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3.  Serum TAG Analysis Differentiates Between Genetic and Obesity-Associated NAFLD 
Diabetes  2013;63(1):42-44.
PMCID: PMC3968431  PMID: 24357693
4.  Pak3 Promotes Cell Cycle Exit and Differentiation of β-Cells in the Embryonic Pancreas and Is Necessary to Maintain Glucose Homeostasis in Adult Mice 
Diabetes  2013;63(1):203-215.
The transcription factor neurogenin3 (Ngn3) triggers islet cell differentiation in the developing pancreas. However, little is known about the molecular mechanisms coupling cell cycle exit and differentiation in Ngn3+ islet progenitors. We identified a novel effector of Ngn3 endocrinogenic function, the p21 protein–activated kinase Pak3, known to control neuronal differentiation and implicated in X-linked intellectual disability in humans. We show that Pak3 expression is initiated in Ngn3+ endocrine progenitor cells and next maintained in maturing hormone-expressing cells during pancreas development as well as in adult islet cells. In Pak3-deficient embryos, the proliferation of Ngn3+ progenitors and β-cells is transiently increased concomitantly with an upregulation of Ccnd1. β-Cell differentiation is impaired at E15.5 but resumes at later stages. Pak3-deficient mice do not develop overt diabetes but are glucose intolerant under high-fat diet (HFD). In the intestine, Pak3 is expressed in enteroendocrine cells but is not necessary for their differentiation. Our results indicate that Pak3 is a novel regulator of β-cell differentiation and function. Pak3 acts downstream of Ngn3 to promote cell cycle exit and differentiation in the embryo by a mechanism that might involve repression of Ccnd1. In the adult, Pak3 is required for the proper control of glucose homeostasis under challenging HFD.
PMCID: PMC3968432  PMID: 24163148
6.  Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism 
Diabetes  2013;63(1):48-49.
PMCID: PMC3968434  PMID: 24357695
9.  Nitrite Anion Therapy Protects Against Chronic Ischemic Tissue Injury in db/db Diabetic Mice in a NO/VEGF-Dependent Manner 
Diabetes  2013;63(1):270-281.
Nitrite anion has been demonstrated to be a prodrug of nitric oxide (NO) with positive effects on tissue ischemia/reperfusion injury, cytoprotection, and vasodilation. However, effects of nitrite anion therapy for ischemic tissue vascular remodeling during diabetes remain unknown. We examined whether sodium nitrite therapy altered ischemic revascularization in BKS-Leprdb/db mice subjected to permanent unilateral femoral artery ligation. Sodium nitrite therapy completely restored ischemic hind limb blood flow compared with nitrate or PBS therapy. Importantly, delayed nitrite therapy 5 days after ischemia restored ischemic limb blood flow in aged diabetic mice. Restoration of blood flow was associated with increases in ischemic tissue angiogenesis activity and cell proliferation. Moreover, nitrite but not nitrate therapy significantly prevented ischemia-mediated tissue necrosis in aged mice. Nitrite therapy significantly increased ischemic tissue vascular endothelial growth factor (VEGF) protein expression that was essential for nitrite-mediated reperfusion of ischemic hind limbs. Nitrite significantly increased ischemic tissue NO bioavailability along with concomitant reduction of superoxide formation. Lastly, nitrite treatment also significantly stimulated hypoxic endothelial cell proliferation and migration in the presence of high glucose in an NO/VEGF-dependent manner. These results demonstrate that nitrite therapy effectively stimulates ischemic tissue vascular remodeling in the setting of metabolic dysfunction that may be clinically useful.
PMCID: PMC4179307  PMID: 24009258
10.  Glutathionylated Lipid Aldehydes Are Products of Adipocyte Oxidative Stress and Activators of Macrophage Inflammation 
Diabetes  2013;63(1):89-100.
