Skip to main content
SpringerLink
Log in

Targeting Type 2 Diabetes

  • Chapter
  • First Online:
Diabetes - Perspectives in Drug Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 203))

Abstract

The evolving concept of how nutrient excess and inflammation modulate metabolism provides new opportunities for strategies to correct the detrimental health consequences of obesity. In this review, we focus on the complex interplay among lipid overload, immune response, proinflammatory pathways and organelle dysfunction through which excess adiposity might lead to type 2 diabetes. We then consider evidence linking dysregulated CNS circuits to insulin resistance and results on nutrient-sensing pathways emerging from studies with calorie restriction. Subsequently, recent recommendations for the management of type 2 diabetes are discussed with emphasis on prevailing current therapeutic classes of biguanides, thiazolidinediones and incretin-based approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abdul-Ghani MA, DeFronzo RA (2010) Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010:476279

    PubMed Central  PubMed  Google Scholar 

  • Abumrad N, Coburn C, Ibrahimi A (1999) Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm. Biochim Biophys Acta 1441:4–13

    CAS  PubMed  Google Scholar 

  • Adams M, Montague CT, Prins JB, Holder JC, Smith SA, Sanders L, Digby JE, Sewter CP, Lazar MA, Chatterjee VK, O'Rahilly S (1997) Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 100:3149–3153

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ader M, Kim SP, Catalano KJ, Ionut V, Hucking K, Richey JM, Kabir M, Bergman RN (2005) Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes 54:862–871

    CAS  PubMed  Google Scholar 

  • Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277:1531–1537

    CAS  PubMed  Google Scholar 

  • Alquier T, Kawashima J, Tsuji Y, Kahn BB (2007) Role of hypothalamic adenosine 5′-monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia. Endocrinology 148:1367–1375

    CAS  PubMed  Google Scholar 

  • Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ (2004) AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279:12005–12008

    CAS  PubMed  Google Scholar 

  • Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198

    CAS  PubMed  Google Scholar 

  • Assali AR, Ganor A, Beigel Y, Shafer Z, Hershcovici T, Fainaru M (2001) Insulin resistance in obesity: body-weight or energy balance? J Endocrinol 171:293–298

    CAS  PubMed  Google Scholar 

  • Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–2157

    CAS  PubMed  Google Scholar 

  • Bailey CJ (2005) Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab 7:675–691

    CAS  PubMed  Google Scholar 

  • Bajaj M, Suraamornkul S, Romanelli A, Cline GW, Mandarino LJ, Shulman GI, DeFronzo RA (2005) Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients. Diabetes 54:3148–3153

    CAS  PubMed  Google Scholar 

  • Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2005) Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54:2351–2359

    CAS  PubMed  Google Scholar 

  • Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2006) Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 55: 2277–2285

    Google Scholar 

  • Barnett AH (2009) Redefining the role of thiazolidinediones in the management of type 2 diabetes. Vasc Health Risk Manag 5:141–151

    PubMed Central  CAS  PubMed  Google Scholar 

  • Barroso I (2005) Genetics of Type 2 diabetes. Diabet Med 22:517–535

    CAS  PubMed  Google Scholar 

  • Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421:856–859

    Google Scholar 

  • Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA, Cusi K (2005) Dose–response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 54:1640–1648

    CAS  PubMed  Google Scholar 

  • Beutler B (2004) Innate immunity: an overview. Mol Immunol 40:845–859

    CAS  PubMed  Google Scholar 

  • Boden G, Chen X (1995) Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 96:1261–1268

    PubMed Central  CAS  PubMed  Google Scholar 

  • Boden G, Lebed B, Schatz M, Homko C, Lemieux S (2001) Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 50:1612–1617

    CAS  PubMed  Google Scholar 

  • Bodles AM, Varma V, Yao-Borengasser A, Phanavanh B, Peterson CA, McGehee RE Jr, Rasouli N, Wabitsch M, Kern PA (2006) Pioglitazone induces apoptosis of macrophages in human adipose tissue. J Lipid Res 47:2080–2088

    CAS  PubMed  Google Scholar 

  • Bogardus C, Lillioja S, Mott D, Reaven GR, Kashiwagi A, Foley JE (1984) Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. J Clin Invest 73:800–805

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bonen A, Benton CR, Campbell SE, Chabowski A, Clarke DC, Han XX, Glatz JF, Luiken JJ (2003) Plasmalemmal fatty acid transport is regulated in heart and skeletal muscle by contraction, insulin and leptin, and in obesity and diabetes. Acta Physiol Scand 178:347–356

