the diet is associated with lower intake of cereal fibre and possibly other beneficial nutrients that contribute to good health.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4697-9
      Issue No: Vol. 61, No. 10 (2018)
       
  • Genome-wide association study of coronary artery disease among individuals
           with diabetes: the UK Biobank
    • Authors: Tove Fall; Stefan Gustafsson; Marju Orho-Melander; Erik Ingelsson
      Pages: 2174 - 2179
      Abstract: Aims/hypothesis Coronary artery disease (CAD) is a common complication among individuals with diabetes. A better understanding of the genetic background of CAD in this population has the potential to suggest novel molecular targets for screening, risk assessment and drug development. Methods We performed a genome-wide association study of CAD in 15,666 unrelated individuals (3,968 CAD cases and 11,698 controls) of white British ancestry with diabetes at inclusion in the UK Biobank study. Our results were compared with results from participants without diabetes. Results We found genome-wide significant evidence for association with CAD at the previously well-established LPA locus (lead variant: rs74617384; OR 1.38 [95% CI 1.26, 1.51], p = 3.2 × 10−12) and at 9p21 (lead variant: rs10811652; OR 1.19 [95% CI 1.13, 1.26], p = 6.0 × 10−11). Moreover, other variants previously associated with CAD showed similar effects in the participants with and without diabetes, indicating that the genetic architecture of CAD is largely the same. Conclusions/interpretation Our results indicate large similarities between the genetic architecture of CAD in participants with and without diabetes. Larger studies are needed to establish whether there are important diabetes-specific CAD loci.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4686-z
      Issue No: Vol. 61, No. 10 (2018)
       
  • Identification of a missense variant in the WFS1 gene that causes a mild
           form of Wolfram syndrome and is associated with risk for type 2 diabetes
           in Ashkenazi Jewish individuals
    • Authors: Vikas Bansal; Bernhard O. Boehm; Ariel Darvasi
      Pages: 2180 - 2188
      Abstract: Aims/hypothesis Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and optic atrophy and is caused by bi-allelic mutations in the WFS1 gene. In a recent sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the WFS1 gene. The aim of this study was to perform the genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome. Methods We analysed the allele frequency of the missense variant in multiple variant databases. We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes. We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls. Results The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3, p = 3.4 × 10−15). The age at diagnosis of diabetes for these eight individuals (17.8 ± 8.3 years) was several times greater than for typical Wolfram syndrome (5 ± 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had the Wolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case–control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81, p = 0.004). Conclusions/interpretation We have identified a low-frequency coding variant in the WFS1 gene that is enriched in Ashkenazi Jewish individuals and causes a mild form of Wolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4690-3
      Issue No: Vol. 61, No. 10 (2018)
       