Obesity-induced insulin resistance has been linked to adipose tissue lipid aldehyde production and protein carbonylation. Trans-4-hydroxy-2-nonenal (4-HNE) is the most abundant lipid aldehyde in murine adipose tissue and is metabolized by glutathione S-transferase A4 (GSTA4), producing glutathionyl-HNE (GS-HNE) and its metabolite glutathionyl-1,4-dihydroxynonene (GS-DHN). The objective of this study was to evaluate adipocyte production of GS-HNE and GS-DHN and their effect on macrophage inflammation. Compared with lean controls, GS-HNE and GS-DHN were more abundant in visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. High glucose and oxidative stress induced production of GS-HNE and GS-DHN by 3T3-L1 adipocytes in a GSTA4-dependent manner, and both glutathionylated metabolites induced secretion of tumor necrosis factor-α from RAW 264.7 and primary peritoneal macrophages. Targeted microarray analysis revealed GS-HNE and GS-DHN induced expression of inflammatory genes, including C3, C4b, c-Fos, igtb2, Nfkb1, and Nos2. Transgenic overexpression of GSTA4 in mouse adipose tissue led to increased production of GS-HNE associated with higher fasting glucose levels and moderately impaired glucose tolerance. These results indicated adipocyte oxidative stress results in GSTA4-dependent production of proinflammatory glutathione metabolites, GS-HNE and GS-DHN, which may represent a novel mechanism by which adipocyte dysfunction results in tissue inflammation and insulin resistance.
PMCID: PMC3868039  PMID: 24062247
11.  Relationship of Glycated Albumin to Blood Glucose and HbA1c Values and to Retinopathy, Nephropathy, and Cardiovascular Outcomes in the DCCT/EDIC Study 
Diabetes  2013;63(1):282-290.
The association of chronic glycemia, measured by HbA1c, with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease (CVD) is less clear. In order to examine the interrelationships among long-term, intermediate-term, and acute measures of glucose and its daily variability, we compared HbA1c, glycated albumin (GA), and seven-point glucose profile concentrations measured longitudinally in a case-cohort subpopulation of the DCCT. HbA1c and GA were closely correlated with each other and with the mean blood glucose (MBG) calculated from the seven-point profile. The associations of glucose variability and postprandial concentrations with HbA1c and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA1c and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA1c was significantly associated with CVD. The demonstrated interrelationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes.
PMCID: PMC3868040  PMID: 23990364
12.  Insulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 Signaling Pathway 
Diabetes  2013;63(1):75-88.
Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFκB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFκB pathway.
PMCID: PMC3868041  PMID: 24009260
13.  Hepatocyte Growth Factor/c-Met Signaling Is Required for β-Cell Regeneration 
Diabetes  2013;63(1):216-223.
Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for β-cell regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models of reduced β-cell mass and regeneration: multiple low-dose streptozotocin (MLDS) and partial pancreatectomy (Ppx). We also analyzed whether HGF administration could accelerate β-cell regeneration in wild-type (WT) mice after Ppx. Mouse islets obtained 7 days post-Ppx displayed significantly increased c-Met, suggesting a potential role for HGF/c-Met in β-cell proliferation in situations of reduced β-cell mass. Indeed, adult PancMet KO mice displayed markedly reduced β-cell replication compared with WT mice 7 days post-Ppx. Similarly, β-cell proliferation was decreased in PancMet KO mice in the MLDS mouse model. The decrease in β-cell proliferation post-Ppx correlated with a striking decrease in D-cyclin levels. Importantly, PancMet KO mice showed significantly diminished β-cell mass, decreased glucose tolerance, and impaired insulin secretion compared with WT mice 28 days post-Ppx. Conversely, HGF administration in WT Ppx mice further accelerated β-cell regeneration. These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration.
PMCID: PMC3868042  PMID: 24089510
14.  Short Leukocyte Telomere Length Predicts Risk of Diabetes in American Indians: the Strong Heart Family Study 
Diabetes  2013;63(1):354-362.
