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Diabetologia
Published in: Diabetologia 11/2015

01-11-2015 | Review

The new biology of diabetes

Authors: Utpal B. Pajvani, Domenico Accili

Published in: Diabetologia | Issue 11/2015

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Abstract

Until recently, type 2 diabetes was seen as a disease caused by an impaired ability of insulin to promote the uptake and utilisation of glucose. Work on forkhead box protein O (FOXO) transcription factors revealed new aspects of insulin action that have led us to articulate a liver- and beta cell-centric narrative of diabetes pathophysiology and treatment. FOXO integrate a surprisingly diverse subset of biological functions to promote metabolic flexibility. In the liver, they controls the glucokinase/glucose-6-phosphatase switch and bile acid pool composition, directing carbons to glucose or lipid utilisation, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production and increased lipid synthesis and secretion. Moreover, FOXO are necessary to maintain beta cell differentiation, and diabetes development is associated with a gradual loss of FOXO function that brings about beta cell dedifferentiation. We proposed that dedifferentiation is the main cause of beta cell failure and conversion into non-beta endocrine cells, and that treatment should restore beta cell differentiation. Our studies investigating these proposals have revealed new dimensions to the pathophysiology of diabetes that can be leveraged to design new therapies.
Literature
1.
Accili D (2004) Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic. Diabetes 53:1633–1642CrossRefPubMed
2.
Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443CrossRefPubMed
3.
Duckworth W, Abraira C, Moritz T et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139CrossRefPubMed
4.
Chen KK, Anderson RC (1947) The toxicity and general pharmacology of N1-p-chlorophenyl-N5-isopropyl biguanide. J Pharmacol Exp Ther 91:157–160PubMed
5.
Baggio LL, Drucker DJ (2006) Therapeutic approaches to preserve islet mass in type 2 diabetes. Annu Rev Med 57:265–281CrossRefPubMed
6.
Accili D, Ahren B, Boitard C, Cerasi E, Henquin JC, Seino S (2010) What ails the beta-cell? Diabetes Obes Metab 12(Suppl 2):1–3CrossRefPubMed
7.
Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117:421–426CrossRefPubMed
8.
9.
Kitamura YI, Kitamura T, Kruse JP et al (2005) FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2:153–163CrossRefPubMed
10.
Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150:1223–1234PubMedCentralCrossRefPubMed
11.
12.
Rothman DL, Magnusson I, Cline G et al (1995) Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 92:983–987PubMedCentralCrossRefPubMed
13.
Kahn BB (1996) Lilly lecture 1995. Glucose transport: pivotal step in insulin action. Diabetes 45:1644–1654CrossRefPubMed
14.
Bearn AG, Billing BH, Sherlock S (1951) Hepatic glucose output and hepatic insulin sensitivity in diabetes mellitus. Lancet 2:698–701CrossRefPubMed
15.
O’Brien RM, Lucas PC, Forest CD, Magnuson MA, Granner DK (1990) Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. Science 249:533–537CrossRefPubMed
16.
Yamamoto KK, Gonzalez GA, Biggs WH 3rd, Montminy MR (1988) Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature 334:494–498CrossRefPubMed
17.
Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D (2007) Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab 6:208–216CrossRefPubMed
18.
Dong XC, Copps KD, Guo S et al (2008) Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 8:65–76PubMedCentralCrossRefPubMed
19.
Kubota N, Kubota T, Itoh S et al (2008) Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab 8:49–64CrossRefPubMed
20.
Altomonte J, Richter A, Harbaran S et al (2003) Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab 285:E718–E728CrossRefPubMed
21.
Kitamura T, Nakae J, Kitamura Y et al (2002) The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 110:1839–1847PubMedCentralCrossRefPubMed
22.
Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278:1319–1322CrossRefPubMed
23.
Ogg S, Paradis S, Gottlieb S et al (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999CrossRefPubMed
24.
Haeusler RA, Hartil K, Vaitheesvaran B et al (2014) Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat Commun 5:5190PubMedCentralCrossRefPubMed