    CAS  PubMed  Google Scholar 

  • Bonen A, Parolin ML, Steinberg GR, Calles-Escandon J, Tandon NN, Glatz JF, Luiken JJ, Heigenhauser GJ, Dyck DJ (2004) Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. FASEB J 18:1144–1146

    CAS  PubMed  Google Scholar 

  • Bonnefont-Rousselot D, Raji B, Walrand S, Gardes-Albert M, Jore D, Legrand A, Peynet J, Vasson MP (2003) An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 52:586–589

    CAS  PubMed  Google Scholar 

  • Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6:137–143

    CAS  PubMed  Google Scholar 

  • Breen DM, Giacca A (2010) Effects of insulin on the vasculature. Curr Vasc Pharmacol. Sep 1 [Epub ahead of print]

    Google Scholar 

  • Buettner C, Pocai A, Muse ED, Etgen AM, Myers MG Jr, Rossetti L (2006) Critical role of STAT3 in leptin's metabolic actions. Cell Metab 4:49–60

    Google Scholar 

  • Bunck MC, Diamant M, Corner A, Eliasson B, Malloy JL, Shaginian RM, Deng W, Kendall DM, Taskinen MR, Smith U, Yki-Jarvinen H, Heine RJ (2009) One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diab Care 32:762–768

    CAS  Google Scholar 

  • Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772

    CAS  PubMed  Google Scholar 

  • Chen C, Hosokawa H, Bumbalo LM, Leahy JL (1994) Regulatory effects of glucose on the catalytic activity and cellular content of glucokinase in the pancreatic beta cell. Study using cultured rat islets. J Clin Invest 94:1616–1620

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chintoh AF, Mann SW, Lam L, Lam C, Cohn TA, Fletcher PJ, Nobrega JN, Giacca A, Remington G (2008) Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration. J Clin Psychopharmacol 28:494–499

    CAS  PubMed  Google Scholar 

  • Chu NV, Kong AP, Kim DD, Armstrong D, Baxi S, Deutsch R, Caulfield M, Mudaliar SR, Reitz R, Henry RR, Reaven PD (2002) Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diab Care 25:542–549

    CAS  Google Scholar 

  • Cincotta AH, Tozzo E, Scislowski PW (1997) Bromocriptine/SKF38393 treatment ameliorates obesity and associated metabolic dysfunctions in obese (ob/ob) mice. Life Sci 61:951–956

    CAS  PubMed  Google Scholar 

  • Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355

    CAS  PubMed  Google Scholar 

  • Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4:e76

    PubMed Central  PubMed  Google Scholar 

  • Coleman RA, Lee DP (2004) Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43:134–176

    CAS  PubMed  Google Scholar 

  • Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA 84:8628–8632

    PubMed Central  CAS  PubMed  Google Scholar 

  • Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, Tang V, Liu SM, Ludwig T, Chua SC Jr, Lowell BB, Elmquist JK (2005) The hypothalamic arcuate nucleus: a key site for mediating leptin‘s effects on glucose homeostasis and locomotor activity. Cell Metab 1:63–72

    CAS  PubMed  Google Scholar 

  • Cornier MA, Bessesen DH, Gurevich I, Leitner JW, Draznin B (2006) Nutritional upregulation of p85alpha expression is an early molecular manifestation of insulin resistance. Diabetologia 49:748–754

    CAS  PubMed  Google Scholar 

  • Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006) Hypothalamic mTOR signaling regulates food intake. Science 312:927–930

    CAS  PubMed  Google Scholar 

  • Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105:311–320

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dardevet D, Moore MC, DiCostanzo CA, Farmer B, Neal DW, Snead W, Lautz M, Cherrington AD (2005) Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors. Am J Physiol Gastrointest Liver Physiol 289:G806–G814

    PubMed Central  CAS  PubMed  Google Scholar 

  • Davidson JA (2009) Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. Cleve Clin J Med 76(Suppl 5):S28–S38

    PubMed  Google Scholar 

  • Deacon CF, Johnsen AH, Holst JJ (1995a) Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 80:952–957

    CAS  PubMed  Google Scholar 

  • Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ (1995b) Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44:1126–1131

    CAS  PubMed  Google Scholar 

  • DeFronzo RA (1988) Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667–687

    CAS  PubMed  Google Scholar 

  • DeFronzo RA (1999) Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281–303

    CAS  PubMed  Google Scholar 

  • Defronzo RA (2009) Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58:773–795