Telomeres play a central role in cellular aging, and shorter telomere length has been associated with age-related disorders including diabetes. However, a causal link between telomere shortening and diabetes risk has not been established. In a well-characterized longitudinal cohort of American Indians participating in the Strong Heart Family Study, we examined whether leukocyte telomere length (LTL) at baseline predicts incident diabetes independent of known diabetes risk factors. Among 2,328 participants free of diabetes at baseline, 292 subjects developed diabetes during an average 5.5 years of follow-up. Compared with subjects in the highest quartile (longest) of LTL, those in the lowest quartile (shortest) had an almost twofold increased risk of incident diabetes (hazard ratio [HR] 1.83 [95% CI 1.26–2.66]), whereas the risk for those in the second (HR 0.87 [95% CI 0.59–1.29]) and the third (HR 0.95 [95% CI 0.65–1.38]) quartiles was statistically nonsignificant. These findings suggest a nonlinear association between LTL and incident diabetes and indicate that LTL could serve as a predictive marker for diabetes development in American Indians, who suffer from disproportionately high rates of diabetes.
PMCID: PMC3868043  PMID: 23949319
15.  HDAC9 Knockout Mice Are Protected From Adipose Tissue Dysfunction and Systemic Metabolic Disease During High-Fat Feeding 
Diabetes  2013;63(1):176-187.
During chronic caloric excess, adipose tissue expands primarily by enlargement of individual adipocytes, which become stressed with lipid overloading, thereby contributing to obesity-related disease. Although adipose tissue contains numerous preadipocytes, differentiation into functionally competent adipocytes is insufficient to accommodate the chronic caloric excess and prevent adipocyte overloading. We report for the first time that a chronic high-fat diet (HFD) impairs adipogenic differentiation, leading to accumulation of inefficiently differentiated adipocytes with blunted expression of adipogenic differentiation-specific genes. Preadipocytes from these mice likewise exhibit impaired adipogenic differentiation, and this phenotype persists during in vitro cell culture. HFD-induced impaired adipogenic differentiation is associated with elevated expression of histone deacetylase 9 (HDAC9), an endogenous negative regulator of adipogenic differentiation. Genetic ablation of HDAC9 improves adipogenic differentiation and systemic metabolic state during an HFD, resulting in diminished weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatosteatosis. Moreover, compared with wild-type mice, HDAC9 knockout mice exhibit upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis. These results suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.
PMCID: PMC3868044  PMID: 24101673
16.  Multiple HLA Epitopes Contribute to Type 1 Diabetes Susceptibility 
Diabetes  2013;63(1):323-331.
Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed. To identify the HLA shared epitopes associated with diabetes, we analyzed high-resolution genotyping for class I and class II loci. The HLA epitopes most strongly associated with susceptibility for disease were DQB1 A57, DQA1 V76, DRB1 H13, and DRB1 K71, whereas DPB1 YD9,57, HLA-B C67, and HLA-C YY9,116 were more weakly associated. The HLA epitopes strongly associated with resistance were DQB1 D57, DQA1 Y80, DRB1 R13, and DRB1 A71. A dominant resistance phenotype was observed for individuals bearing a protective HLA epitope, even in the presence of a susceptibility epitope. In addition, an earlier age of disease onset correlated with significantly greater numbers of susceptibility epitopes and fewer resistance epitopes (P < 0.0001). The prevalence of both DQ and DR susceptibility epitopes was higher in patients than in control subjects and was not exclusively a result of linkage disequilibrium, suggesting that multiple HLA epitopes may work together to increase the risk of developing diabetes.
PMCID: PMC3868045  PMID: 24357703
17.  Both Acyl and Des-Acyl Ghrelin Regulate Adiposity and Glucose Metabolism via Central Nervous System Ghrelin Receptors 
Diabetes  2013;63(1):122-131.
Growth hormone secretagogue receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-AG (dAG) has biological activity through GHSR-independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100 nmol/L) and dAG (100 nmol/L) significantly increased inositol triphosphate formation in human embryonic kidney-293 cells transfected with human GHSR. As expected, intracerebroventricular infusion of AG in mice increased fat mass (FM), in comparison with the saline-infused controls. Intracerebroventricular dAG also increased FM at the highest dose tested (5 nmol/day). Chronic intracerebroventricular infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison with saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered intracerebroventricularly. Furthermore, intracerebroventricular dAG failed to regulate FM and induce hyperinsulinemia in GHSR-deficient (Ghsr−/−) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that intracerebroventricular dAG impairs glucose clearance without affecting endogenous glucose production. Together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism.
