Diabetes (DIABETES )

Publisher: American Diabetes Association, American Diabetes Association


Diabetes publishes original research about the physiology and pathophysiology of diabetes mellitus. Submitted manuscripts can report any aspect of laboratory, animal, or human research. Emphasis is on investigative reports focusing on areas such as the pathogenesis of diabetes and its complications, normal and pathologic pancreatic islet function and intermediary metabolism, pharmacological mechanisms of drug and hormone action, and biochemical and molecular aspects of normal and abnormal biological processes. Studies in the areas of diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus are not published.

  • Impact factor
    Show impact factor history
    Impact factor
  • 5-year impact
  • Cited half-life
  • Immediacy index
  • Eigenfactor
  • Article influence
  • Website
    Diabetes website
  • Other titles
  • ISSN
  • OCLC
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

American Diabetes Association

  • Pre-print
    • Archiving status unclear
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • On author website, institutional repository or funding body (eg NIH)
    • Post-prints must include the set statement (see copyright assignment information)
    • Must link to publisher version
    • Must be identical to final accepted version
    • Authors may make erratum at any time
    • Publisher's version/PDF cannot be used
  • Classification
    ​ blue

Publications in this journal

  • Diabetes 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: γ-aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABAAR and GABABR. This activated the PI3K-Akt and CREB-IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation.
    Diabetes 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic TGF-β1 signaling and increases mitochondrial biogenesis. Here we report that inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production and mitochondrial fusion. Conversely, overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species-induced apoptosis. IHG-1 forms complexes with known mediators of mitochondrial fusion - mitofusin 1 (Mfn1) and Mfn2, and enhances the GTP-binding capacity of Mfn2 suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localised to mitochondria to interact with Mfn1 and Mfn2 and this interaction is necessary for increased IHG-1-mediated mitochondrial fusion. Together, these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. We propose that in diabetic kidney disease increased IHG-1 expression protects cell viability and enhances the actions of TGF-β leading to renal proximal tubule dedifferentiation an important event in the pathogenesis of this devastating condition.
    Diabetes 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13, have been previously associated with risk for several autoimmune diseases including type 1 diabetes. In order to identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we re-sequenced a 455 kb region in type 1 diabetes patients and unaffected controls, identifying 93 novel variants. A panel of 939 SNPs, that included 46 of these novel variants, was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided statistically significant association (P < 5.32 x 10(-5)) with disease, with rs34306440 (P = 5.74 x 10(-6)) being most significantly associated. The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease, and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to risk for type 1 diabetes is through reduced expression of DEXI.
    Diabetes 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is accompanied by the presence of chronic low grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied WT and MBL-/- mice rendered obese by high fat feeding (HFD). Whereas no gross morphological differences were observed in liver, HFD feeding provoked distinct changes in adipose tissue morphology of MBL-/- mice. In parallel with increased adipocyte size, MBL-/- mice displayed increased influx of macrophages into adipose tissue. Macrophages were polarized towards an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, absence of MBL did not impact systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in recognition and clearance of apoptotic adipocytes during obesity.
    Diabetes 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes mellitus, diabetic nephropathy (DN) became the leading cause of end stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in DN. These events are fueled by heterotypic interactions between glomerular, tubular and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and post-translationally activated by Cathepsin L of tubular origin, sustains continuous activation of kidney-damaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury.Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in DN and perhaps other complications of diabetes.
    Diabetes 07/2014;
  • Diabetes 07/2014; 63(7):2216-8.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release and thereby glucose homeostasis is associated with subtle changes in Ca(2+) dynamics in mouse β-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve PLC/InsP3-mediated Ca(2+) mobilization from intracellular stores as well as decreased β-cell Ca(2+) influx over the plasma membrane. We use three mouse models, namely a premature ageing phenotype, a mature ageing phenotype and an ageing-resistant phenotype. Premature ageing is studied in a genetically modified mouse model with an age-dependent accumulation of mtDNA mutations. Mature ageing is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that ageing is associated with a progressive decline in β-cell mitochondrial function that negatively impacts on the fine tuning of Ca(2+) dynamics. This is conceptually important since it emphasizes that even relatively modest changes in β-cell signal-transduction over time lead to compromised insulin release and a diabetic phenotype.