25.
26.
Kim-Muller JY, Zhao S, Srivastava S et al (2014) Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab 20:593–602CrossRefPubMed
27.
Kitamura T, Feng Y, Kitamura YI et al (2006) Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med 12:534–540CrossRefPubMed
28.
Plum L, Lin HV, Dutia R et al (2009) The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 15:1195–1201PubMedCentralCrossRefPubMed
29.
30.
Zhang W, Patil S, Chauhan B et al (2006) FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281:10105–10117CrossRefPubMed
31.
Chakrabarti P, Kandror KV (2009) FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes. J Biol Chem 284:13296–13300PubMedCentralCrossRefPubMed
32.
Potente M, Urbich C, Sasaki K et al (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115:2382–2392PubMedCentralCrossRefPubMed
33.
Tsuchiya K, Tanaka J, Shuiqing Y et al (2012) FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab 15:372–381PubMedCentralCrossRefPubMed
34.
35.
Wang Z, York NW, Nichols CG, Remedi MS (2014) Pancreatic beta cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab 19:872–882PubMedCentralCrossRefPubMed
36.
Nakae J, Kitamura T, Silver DL, Accili D (2001) The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 108:1359–1367PubMedCentralCrossRefPubMed
37.
Frescas D, Valenti L, Accili D (2005) Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280:20589–20595CrossRefPubMed
38.
Ramnanan CJ, Edgerton DS, Rivera N et al (2010) Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. Diabetes 59:1302–1311PubMedCentralCrossRefPubMed
39.
Matveyenko AV, Liuwantara D, Gurlo T et al (2012) Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling. Diabetes 61:2269–2279PubMedCentralCrossRefPubMed
40.
41.
Qu S, Altomonte J, Perdomo G et al (2006) Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 147:5641–5652PubMedCentralCrossRefPubMed
42.
Matsumoto M, Han S, Kitamura T, Accili D (2006) Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 116:2464–2472PubMedCentralPubMed
43.
Wan M, Leavens KF, Saleh D et al (2011) Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab 14:516–527PubMedCentralCrossRefPubMed
44.
45.
Xiong X, Tao R, DePinho RA, Dong XC (2013) Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis. PLoS One 8:e74340PubMedCentralCrossRefPubMed
46.
DeFronzo RA (2010) Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 53:1270–1287PubMedCentralCrossRefPubMed
47.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589CrossRefPubMed
48.
Caro JJ, Ward AJ, O’Brien JA (2002) Lifetime costs of complications resulting from type 2 diabetes in the U.S. Diabetes Care 25:476–481CrossRefPubMed
49.
50.
51.
Massa ML, Gagliardino JJ, Francini F (2011) Liver glucokinase: an overview on the regulatory mechanisms of its activity. IUBMB Life 63:1–6CrossRefPubMed
52.
Pajvani UB, Qiang L, Kangsamaksin T, Kitajewski J, Ginsberg HN, Accili D (2013) Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat Med 19:1054–1060PubMedCentralCrossRefPubMed
53.
Zhang K, Li L, Qi Y et al (2012) Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice. Endocrinology 153:631–646CrossRefPubMed
54.
Haeusler RA, Pratt-Hyatt M, Welch CL, Klaassen CD, Accili D (2012) Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia. Cell Metab 15:65–74PubMedCentralCrossRefPubMed
55.
Tao R, Wei D, Gao H, Liu Y, DePinho RA, Dong XC (2011) Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J Biol Chem 286:14681–14690PubMedCentralCrossRefPubMed
56.
Peter A, Stefan N, Cegan A et al (2011) Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans. J Clin Endocrinol Metab 96:E1126–E1130CrossRefPubMed
57.
Matschinsky FM, Zelent B, Doliba NM et al (2011) Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects. Handb Exp Pharmacol 203:357–401CrossRefPubMed
58.
Apelqvist A, Li H, Sommer L et al (1999) Notch signalling controls pancreatic cell differentiation. Nature 400:877–881CrossRefPubMed
59.
60.
Pajvani UB, Shawber CJ, Samuel VT et al (2011) Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat Med 17:961–967PubMedCentralCrossRefPubMed
61.
Valenti L, Mendoza RM, Rametta R et al (2013) Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Diabetes 62:4052–4062PubMedCentralCrossRefPubMed
62.
63.
64.
Liu X, Chhipa RR, Pooya S et al (2014) Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci U S A 111:E435–E444PubMedCentralCrossRefPubMed