PMCID: PMC3868046  PMID: 24062249
18.  Soluble Factors Secreted by T Cells Promote β-Cell Proliferation 
Diabetes  2013;63(1):188-202.
Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4+ and CD8+ T cells, but not B cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic CD4+ and CD8+ T cells with NOD.RAG1−/− islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.
PMCID: PMC3868047  PMID: 24089508
19.  A Genome-Wide Association Study in American Indians Implicates DNER as a Susceptibility Locus for Type 2 Diabetes 
Diabetes  2013;63(1):369-376.
Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls, and a family-based association test was conducted. Tag SNPs (n = 311) were selected for 499 SNPs associated with diabetes (P < 0.0005 in case-control analyses or P < 0.0003 in family-based analyses), and these SNPs were genotyped in up to 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10−8, which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.
PMCID: PMC3868048  PMID: 24101674
20.  Gene Targeting in NOD Mouse Embryos Using Zinc-Finger Nucleases 
Diabetes  2013;63(1):68-74.
Studies in NOD mice have provided important insight into the genetics and pathogenesis of type 1 diabetes (T1D). Our goal was to further explore novel methods of genetic manipulation in this mouse model. We tested the feasibility of using zinc-finger nucleases (ZFNs) to knock out a gene directly in a pure NOD background, bypassing the need of embryonic stem cells. We report here the successful application of ZFN pairs to specifically and efficiently knock out Tnfrsf9 (encoding CD137/4–1BB) directly in the NOD mouse by embryo microinjection. Histology and T1D incidence studies indicated that CD137 was dispensable for the development of insulitis but played a role to promote progression to overt diabetes in NOD mice. We also demonstrated that CD137-deficient T-cells were less diabetogenic than their wild-type counterpart when adoptively transferred into NOD.Rag1−/− recipients, even when CD25+ cells were predepleted. In vitro assays suggested that CD137 deficiency had a limited effect on the suppressive function of CD4+CD25+ regulatory T-cells (Tregs). Therefore, CD137 deficiency predominately affected effector T-cells rather than Tregs. Our study demonstrates the ability to generate gene-targeted knockouts in a pure NOD background by using ZFNs without potential confounding factors introduced by contaminating genetic materials obtained from other strains.
PMCID: PMC3868049  PMID: 23974926
21.  Neuroanatomical Correlates of Dysglycemia in Young Children With Type 1 Diabetes 
Diabetes  2013;63(1):343-353.
Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 ± 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.
PMCID: PMC3868050  PMID: 24170697
22.  Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice 
Diabetes  2013;63(1):291-299.
Differences in susceptibility to diabetic nephropathy (DN) between mouse strains with identical levels of hyperglycemia correlate with renal levels of oxidative stress, shown previously to play a central role in the pathogenesis of DN. Susceptibility to DN appears to be genetically determined, but the critical genes have not yet been identified. Overexpression of the enzyme glyoxalase 1 (Glo1), which prevents posttranslational modification of proteins by the glycolysis-derived α-oxoaldehyde, methylglyoxal (MG), prevents hyperglycemia-induced oxidative stress in cultured cells and model organisms. In this study, we show that in nondiabetic mice, knockdown of Glo1 increases to diabetic levels both MG modification of glomerular proteins and oxidative stress, causing alterations in kidney morphology indistinguishable from those caused by diabetes. We also show that in diabetic mice, Glo1 overexpression completely prevents diabetes-induced increases in MG modification of glomerular proteins, increased oxidative stress, and the development of diabetic kidney pathology, despite unchanged levels of diabetic hyperglycemia. Together, these data indicate that Glo1 activity regulates the sensitivity of the kidney to hyperglycemic-induced renal pathology and that alterations in the rate of MG detoxification are sufficient to determine the glycemic set point at which DN occurs.