  • Activation of GLP-1 receptor signalling alleviates cellular stresses and
           improves beta cell function in a mouse model of Wolfram syndrome
    • Authors: Manabu Kondo; Katsuya Tanabe; Kikuko Amo-Shiinoki; Masayuki Hatanaka; Tsukasa Morii; Harumi Takahashi; Susumu Seino; Yuichiro Yamada; Yukio Tanizawa
      Pages: 2189 - 2201
      Abstract: Aims/hypothesis Loss of functional beta cells results in a gradual progression of insulin insufficiency in Wolfram syndrome caused by recessive WFS1 mutations. However, beta cell dysfunction in Wolfram syndrome has yet to be fully characterised, and there are also no specific treatment recommendations. In this study, we aimed to characterise beta cell secretory defects and to examine the potential effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on diabetes in Wolfram syndrome. Methods Insulin secretory function was assessed by the pancreatic perfusion method in mice used as a model of Wolfram syndrome. In addition, granule dynamics in living beta cells were examined using total internal reflection fluorescence microscopy. Acute and chronic effects of exendin-4 (Ex-4) on glucose tolerance and insulin secretion were examined in young Wfs1−/− mice without hyperglycaemia. Molecular events associated with Ex-4 treatment were investigated using pancreatic sections and isolated islets. In addition, we retrospectively observed a woman with Wolfram syndrome who had been treated with liraglutide for 24 weeks. Results Treatment with liraglutide ameliorated our patient’s glycaemic control and resulted in a 20% reduction of daily insulin dose along with an off-drug elevation of fasting C-peptide immunoreactivity. Glucose-stimulated first-phase insulin secretion and potassium-stimulated insulin secretion decreased by 53% and 59%, respectively, in perfused pancreases of 10-week-old Wfs1−/− mice compared with wild-type (WT) mice. The number of insulin granule fusion events in the first phase decreased by 41% in Wfs1−/− beta cells compared with WT beta cells. Perfusion with Ex-4 increased insulin release in the first and second phases by 3.9-fold and 5.6-fold, respectively, in Wfs1−/− mice compared with perfusion with saline as a control. The physiological relevance of the effects of Ex-4 was shown by the fact that a single administration potentiated glucose-stimulated insulin secretion and improved glucose tolerance in Wfs1−/− mice. Four weeks of administration of Ex-4 resulted in an off-drug amelioration of glucose excursions after glucose loading in Wfs1−/− mice, with insulin secretory dynamics that were indistinguishable from those in WT mice, despite the fact that there was no alteration in beta cell mass. In association with the functional improvements, Ex-4 treatment reversed the increases in phosphorylated eukaryotic initiation factor (EIF2α) and thioredoxin interacting protein (TXNIP), and the decrease in phosphorylated AMP-activated kinase (AMPK), in the beta cells of the Wfs1−/− mice. Furthermore, Ex-4 treatment modulated the transcription of oxidative and endoplasmic reticulum stress-related markers in isolated islets, implying that it was able to mitigate the cellular stresses resulting from Wfs1 deficiency. Conclusions/interpretation Our study provides deeper insights into the pathophysiology of beta cell dysfunction caused by WFS1 deficiency and implies that activation of the GLP-1 receptor signal may alleviate insulin insufficiency and aid glycaemic control in Wolfram syndrome.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4679-y
      Issue No: Vol. 61, No. 10 (2018)
       
  • MANF protects human pancreatic beta cells against stress-induced cell
           death
    • Authors: Elina Hakonen; Vikash Chandra; Christopher L. Fogarty; Nancy Yiu-Lin Yu; Jarkko Ustinov; Shintaro Katayama; Emilia Galli; Tatiana Danilova; Päivi Lindholm; Aki Vartiainen; Elisabet Einarsdottir; Kaarel Krjutškov; Juha Kere; Mart Saarma; Maria Lindahl; Timo Otonkoski
      Pages: 2202 - 2214
      Abstract: Aims/hypothesis There is a great need to identify factors that could protect pancreatic beta cells against apoptosis or stimulate their replication and thus prevent or reverse the development of diabetes. One potential candidate is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress inducible protein. Manf knockout mice used as a model of diabetes develop the condition because of increased apoptosis and reduced proliferation of beta cells, apparently related to ER stress. Given this novel association between MANF and beta cell death, we studied the potential of MANF to protect human beta cells against experimentally induced ER stress. Methods Primary human islets were challenged with proinflammatory cytokines, with or without MANF. Cell viability was analysed and global transcriptomic analysis performed. Results were further validated using the human beta cell line EndoC-βH1. Results There was increased expression and secretion of MANF in human beta cells in response to cytokines. Addition of recombinant human MANF reduced cytokine-induced cell death by 38% in human islets (p < 0.05). MANF knockdown in EndoC-βH1 cells led to increased ER stress after cytokine challenge. Mechanistic studies showed that the protective effect of MANF was associated with repression of the NF-κB signalling pathway and amelioration of ER stress. MANF also increased the proliferation of primary human beta cells twofold when TGF-β signalling was inhibited (p < 0.01). Conclusions/interpretation Our studies show that exogenous MANF protein can provide protection to human beta cells against death induced by inflammatory stress. The antiapoptotic and mitogenic properties of MANF make it a potential therapeutic agent for beta cell protection.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4687-y
      Issue No: Vol. 61, No. 10 (2018)
       