    PubMed Central  CAS  PubMed  Google Scholar 

  • DeFronzo RA, Goodman AM (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 333:541–549

    CAS  PubMed  Google Scholar 

  • DeFronzo RA, Soman V, Sherwin RS, Hendler R, Felig P (1978) Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding. J Clin Invest 62:204–213

    PubMed Central  CAS  PubMed  Google Scholar 

  • DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J (1985) Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 76:149–155

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G (2001) Mammalian TOR: a homeostatic ATP sensor. Science 294:1102–1105

    Google Scholar 

  • Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM, Ranganathan G, Peterson CA, McGehee RE, Kern PA (2005) Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 54:2305–2313

    PubMed  Google Scholar 

  • Di Marzo V (2008) The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 51:1356–1367

    CAS  PubMed  Google Scholar 

  • Diani AR, Sawada G, Wyse B, Murray FT, Khan M (2004) Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes. Am J Physiol Endocrinol Metab 286:E116–E122

    CAS  PubMed  Google Scholar 

  • Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279–1289

    CAS  PubMed  Google Scholar 

  • Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI (1999) Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253–259

    PubMed Central  CAS  PubMed  Google Scholar 

  • Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705

    CAS  PubMed  Google Scholar 

  • Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42–61

    CAS  PubMed  Google Scholar 

  • El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228

    CAS  PubMed  Google Scholar 

  • Febbraio M, Abumrad NA, Hajjar DP, Sharma K, Cheng W, Pearce SF, Silverstein RL (1999) A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J Biol Chem 274:19055–19062

    CAS  PubMed  Google Scholar 

  • Fehmann HC, Goke R, Goke B (1995) Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev 16:390–410

    CAS  PubMed  Google Scholar 

  • Flint A, Raben A, Astrup A, Holst JJ (1998) Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101:515–520

    PubMed Central  CAS  PubMed  Google Scholar 

  • Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D (2004) Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53:1360–1368

    CAS  PubMed  Google Scholar 

  • Fontana L, Klein S (2007) Aging, adiposity, and calorie restriction. JAMA 297:986–994

    CAS  PubMed  Google Scholar 

  • Fontana L, Meyer TE, Klein S, Holloszy JO (2004) Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA 101:6659–6663

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fontana L, Partridge L, Longo VD (2010) Extending healthy life span – from yeast to humans. Science 328:321–326

    PubMed Central  CAS  PubMed  Google Scholar 

  • Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120:2355–2369

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096–1105

    CAS  PubMed  Google Scholar 

  • Goodarzi MO, Bryer-Ash M (2005) Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab 7:654–665

    CAS  PubMed  Google Scholar 

  • Goodpaster BH, He J, Watkins S, Kelley DE (2001) Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86: 5755–5761

    Google Scholar 

  • Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E (2002) Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes 51:144–151

    CAS  PubMed  Google Scholar 

  • Gregor MF, Hotamisligil GS (2007) Thematic review series: adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48:1905–1914

    CAS  PubMed  Google Scholar 

  • Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI (1999) Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48:1270–1274

    CAS  PubMed  Google Scholar 

  • Griffin JM, Gilbert KM, Pumford NR (2000) Inhibition of CYP2E1 reverses CD4+ T-cell alterations in trichloroethylene-treated MRL+/+ mice. Toxicol Sci 54:384–389

    CAS  PubMed  Google Scholar 

  • Gual P, Le Marchand-Brustel Y, Tanti JF (2005) Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 87:99–109

    CAS  PubMed  Google Scholar 

  • Gutierrez-Juarez R, Obici S, Rossetti L (2004) Melanocortin-independent effects of leptin on hepatic glucose fluxes. J Biol Chem 279:49704–49715

    CAS  PubMed  Google Scholar 

  • Gyte A, Pritchard LE, Jones HB, Brennand JC, White A (2007) Reduced expression of the KATP channel subunit, Kir6.2, is associated with decreased expression of neuropeptide Y and agouti-related protein in the hypothalami of Zucker diabetic fatty rats. J Neuroendocrinol 19:941–951

    CAS  PubMed  Google Scholar 

  • Hansen L, Deacon CF, Orskov C, Holst JJ (1999) Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140:5356–5363

    CAS  PubMed  Google Scholar 

  • Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163

    CAS  PubMed  Google Scholar 

  • He W, Lam TK, Obici S, Rossetti L (2006) Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci 9:227–233

    CAS  PubMed  Google Scholar 

  • Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M (2007) Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117:1658–1669