    Diabetes 07/2014;
  • Diabetes 07/2014; 63(7):2225-8.
  • Diabetes 07/2014; 63(7):2222-4.
  • Diabetes 07/2014; 63(7):e11-2.
  • Diabetes 07/2014; 63(7):2206-8.
  • Diabetes 07/2014; 63(7):2213-5.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adipose tissue macrophages (ATMs) recruitment and activation play a critical role in obesity-induced inflammation and insulin resistance (IR). Mechanism regulating ATM activation and infiltration remains unclear. In this study, we found Receptor Interacting Protein 140 (RIP140) can regulate the dynamics of ATM that contributes to adipose tissue remodeling. A high fat diet (HFD) elevates RIP140 expression in macrophage. We generated mice with RIP140 knockdown in macrophages using transgenic and bone marrow transplantation procedures to blunt HFD-induced elevation in RIP140. We detected significant white adipose tissue (WAT) browning and improved systemic insulin sensitivity in these mice, particularly under a HFD feeding. These mice have decreased circulating monocyte population and altered ATM profile in WAT (a dramatic reduction in inflammatory M1 and expansion in M2 macrophage), which could improve HFD-induced IR. These studies suggest that reducing RIP140 expression in monocytes/macrophages can be a new therapeutic strategy in treating HFD-induced and inflammation-related diseases.
    Diabetes 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously demonstrated that micro-RNAs 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of micro-RNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including non-fuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT, Slc25a20) is a direct target of these miRNAs. CACT is responsible for transporting long-chain acyl-carnitines into the mitochondria for β-oxidation. SiRNA mediated knockdown of CACT in β-cells led to the accumulation of fatty acyl-carnitines, and enhanced IS. The addition of long-chain fatty acyl-carnitines promoted IS from INS-1 β-cells as well as primary mouse islets. The effect in INS-1 cells was augmented in response to suppression of CACT. A non-hydrolyzable ether analog of palmitoyl-carnitine stimulated IS, showing that β-oxidation of palmitoyl-carnitine is not required for its stimulation of IS. These studies establish a link between miRNA-dependent regulation of CACT and fatty acyl-carnitine mediated regulation of IS.
    Diabetes 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: In rodents, brown adipose tissue (BAT) regulates cold- (CIT) and diet-induced thermogenesis (DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism has not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance and substrate metabolism in a prospective crossover study of 4-month duration, consisting of 4 consecutive blocks of 1-month overnight temperature acclimation [24°C (month 1) → 19°C (month 2) → 24°C (month 3) → 27°C (month 4)] of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (p<0.05), respectively, independent of seasonal fluctuations (p<0.01). BAT-acclimation did not alter CIT but was accompanied by DIT (p<0.05) and post-prandial insulin sensitivity enhancement (p<0.05), evident only after cold-acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits.
    Diabetes 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2(+/+)) and heterozygous knockout mice (sod2(+/-)) were fed chow or high fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2(+/-) and sod2(+/+) but was markedly decreased in HF-fed sod2(+/-). Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2(+/-) was associated with increased ROS, such as O2˙-. Surprisingly, insulin action determined by HI clamps, did not differ between sod2(+/-) and sod2(+/+) of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2(+/-) was due to increased glucose effectiveness. Increased GLUT1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2(+/-) support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action.
    Diabetes 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is unknown whether independent neural damage may occur in the pre-/absent vascular diabetic retinopathy (DR). To exclude vasculopathy, it is important to measure the integrity of the blood-retinal barrier (BRB). This cross-sectional study addressed this problem in type 1 diabetic patients with normal ocular fundus and absent breakdown of the BRB (confirmed with vitreous fluorometry). These were compared with a group with disrupted BRB (with normal fundus or initial DR) and normal controls. Multifocal electroretinography and chromatic/achromatic contrast sensitivity were measured in these 42 patients with preserved visual acuity. Amplitudes of neurophysiological responses (multifocal electroretinogram) were decreased in all eccentricity rings in both clinical groups, when compared with controls, with sensitivity >78% for a specificity level of 90%. Implicit time changes were also found in the absence of initial DR. Impaired contrast sensitivity along chromatic axes was also observed, and achromatic thresholds were also different between controls and both clinical groups. The pattern of changes in the group without baseline BRB permeability alterations, as probed by psychophysical and electrophysiological measurements, does thereby confirm independent damage mechanisms. We conclude that retinal neuronal changes can be diagnosed in type 1 diabetes, independently of breakdown of the BRB and onset of vasculopathy.
    Diabetes 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin D1 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1-mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC1α is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1α and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis.
    Diabetes 06/2014;

Related Journals