Circulation. 2007;115:1371-1375

Glucose Levels Predict Hospitalization for Congestive Heart Failure in Patients at High Cardiovascular Risk
C. Held, MD, PhD; H.C. Gerstein, MD, MSc; S. Yusuf, MD, DPhil; F. Zhao, MSc; L. Hilbrich, MD; C. Anderson, MBBS, PhD, FRACP; P. Sleight, MD; K. Teo, MD, PhD, for the ONTARGET/TRANSCEND Investigators
From the Karolinska Institutet, Department of Medicine, Unit of Cardiology, Karolinska University Hospital, Stockholm, Sweden (C.H.); Population Health Research Institute, Hamilton General Hospital, McMaster Clinic, Hamilton, Ontario, Canada (C.H., H.C.G., S.Y., F.Z., K.T.); Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim am Rhein, Germany (L.H.); The George Institute, Royal Prince Alfred Hospital, Sydney, Australia (C.A.); and John Radcliffe Hospital, Oxford, UK (P.S.).

Correspondence to Claes Held, Karolinska Institutet, Department of Medicine, Unit of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden.



Background— Patients with diabetes mellitus (DM) are at high risk of developing congestive heart failure (CHF). However, the relationships between glucose levels and CHF in people with or without a history of DM have not been well characterized.

Methods and Results— We evaluated the associations between fasting plasma glucose and risk of hospitalization for CHF during follow-up in patients at high cardiovascular risk and without CHF enrolled in a large-scale clinical trials program. Baseline fasting plasma glucose levels were assessed in 31 546 high-risk subjects with 1 coronary, peripheral, or cerebrovascular disease or DM with end-organ damage who are participating in 2 ongoing parallel trials evaluating the effects of telmisartan, ramipril, or their combination (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; n=25 620) and the effects of telmisartan against placebo in angiotensin-converting enzyme–intolerant patients (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease [TRANSCEND]; n=5926). Interim analyses blinded for randomized treatment were performed to compare baseline fasting plasma glucose with the adjusted CHF event rate at a mean follow-up of 886 days. Multivariable Cox regression models were performed, and associations were reported as hazard ratios and 95% confidence intervals. Among all subjects (mean age, 67 years; 69% men), of whom 11 708 (37%) had known DM and 1006 (3.2%) had newly diagnosed DM at baseline, 668 patients were hospitalized for CHF during follow-up. After adjustment for age and sex, a 1-mmol/L-higher fasting plasma glucose was associated with a 1.10-fold-increased risk of CHF hospitalization (95% confidence interval, 1.08 to 1.12; P<0.0001). The association persisted after adjustment for age, sex, smoking, previous myocardial infarction, hypertension, waist-to-hip ratio, creatinine, DM, and use of aspirin, ß-blockers, or statins (hazard ratio, 1.05; 95% confidence interval, 1.02 to 1.08; P<0.001). Conclusions— Fasting plasma glucose is an independent predictor of hospitalization for CHF in high-risk subjects. These data provide theoretical support for potential direct beneficial effects of glucose lowering in reducing the risk of CHF and suggests the need for specific studies targeted at this issue.


Kaplan-Meier estimates of the proportion of patients with hospitalization for CHF divided into classes of glycemia at baseline (log rank P<0.001). IFG indicates impaired fasting glucose.

PRKAG2

PRKAG2 cardiomyopathy in the context of glycogen metabolism and the other muscle glycogenoses. Glycogen is a branched glucose polymer containing 93% 1-4 bonds and 7% 1-6 bonds and contains a protein core. It constitutes an immediate reserve of glucose for glycolysis under intense muscle activity or reduced energy supply. Glycogen undergoes a constant turnover: new units are being added by glycogen synthase and brancher enzymes, or being broken down by glycogen phosphorylase and debrancher enzyme. Aged glycogen is degraded in the lysosome. Classic glycogen storage disorders result from deficiency in glycogen-degrading enzymes and are inherited as autosomal recessive or X-linked trait. Prominent cardiac involvement is associated with most glycogenoses (red). Phosphorylase deficiency, phosphorylase kinase deficiency, and debrancher enzyme deficiency cause cytoplasmic glycogen accumulation and often manifest on exercise as myalgia and myoglobinuria resulting from inability to metabolize glycogen. In brancher enzyme deficiency, an abnormal nonsoluble glycogen polymer is created, leading to polyglucosan deposits. Lysosomal glycogen storage diseases cause insidious accumulation and may manifest as cardiac hypertrophy often associated with electrophysiological abnormalities as well as myopathy. Lysosomal acid maltase deficiency causes Pompe disease. Lysosomal-associated membrane protein II defects lead to glycogen deposits in the context of generalized lysosomal dysfunction. PRKAG2 cardiomyopathy is characterized by cytoplasmic glycogen accumulation attributable to dysregulated metabolism. Unlike other diseases, there is no enzyme deficiency and the heart can reuse this glycogen on appropriate stimulation. The glycogen stored is less branched, having some features reminiscent of polyglucosan.109 The model is reproduced by permission of the Massachusetts Medical Society from Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, Perez-Atayde AR, Spirito P, Wright GB, Kanter RJ, Seidman CE, Seidman JG. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005;352:362–372.

Biochemistry. 2004 Dec 14;43(49):15494-502.

Requirements for pYXXM motifs in Cbl for binding to the p85 subunit of phosphatidylinositol 3-kinase and Crk, and activation of atypical protein kinase C and glucose transport during insulin action in 3T3/L1 adipocytes.

Standaert ML, Sajan MP, Miura A, Bandyopadhyay G, Farese RV.

Research Service, James A. Haley Veterans Medical Center, and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612, USA.