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336

    CAS  PubMed  Google Scholar 

  • Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167–179

    CAS  PubMed  Google Scholar 

  • Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:901–911

    CAS  PubMed  Google Scholar 

  • Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    CAS  PubMed  Google Scholar 

  • Houmard JA (2008) Intramuscular lipid oxidation and obesity. Am J Physiol Regul Integr Comp Physiol 294:R1111–R1116

    PubMed Central  CAS  PubMed  Google Scholar 

  • Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H (2007) Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 32:289–297

    CAS  PubMed  Google Scholar 

  • Hsueh WA, Law RE (1999) Insulin signaling in the arterial wall. Am J Cardiol 84:21J–24J

    CAS  PubMed  Google Scholar 

  • Hu Z, Cha SH, van Haasteren G, Wang J, Lane MD (2005) Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects. Proc Natl Acad Sci USA 102:3972–3977

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI (2002) Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 109:1321–1326

    PubMed Central  CAS  PubMed  Google Scholar 

  • Inzucchi SE (2002) Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287:360–372

    CAS  PubMed  Google Scholar 

  • Ionut V, Hucking K, Liberty IF, Bergman RN (2005) Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones. Diabetologia 48:967–975

    CAS  PubMed  Google Scholar 

  • Itani SI, Pories WJ, Macdonald KG, Dohm GL (2001) Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism 50:553–557

    CAS  PubMed  Google Scholar 

  • Itani SI, Ruderman NB, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51:2005–2011

    CAS  PubMed  Google Scholar 

  • Jean-Baptiste G, Yang Z, Khoury C, Greenwood MT (2005) Lysophosphatidic acid mediates pleiotropic responses in skeletal muscle cells. Biochem Biophys Res Commun 335:1155–1162

    CAS  PubMed  Google Scholar 

  • Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL (1999) Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 104:447–457

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G (2006a) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443

    CAS  PubMed  Google Scholar 

  • Kahn SE, Hull RL, Utzschneider KM (2006b) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846

    CAS  PubMed  Google Scholar 

  • Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505

    PubMed Central  CAS  PubMed  Google Scholar 

  • Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y, Makris C, Rothwarf D, Baud V, Natoli G, Guido F, Li N (2001) Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. Biofactors 15:87–89

    CAS  PubMed  Google Scholar 

  • Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons M (1993) Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 77:1287–1293

    CAS  PubMed  Google Scholar 

  • Khaldi MZ, Guiot Y, Gilon P, Henquin JC, Jonas JC (2004) Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose. Am J Physiol Endocrinol Metab 287:E207–E217

    CAS  PubMed  Google Scholar 

  • Kiens B, Roemen TH, van der Vusse GJ (1999) Muscular long-chain fatty acid content during graded exercise in humans. Am J Physiol 276:E352–E357

    Google Scholar 

  • Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI (2001) Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98:7522–7527

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O’Brien WR, Littman DR, Shulman GI (2004) PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 114:823–827

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, Lehmann JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 94:4318–4323

    PubMed Central  CAS  PubMed  Google Scholar 

  • Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Gremeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM, Postic C, Burcelin R (2005) Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest 115:3554–3563

    PubMed Central  CAS  PubMed  Google Scholar 

  • Konner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Bruning JC (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438–449

    Google Scholar 

  • Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45–56

    CAS  PubMed  Google Scholar 

  • Krebs M, Brunmair B, Brehm A, Artwohl M, Szendroedi J, Nowotny P, Roth E, Furnsinn C, Promintzer M, Anderwald C, Bischof M, Roden M (2007) The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 56:1600–1607

    CAS  PubMed  Google Scholar 

  • Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG Jr, Wallberg-Henriksson H, Zierath JR (2000) Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284–292

    CAS  PubMed  Google Scholar 

  • Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI (1999) Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113–116

    CAS  PubMed  Google Scholar 

  • Kuningas M, Magi R, Westendorp RG, Slagboom PE, Remm M, van Heemst D (2007) Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age. Eur J Hum Genet 15:294–301

    CAS  PubMed  Google Scholar 

  • Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L (2005a) Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309:943–947

    CAS  PubMed  Google Scholar 

  • Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L (2005b) Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11:320–327

    CAS  PubMed  Google Scholar 

  • Leclerc V, Reichhart JM (2004) The immune response of Drosophila melanogaster. Immunol Rev 198:59–71

    Google Scholar 

  • Leite CE, Mocelin CA, Petersen GO, Leal MB, Thiesen FV (2009) Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep 61:217–224