PMCID: PMC3868051  PMID: 24062246
23.  Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans 
Diabetes  2013;63(1):132-141.
Considerable debate exists about whether alterations in mitochondrial respiratory capacity and/or content play a causal role in the development of insulin resistance during obesity. The current study was undertaken to determine whether such alterations are present during the initial stages of insulin resistance in humans. Young (∼23 years) insulin-sensitive lean and insulin-resistant obese men and women were studied. Insulin resistance was confirmed through an intravenous glucose tolerance test. Measures of mitochondrial respiratory capacity and content as well as H2O2 emitting potential and the cellular redox environment were performed in permeabilized myofibers and primary myotubes prepared from vastus lateralis muscle biopsy specimens. No differences in mitochondrial respiratory function or content were observed between lean and obese subjects, despite elevations in H2O2 emission rates and reductions in cellular glutathione. These findings were apparent in permeabilized myofibers as well as in primary myotubes. The results suggest that reductions in mitochondrial respiratory capacity and content are not required for the initial manifestation of peripheral insulin resistance.
PMCID: PMC3868052  PMID: 23974920
24.  Constitutively Active CaMKKα Stimulates Skeletal Muscle Glucose Uptake in Insulin-Resistant Mice In Vivo 
Diabetes  2013;63(1):142-151.
In insulin-sensitive skeletal muscle, the expression of constitutively active Ca2+/calmodulin-dependent protein kinase kinase α (caCaMKKα) stimulates glucose uptake independent of insulin signaling (i.e., Akt and Akt-dependent TBC1D1/TBC1D4 phosphorylation). Our objectives were to determine whether caCaMKKα could stimulate glucose uptake additively with insulin in insulin-sensitive muscle, in the basal state in insulin-resistant muscle, and if so, to determine whether the effects were associated with altered TBC1D1/TBC1D4 phosphorylation. Mice were fed a control or high-fat diet (60% kcal) for 12 weeks to induce insulin resistance. Muscles were transfected with empty vector or caCaMKKα plasmids using in vivo electroporation. After 2 weeks, caCaMKKα protein was robustly expressed. In insulin-sensitive muscle, caCaMKKα increased basal in vivo [3H]-2-deoxyglucose uptake approximately twofold, insulin increased glucose uptake approximately twofold, and caCaMKKα plus insulin increased glucose uptake approximately fourfold. caCaMKKα did not increase basal TBC1D1 (Ser237, Thr590, Ser660, pan-Thr/Ser) or TBC1D4 (Ser588, Thr642, pan-Thr/Ser) phosphorylation. In insulin-resistant muscle, caCaMKKα increased basal glucose uptake approximately twofold, and attenuated high-fat diet–induced basal TBC1D1 (Thr590, pan-Thr/Ser) and TBC1D4 (Ser588, Thr642, pan-Thr/Ser) phosphorylation. In cell-free assays, CaMKKα increased TBC1D1 (Thr590, pan-Thr/Ser) and TBC1D4 (Ser588, pan-Thr/Ser) phosphorylation. Collectively, these results demonstrate that caCaMKKα stimulates glucose uptake additively with insulin, and in insulin-resistant muscle, and alters the phosphorylation of TBC1D1/TBC1D4.
PMCID: PMC3868053  PMID: 24101676
25.  A Smad Signaling Network Regulates Islet Cell Proliferation 
Diabetes  2013;63(1):224-236.
Pancreatic β-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent β-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-β (TGF-β) signaling has been shown to affect β-cell development, proliferation, and function, but β-cell proliferation is thought to be the only source of new β-cells in the adult. Recently, β-cell dedifferentiation has been shown to be an important contributory mechanism to β-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-β regulators, smads 7, 2, and 3, control β-cell proliferation after β-cell loss, and specifically, smad7 is necessary for that β-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of β-cells to a pancreatic polypeptide–fold hormone-positive state. TGF-β receptor II appears to be a receptor important for controlling the status of the smad network in β-cells. These studies should help our understanding of properly regulated β-cell replication.
PMCID: PMC3868054  PMID: 24089514

Results 1-25 (2480)