65.
66.
Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365CrossRefPubMed
67.
Haeusler RA, Astiarraga B, Camastra S, Accili D, Ferrannini E (2013) Human insulin resistance is associated with increased plasma levels of 12alpha-hydroxylated bile acids. Diabetes 62:4184–4191PubMedCentralCrossRefPubMed
68.
Weyer C, Bogardus C, Mott DM, Pratley RE (1999) The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104:787–794PubMedCentralCrossRefPubMed
69.
70.
Prentki M, Matschinsky FM, Madiraju SR (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18:162–185CrossRefPubMed
71.
Harbeck MC, Louie DC, Howland J, Wolf BA, Rothenberg PL (1996) Expression of insulin receptor mRNA and insulin receptor substrate 1 in pancreatic islet beta-cells. Diabetes 45:711–717CrossRefPubMed
72.
Withers DJ, Sanchez-Gutierrez J, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904CrossRefPubMed
73.
Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR (1999) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329–339CrossRefPubMed
74.
Matschinsky FM (1996) Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223–241CrossRefPubMed
75.
Odegaard ML, Joseph JW, Jensen MV et al (2010) The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion. J Biol Chem 285:16530–16537PubMedCentralCrossRefPubMed
76.
Eto K, Tsubamoto Y, Terauchi Y et al (1999) Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science 283:981–985CrossRefPubMed
77.
Schuit F, de Vos A, Farfari S et al (1997) Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. J Biol Chem 272:18572–18579CrossRefPubMed
78.
Gheni G, Ogura M, Iwasaki M et al (2014) Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion. Cell Rep 9:661–673PubMedCentralCrossRefPubMed
79.
Ivarsson R, Quintens R, Dejonghe S et al (2005) Redox control of exocytosis: regulatory role of NADPH, thioredoxin, and glutaredoxin. Diabetes 54:2132–2142CrossRefPubMed
80.
MacDonald MJ, Fahien LA, Brown LJ, Hasan NM, Buss JD, Kendrick MA (2005) Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. Am J Physiol Endocrinol Metab 288:E1–E15CrossRefPubMed
81.
Buteau J, Shlien A, Foisy S, Accili D (2007) Metabolic diapause in pancreatic beta-cells expressing a gain-of-function mutant of the forkhead protein Foxo1. J Biol Chem 282:287–293CrossRefPubMed
82.
Kelley DE, Mandarino LJ (2000) Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49:677–683CrossRefPubMed
83.
Puri S, Akiyama H, Hebrok M (2013) VHL-mediated disruption of Sox9 activity compromises beta-cell identity and results in diabetes mellitus. Genes Dev 27:2563–2575PubMedCentralCrossRefPubMed
84.
85.
Blum B, Roose AN, Barrandon O et al (2014) Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway. eLife 3:e02809PubMedCentralPubMed
86.
Burgess SC, He T, Yan Z et al (2007) Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. Cell Metab 5:313–320PubMedCentralCrossRefPubMed
87.
Henquin JC, Accili D, Ahren B, Boitard C, Seino S, Cerasi E (2011) Long in the shade, glucagon re-occupies centre court. Diabetes Obes Metab 13(Suppl 1):v–viiiCrossRefPubMed
88.
Dentin R, Liu Y, Koo SH et al (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449:366–369CrossRefPubMed
89.
Dentin R, Hedrick S, Xie J, Yates J 3rd, Montminy M (2008) Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319:1402–1405CrossRefPubMed
90.
91.
Ozcan L, Wong CC, Li G et al (2012) Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab 15:739–751PubMedCentralCrossRefPubMed
92.
Okamoto H, Obici S, Accili D, Rossetti L (2005) Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest 115:1314–1322PubMedCentralCrossRefPubMed
93.
Okamoto H, Nakae J, Kitamura T, Park BC, Dragatsis I, Accili D (2004) Transgenic rescue of insulin receptor-deficient mice. J Clin Invest 114:214–223PubMedCentralCrossRefPubMed
94.
Lin HV, Plum L, Ono H et al (2010) Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59:337–346PubMedCentralCrossRefPubMed
95.
Konner AC, Janoschek R, Plum L et al (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438–449CrossRefPubMed
96.
97.
98.
Metadata
Title
The new biology of diabetes
Authors
Utpal B. Pajvani
Domenico Accili
Publication date
01-11-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 11/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-015-3722-5

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