    CAS  PubMed  Google Scholar 

  • Lenhard JM, Croom DK, Minnick DT (2004) Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments. Biochem Biophys Res Commun 324:92–97

    CAS  PubMed  Google Scholar 

  • Li L, Shi Y, Wang X, Shi W, Jiang C (2005a) Single nucleotide polymorphisms in K(ATP) channels: muscular impact on type 2 diabetes. Diabetes 54:1592–1597

    CAS  PubMed  Google Scholar 

  • Li Y, Schwabe RF, DeVries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, Davis RJ, Flavell R, Brenner DA, Tabas I (2005b) Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem 280:21763–21772

    CAS  PubMed  Google Scholar 

  • Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223

    CAS  PubMed  Google Scholar 

  • Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, Wang J, Rossetti L (1998) Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem 273:31160–31167

    CAS  PubMed  Google Scholar 

  • Liu L, Zhang Y, Chen N, Shi X, Tsang B, Yu YH (2007) Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest 117: 1679–1689

    Google Scholar 

  • Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288:2379–2381

    CAS  PubMed  Google Scholar 

  • Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23

    CAS  PubMed  Google Scholar 

  • Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, Ciani S, Messeri G, Rotella CM (2001) Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diab Care 24:489–494

    CAS  Google Scholar 

  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    CAS  PubMed  Google Scholar 

  • Mari A, Nielsen LL, Nanayakkara N, DeFronzo RA, Ferrannini E, Halseth A (2006) Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea. Horm Metab Res 38:838–844

    CAS  PubMed  Google Scholar 

  • Mari A, Degn K, Brock B, Rungby J, Ferrannini E, Schmitz O (2007) Effects of the long-acting human glucagon-like peptide-1 analog liraglutide on beta-cell function in normal living conditions. Diab Care 30:2032–2033

    CAS  Google Scholar 

  • Mari A, Scherbaum WA, Nilsson PM, Lalanne G, Schweizer A, Dunning BE, Jauffret S, Foley JE (2008) Characterization of the influence of vildagliptin on model-assessed -cell function in patients with type 2 diabetes and mild hyperglycemia. J Clin Endocrinol Metab 93:103–109

    CAS  PubMed  Google Scholar 

  • Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J (1997) Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators. J Biol Chem 272:28210–28217

    CAS  PubMed  Google Scholar 

  • Matveyenko AV, Butler PC (2006) Beta-cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes. Diabetes 55:2106–2114

    CAS  PubMed  Google Scholar 

  • McCurdy CE, Davidson RT, Cartee GD (2005) Calorie restriction increases the ratio of phosphatidylinositol 3-kinase catalytic to regulatory subunits in rat skeletal muscle. Am J Physiol Endocrinol Metab 288:E996–E1001

    CAS  PubMed  Google Scholar 

  • McGarry JD, Dobbins RL (1999) Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42:128–138

    CAS  PubMed  Google Scholar 

  • McGuire DK, Inzucchi SE (2008) New drugs for the treatment of diabetes mellitus: part I: Thiazolidinediones and their evolving cardiovascular implications. Circulation 117:440–449

    PubMed  Google Scholar 

  • Meguid MM, Fetissov SO, Blaha V, Yang ZJ (2000) Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats. NeuroReport 11:2069–2072

    CAS  PubMed  Google Scholar 

  • Mentlein R (1999) Dipeptidyl-peptidase IV (CD26) – role in the inactivation of regulatory peptides. Regul Pept 85:9–24

    CAS  PubMed  Google Scholar 

  • Mentlein R, Gallwitz B, Schmidt WE (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214:829–835

    CAS  PubMed  Google Scholar 

  • Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574

    CAS  PubMed  Google Scholar 

  • Mirshamsi S, Laidlaw HA, Ning K, Anderson E, Burgess LA, Gray A, Sutherland C, Ashford ML (2004) Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATP channel activation. BMC Neurosci 5:54

    PubMed Central  PubMed  Google Scholar 

  • Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    CAS  PubMed  Google Scholar 

  • Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2):S9–S15

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morrison CD, Morton GJ, Niswender KD, Gelling RW, Schwartz MW (2005) Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling. Am J Physiol Endocrinol Metab 289:E1051–E1057

    CAS  PubMed  Google Scholar 

  • Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2:11–20

    Google Scholar 

  • Muoio DM, Newgard CB (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9:193–205

    CAS  PubMed  Google Scholar 

  • Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B (2009) Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52:17–30

    CAS  PubMed  Google Scholar 

  • Nauck MA, Meier JJ (2005) Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul Pept 128:135–148