Cbl is phosphorylated by the insulin receptor and reportedly functions within the flotillin/CAP/Cbl/Crk/C3G/TC10 complex during insulin-stimulated glucose transport in 3T3/L1 adipocytes. Cbl, via pYXXM motifs at tyrosine-371 and tyrosine-731, also activates phosphatidylinositol (PI) 3-kinase, which is required to activate atypical protein kinase C (aPKC) and glucose transport during thiazolidinedione action in 3T3/L1 and human adipocytes [Miura et al. (2003) Biochemistry 42, 14335-14341]. Presently, we have examined the importance of Cbl in activating PI 3-kinase and aPKC during insulin action in 3T3/L1 adipocytes by expressing Y371F and Y731F Cbl mutants, which nullify pYXXM binding of Cbl to SH2 domains of downstream effectors. Interestingly, these mutants inhibited insulin-induced increases in (a) binding of Cbl to both Crk and the p85 subunit of PI 3-kinase, (b) activation of Cbl-dependent PI 3-kinase, (c) activation and translocation of aPKC to the plasma membrane, (d) translocation of Glut4 to the plasma membrane, (e) and glucose transport. Importantly, coexpression of wild-type Cbl reversed the inhibitory effects of Cbl mutants. In contrast to Cbl-dependent PI 3-kinase, Cbl mutants did not significantly inhibit the activation of PI 3-kinase by IRS-1, which is also required during insulin action. Our findings suggest that (a) Cbl uses pYXXM motifs to simultaneously activate PI 3-kinase and Crk/C3G/TC10 pathways and (b) Cbl, along with IRS-1, functions upstream of PI 3-kinase and aPKCs during insulin-stimulated glucose transport in 3T3/L1 adipocytes.

すこしマニアックですが，最近の僕の研究テーマですので，のせておきます。

Nature 410, 944-948(19 April 2001)

インスリン刺激によるGLUT4の移行にはCAPに依存したTC10活性化が必要である

Shian-Huey Chiang1,2, Christian A. Baumann2,3, Makoto Kanzaki4, Debbie C. Thurmond4, Robert T. Watson4, Cheryl L. Neudauer5, Ian G. Macara5, Jeffrey E. Pessin4and Alan R. Saltiel2,3

Top of page筋肉や脂肪組織でインスリンによってグルコース取込みが促進されるには,グルコース輸送タンパク質GLUT4が細胞内の貯蔵部位から細胞表面へと移行する必要がある。GLUT4小胞の細胞内移動は詳しく解明されているが，インスリン受容体とGLUT4移行とを結びつける情報伝達経路についてはほとんどわかっていない。GLUT4移行にはホスファチジルイノシトール‐3‐OHキナーゼ（PI(3)K）の活性化が必要だが，それだけではGLUT4移行は起こらない。我々はこれまでに，インスリン刺激によるCblのチロシンリン酸化がかかわる経路を報告した。Cblはアダプタータンパク質CAPによってインスリン受容体へと運ばれる。Cblはリン酸化されると細胞膜の脂質微小領域へと移行するが，この移行を妨げると，インスリンによるGLUT4移行の促進が完全に阻害された。ここでは，リン酸化されたCblの働きでCrkII-C3G複合体が脂質微小領域へ移行し，そこでC3Gが低分子量GTP結合タンパク質TC10を特異的に活性化することを明らかにする。この過程にはPI(3)Kは無関係だが，CblとCrk，C3Gの脂質微小領域への移行は必要である。インスリン刺激によるグルコース取込みの促進とGLUT4の移行には，このTC10の活性化が不可欠である。このTC10経路は，PI(3)K経路と並行して，インスリンによるGLUT4の移行を促進する働きをしている

AJP Heart Circ Physiol 289: H1744-H1751, 2005

Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction

Shubha Varma,2,* Brajesh K. Lal,1,2,* Ruifang Zheng,2 Jerome W. Breslin,1 Satoshi Saito,1,2 Peter J. Pappas,1,2 Robert W. Hobson, II,1,2 and Walter N. Durán1,2
1Program in Vascular Biology, Department of Pharmacology and Physiology, and 2Division of Vascular Surgery, Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey

Submitted 25 October 2004 ; accepted in final form 1 June 2005


Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM D-glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and propidium iodide staining and flow cytometry, analyzed cell lysates obtained on culture day 8 for total and phosphorylated PI3k and Akt by Western blot analysis, and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and LY294002) and after transfection with a constitutively active Akt mutant. ECs in media containing 5 mM D-glucose (control) exhibited log-phase growth on days 7–10. D-Glucose at 20 and 40 mM significantly decreased proliferation versus control (P <0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM D-glucose. D-Glucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM D-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM D-glucose. We conclude that D-glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes. 僕も同様のデータを持っています。

AJP Heart Circ Physiol 289: H1343-H1350, 2005.

PKC--dependent survival signals in diabetic hearts

Ashwani Malhotra,1 Rebecca Begley,3 Barinder P. S. Kang,1 Irmindra Rana,1 Jing Liu,2 Guiping Yang,2 Daria Mochly-Rosen,3 and Leonard G. Meggs1
1Division of Nephrology, Department of Medicine, and 2Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and 3Department of Molecular Pharmacology, Stanford University, Stanford, California


Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The -isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC- will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC- translocation activator [-receptors for activated C kinase (-RACK)]. The results demonstrate a striking PKC- cardioprotective phenotype in diabetic -RACK (-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic -agonist mice exhibited selective trafficking of PKC- to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC- in hearts of diabetic -agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.

バカボンのパパが喜ぶ研究をする人材を育てねばならない。