  • Programming of central and peripheral insulin resistance by low
           birthweight and postnatal catch-up growth in male mice
    • Authors: Lindsey M. Berends; Laura Dearden; Yi Chun L. Tung; Peter Voshol; Denise S. Fernandez-Twinn; Susan E. Ozanne
      Pages: 2225 - 2234
      Abstract: Aims Intra-uterine growth restriction (IUGR) followed by accelerated postnatal growth is associated with an increased risk of obesity and type 2 diabetes. We aimed to determine central and peripheral insulin sensitivity in mice that underwent IUGR followed by postnatal catch-up growth and investigate potential molecular mechanisms underpinning their physiology. Methods We used a C57BL/6J mouse model of maternal diet-induced IUGR (maternal diet, 8% protein) followed by cross-fostering to a normal nutrition dam (maternal diet, 20% protein) and litter size manipulation to cause accelerated postnatal catch-up growth. We performed intracerebroventricular insulin injection and hyperinsulinaemic–euglycaemic clamp studies to examine the effect of this early nutritional manipulation on central and peripheral insulin resistance. Furthermore, we performed quantitative real-time PCR and western blotting to examine the expression of key insulin-signalling components in discrete regions of the hypothalamus. Results IUGR followed by accelerated postnatal growth caused impaired glucose tolerance and peripheral insulin resistance. In addition, these ‘recuperated’ animals were resistant to the anorectic effects of central insulin administration. This central insulin resistance was associated with reduced protein levels of the p110β subunit of phosphoinositide 3-kinase (PI3K) and increased serine phosphorylation of IRS-1 in the arcuate nucleus (ARC) of the hypothalamus. Expression of the gene encoding protein tyrosine phosphatase 1B (PTP1B; Ptpn1) was also increased specifically in this region of the hypothalamus. Conclusions/interpretation Mice that undergo IUGR followed by catch-up growth display peripheral and central insulin resistance in adulthood. Recuperated offspring show changes in expression/phosphorylation of components of the insulin signalling pathway in the ARC. These defects may contribute to the resistance to the anorectic effects of central insulin, as well as the impaired glucose homeostasis seen in these animals.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4694-z
      Issue No: Vol. 61, No. 10 (2018)
       
  • A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications
           in a rat model of type 2 diabetes
    • Authors: Md Abdul Hye Khan; Lauren Kolb; Melissa Skibba; Markus Hartmann; René Blöcher; Ewgenij Proschak; John D. Imig
      Pages: 2235 - 2246
      Abstract: Aims/hypothesis The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes. Methods We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome—the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks. Results RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA1c, improved glucose tolerance, reduced blood pressure and improved lipid profiles in obese ZSF1 rats. A reduction in liver fibrosis and hepatosteatosis was evident in RB394-treated obese ZSF1 rats. Unlike RB394, enalapril did not demonstrate any positive effects in relation to diabetes, hyperlipidaemia or liver dysfunction in obese ZSF1 rats. RB394 ameliorated diabetic nephropathy by reducing renal interstitial fibrosis and renal tubular and glomerular injury in obese diabetic ZSF1 rats. Intriguingly, enalapril demonstrated a weaker action against diabetic nephropathy in obese ZSF1 rats. Conclusions/interpretation These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4685-0
      Issue No: Vol. 61, No. 10 (2018)
       
  • More work is needed to better understand diabetes distress as a predictor
           of all-cause mortality in type 2 diabetes
    • Authors: Nanna Lindekilde; Frans Pouwer
      Pages: 2247 - 2248
      PubDate: 2018-10-01
      DOI: 10.1007/s00125-018-4714-z
      Issue No: Vol. 61, No. 10 (2018)
       
 
 
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