    CAS  PubMed  Google Scholar 

  • Nauck M, Stockmann F, Ebert R, Creutzfeldt W (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46–52

    CAS  PubMed  Google Scholar 

  • Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W (1993) Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91:301–307

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM (2005) JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 280:35361–35371

    CAS  PubMed  Google Scholar 

  • Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282:35279–35292

    CAS  PubMed  Google Scholar 

  • Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, Jones KL, Kawamori R, Cassis LA, Tschop MH, Bruemmer D (2007) Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Invest 117:2877–2888

    PubMed Central  CAS  PubMed  Google Scholar 

  • Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L (2001) Central melanocortin receptors regulate insulin action. J Clin Invest 108:1079–1085

    Google Scholar 

  • Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L (2002a) Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275

    CAS  PubMed  Google Scholar 

  • Obici S, Zhang BB, Karkanias G, Rossetti L (2002b) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382

    CAS  PubMed  Google Scholar 

  • Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L (2002c) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5:566–572

    Google Scholar 

  • Obici S, Feng Z, Arduini A, Conti R, Rossetti L (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756–761

    CAS  PubMed  Google Scholar 

  • Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447:1116–1120

    PubMed Central  CAS  PubMed  Google Scholar 

  • Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T (1998) Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101:1354–1361

    PubMed Central  CAS  PubMed  Google Scholar 

  • Olefsky JM (2000) Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 106:467–472

    PubMed Central  CAS  PubMed  Google Scholar 

  • Oliver MF, Opie LH (1994) Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 343:155–158

    CAS  PubMed  Google Scholar 

  • Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, Schwartz GJ, Rossetti L (2008) Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 118:2959–2968

    PubMed Central  CAS  PubMed  Google Scholar 

  • O’Rahilly S (2009) Human genetics illuminates the paths to metabolic disease. Nature 462:307–314

    PubMed  Google Scholar 

  • Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348(Pt 3):607–614

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    PubMed  Google Scholar 

  • Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140

    PubMed  Google Scholar 

  • Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr, Ozcan U (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9:35–51

    CAS  PubMed  Google Scholar 

  • Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell BB (2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449:228–232

    CAS  PubMed  Google Scholar 

  • Patsouris D, Neels JG, Fan W, Li PP, Nguyen MT, Olefsky JM (2009) Glucocorticoids and thiazolidinediones interfere with adipocyte-mediated macrophage chemotaxis and recruitment. J Biol Chem 284:31223–31235

    PubMed Central  CAS  PubMed  Google Scholar 

  • Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 100:8466–8471

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB, Storlien LH (1997) Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46: 983–988

    Google Scholar 

  • Perrin C, Knauf C, Burcelin R (2004) Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis. Endocrinology 145:4025–4033

    CAS  PubMed  Google Scholar 

  • Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L (1999) Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 48:1600–1606

    CAS  PubMed  Google Scholar 

  • Petersen KF, Krssak M, Inzucchi S, Cline GW, Dufour S, Shulman GI (2000) Mechanism of troglitazone action in type 2 diabetes. Diabetes 49:827–831

    CAS  PubMed  Google Scholar 

  • Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Munzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, Bruning JC (2006) Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 116:1886–1901

    Google Scholar 

  • Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L (2005) Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031

    CAS  PubMed  Google Scholar 

  • Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L (2006) Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis. J Clin Invest 116:1081–1091

    PubMed Central  CAS  PubMed  Google Scholar 

  • Poitout V, Robertson RP (2002) Minireview: Secondary beta-cell failure in type 2 diabetes – a convergence of glucotoxicity and lipotoxicity. Endocrinology 143:339–342

    CAS  PubMed  Google Scholar 

  • Pownall HJ, Hamilton JA (2003) Energy translocation across cell membranes and membrane models. Acta Physiol Scand 178:357–365

    CAS  PubMed  Google Scholar 

  • Prentki M, Joly E, El-Assaad W, Roduit R (2002) Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 51(Suppl 3):S405–S413

    CAS  PubMed  Google Scholar 

  • Proulx K, Cota D, Woods SC, Seeley RJ (2008) Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex 1 signaling in the central nervous system. Diabetes 57:3231–3238

    PubMed Central  CAS  PubMed  Google Scholar 

  • Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ (2005) Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 280:10290–10297

    CAS  PubMed  Google Scholar 

  • Roepstorff C, Vistisen B, Roepstorff K, Kiens B (2004) Regulation of plasma long-chain fatty acid oxidation in relation to uptake in human skeletal muscle during exercise. Am J Physiol Endocrinol Metab 287:E696–E705

    Google Scholar 

  • Rodbard HW, Jellinger PS (2010) The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) algorithm for managing glycaemia in patients with type 2 diabetes mellitus: comparison with the ADA/EASD algorithm. Diabetologia 53(11):2458–2460

    CAS  PubMed  Google Scholar 

  • Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelsman Y, Horton ES, Lebovitz H, Levy P, Moghissi ES, Schwartz SS (2009) Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract 15:540–559

    PubMed  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    CAS  PubMed  Google Scholar 

  • Rosen P, Wiernsperger NF (2006) Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress. Diabetes Metab Res Rev 22:323–330

    PubMed  Google Scholar 

  • Sampson SR, Cooper DR (2006) Specific protein kinase C isoforms as transducers and modulators of insulin signaling. Mol Genet Metab 89:32–47

    PubMed Central  CAS  PubMed  Google Scholar 

  • Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–2277

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sandoval DA, Bagnol D, Woods SC, D’Alessio DA, Seeley RJ (2008) Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57:2046–2054

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sandoval DA, Obici S, Seeley RJ (2009) Targeting the CNS to treat type 2 diabetes. Nat Rev Drug Discov 8:386–398

    CAS  PubMed  Google Scholar 

  • Sathyanarayana P, Barthwal MK, Kundu CN, Lane ME, Bergmann A, Tzivion G, Rana A (2002) Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Mol Cell 10:1527–1533

    CAS  PubMed  Google Scholar 

  • Schenk S, Saberi M, Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992–3002

    PubMed Central  CAS  PubMed  Google Scholar 

  • Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ (2005) Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med 11:757–764

    CAS  PubMed  Google Scholar 

  • Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ (1997) Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 46:169–178

    CAS  PubMed  Google Scholar 

  • Schwanstecher C, Schwanstecher M (2002) Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes 51(Suppl 3):S358–S362

    CAS  PubMed  Google Scholar 

  • Schwanstecher C, Meyer U, Schwanstecher M (2002) K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 51:875–879

    CAS  PubMed  Google Scholar 

  • Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671

    CAS  PubMed  Google Scholar 

  • Shevah O, Laron Z (2007) Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm IGF Res 17:54–57

    CAS  PubMed  Google Scholar 

  • Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shimizu H, Oh IS, Tsuchiya T, Ohtani KI, Okada S, Mori M (2006) Pioglitazone increases circulating adiponectin levels and subsequently reduces TNF-alpha levels in Type 2 diabetic patients: a randomized study. Diabet Med 23:253–257

    CAS  PubMed  Google Scholar 

  • Shimokawa T, Kumar MV, Lane MD (2002) Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc Natl Acad Sci USA 99:66–71

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116: 1793–1801

    Google Scholar 

  • Smith U (2001) Pioglitazone: mechanism of action. Int J Clin Pract Suppl 121:13–18

    CAS  PubMed  Google Scholar 

  • Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M (2007) JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 6:386–397

    CAS  PubMed  Google Scholar 

  • Sondergaard L (1993) Homology between the mammalian liver and the Drosophila fat body. Trends Genet 9:193

    CAS  PubMed  Google Scholar 

  • Song MJ, Kim KH, Yoon JM, Kim JB (2006) Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun 346:739–745

    CAS  PubMed  Google Scholar 

  • Spiegelman BM (1998) PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514

    CAS  PubMed  Google Scholar 

  • Stoehr JP, Nadler ST, Schueler KL, Rabaglia ME, Yandell BS, Metz SA, Attie AD (2000) Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. Diabetes 49:1946–1954

    CAS  PubMed  Google Scholar 

  • Stratford S, DeWald DB, Summers SA (2001) Ceramide dissociates 3′-phosphoinositide production from pleckstrin homology domain translocation. Biochem J 354:359–368

    PubMed Central  CAS  PubMed  Google Scholar 

  • Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW 2nd, DeFuria J, Jick Z, Greenberg AS, Obin MS (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56:2910–2918

    CAS  PubMed  Google Scholar 

  • Stulc T, Sedo A (2010) Inhibition of multifunctional dipeptidyl peptidase-IV: is there a risk of oncological and immunological adverse effects? Diabetes Res Clin Pract 88:125–131

    CAS  PubMed  Google Scholar 

  • Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, Zhai Q (2007) SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 6:307–319

    CAS  PubMed  Google Scholar 

  • Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45:42–72

    Google Scholar 

  • Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    CAS  PubMed  Google Scholar 

  • Thirone AC, Huang C, Klip A (2006) Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab 17:72–78

    PubMed  Google Scholar 

  • Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P (2003) Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 52:2882–2887

    CAS  PubMed  Google Scholar 

  • Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araujo EP, Vassallo J, Curi R, Velloso LA, Saad MJ (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56:1986–1998

    CAS  PubMed  Google Scholar 

  • Tzatsos A, Kandror KV (2006) Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 26:63–76

    PubMed Central  CAS  PubMed  Google Scholar 

  • UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

    Google Scholar 

  • Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205

    CAS  PubMed  Google Scholar 

  • Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863–870

    CAS  PubMed  Google Scholar 

  • Vestergaard P (2009) Bone metabolism in type 2 diabetes and role of thiazolidinediones. Curr Opin Endocrinol Diabetes Obes 16:125–131

    CAS  PubMed  Google Scholar 

  • Wahren J, Ekberg K (2007) Splanchnic regulation of glucose production. Annu Rev Nutr 27:329–345

    CAS  PubMed  Google Scholar 

  • Wang X, Devaiah SP, Zhang W, Welti R (2006) Signaling functions of phosphatidic acid. Prog Lipid Res 45:250–278

    CAS  PubMed  Google Scholar 

  • Wang B, Wood IS, Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 455:479–492

    PubMed Central  CAS  PubMed  Google Scholar 

  • Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    PubMed Central  CAS  PubMed  Google Scholar 

  • Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124

    PubMed Central  CAS  PubMed  Google Scholar 

  • Westermark P, Wernstedt C, O’Brien TD, Hayden DW, Johnson KH (1987) Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am J Pathol 127:414–417

    PubMed Central  CAS  PubMed  Google Scholar 

  • Willson TM, Brown PJ, Sternbach DD, Henke BR (2000) The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527–550

    CAS  PubMed  Google Scholar 

  • Winter WE, Nakamura M, House DV (1999) Monogenic diabetes mellitus in youth. The MODY syndromes. Endocrinol Metab Clin North Am 28:765–785

    CAS  PubMed  Google Scholar 

  • Wolfgang MJ, Lane MD (2006) The role of hypothalamic malonyl-CoA in energy homeostasis. J Biol Chem 281:37265–37269

    CAS  PubMed  Google Scholar 

  • Woltman T, Reidelberger R (1995) Effects of duodenal and distal ileal infusions of glucose and oleic acid on meal patterns in rats. Am J Physiol 269:R7–R14

    CAS  PubMed  Google Scholar 

  • Xu L, Man CD, Charbonnel B, Meninger G, Davies MJ, Williams-Herman D, Cobelli C, Stein PP (2008a) Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach. Diabetes Obes Metab 10:1212–1220

    CAS  PubMed  Google Scholar 

  • Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, Anderson JG, Heisler LK, Zigman JM, Lowell BB, Elmquist JK (2008b) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60:582–589

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946

    CAS  PubMed  Google Scholar 

  • Ye J, Gao Z, Yin J, He Q (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293:E1118–E1128

    CAS  PubMed  Google Scholar 

  • Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI (2002) Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277:50230–50236

    CAS  PubMed  Google Scholar 

  • Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293:1673–1677

    CAS  PubMed  Google Scholar 

  • Zander M, Madsbad S, Madsen JL, Holst JJ (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359:824–830

    CAS  PubMed  Google Scholar 

  • Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61–73

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML, McCrimmon RJ, Elmquist JK, Butler AA, Heisler LK (2007) Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab 6:398–405

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou SY, Lu YX, Owyang C (2008) Gastric relaxation induced by hyperglycemia is mediated by vagal afferent pathways in the rat. Am J Physiol Gastrointest Liver Physiol 294:G1158–G1164

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molekulare Pharmakologie und Toxikologie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany

    Christina Schwanstecher & Mathias Schwanstecher

Authors
  1. Christina Schwanstecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mathias Schwanstecher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mathias Schwanstecher .

Editor information

Editors and Affiliations

  1. Fakultät Lebenswissenschaften Molekulare Pharmakologie und Toxikologie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany

    Mathias Schwanstecher

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Schwanstecher, C., Schwanstecher, M. (2011). Targeting Type 2 Diabetes. In: Schwanstecher, M. (eds) Diabetes - Perspectives in Drug Therapy. Handbook of Experimental Pharmacology, vol 203. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17214-4_1

Download citation

Publish with us

Policies and ethics

Search

Navigation