in

The integrative biology of type 2 diabetes

Abstract

Weight problems and type 2 diabetes are the most frequent metabolic conditions, but their causes stay largely uncertain. Insulin resistance, the common underlying problem, arises from imbalance between energy consumption and expenditure favouring nutrient-storage pathways, which developed to make the most of energy utilization and preserve sufficient substrate supply to the brain. Initially, dysfunction of white fat and distributing metabolites modulate tissue interaction and insulin signalling. When the energy imbalance is persistent, mechanisms such as inflammatory pathways speed up these abnormalities. Here we summarize current studies providing insights into insulin resistance and increased hepatic gluconeogenesis associated with obesity and type 2 diabetes, concentrating on data from people and appropriate animal designs.

  • 3.
  • 5.
  • 6.
  • 11

    Perry, R. J. et al. Systems by which a very-low-calorie diet reverses hyperglycemia in a rat design of type 2 diabetes. Cell Metab 27, 210–217(2018).

  • 12

    Steinhauser, M. L. et al. The flowing metabolome of human hunger. JCI Insight 3, e121434(2018).

  • 13

    Fazeli, P. K. et al. FGF21 and the late adaptive response to hunger in humans. J. Clin. Invest 125, 4601–4611(2015).

  • 14

    Perry, R. J. et al. Hepatic acetyl CoA links fat inflammation to hepatic insulin resistance and type 2 diabetes. Cell160, 745–758(2015).

  • 15

    Roden, M. et al. Effects of totally free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes49, 701–707(2000).

  • 16

    Vatner, D. F. et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc. Natl Acad. Sci. USA112, 1143–1148(2015).

  • 17

    Petersen, M. C. et al. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J. Clin. Invest 126, 4361–4371(2016).

  • 18

    Peterson, K. F., Dufour, F., Cline, G. W. & Shulman, G. I. Policy of hepatic mitochondrial oxidation by glucose-alanine biking throughout hunger in humans. J. Clin. Invest 129, 4671–4675(2019).

  • 19

    Sarabhai, T. & Roden, M. Hungry for your alanine: when liver depends upon muscle proteolysis. J. Clin. Invest 129, 4563–4566(2019).

  • 20

    Pasiakos, S. M., Caruso, C. M., Kellogg, M. D., Kramer, F. M. & Lieberman, H. R. Hunger and endocrine regulators of energy balance after 2 days of energy constraint: insulin, leptin, ghrelin, and DHEA-S. Obesity19, 1124–1130(2011).

  • 21

    Schorr, M. & Miller, K. K. The endocrine manifestations of anorexia: systems and management. Nat. Rev. Endocrinol 13, 174–186(2017).

  • 22

    Ravussin, Y., Leibel, R. L. & Ferrante, A. W. Jr. A missing link in body weight homeostasis: the catabolic signal of the overfed state. Cell Metab 20, 565–572(2014).

  • 23

    Friedman, J. The long road to leptin. J. Clin. Invest 126, 4727–4734(2016).

  • 24

    Riddle, M. R. et al. Insulin resistance in cavefish as an adjustment to a nutrient-limited environment. Nature555, 647–651(2018). Particular cave-adapted fish populations establish lessened insulin signalling in a nutrient-restricted environment, which safeguards them from blood sugar decrease, reflecting an useful effect of insulin resistance.

  • 25

    Carrera, P. et al. Replacement of Leu for Pro-193 in the insulin receptor in a patient with a genetic type of severe insulin resistance. Hum. Mol. Genet 2, 1437–1441(1993).

  • 26

    Abdul-Ghani, M. A. & DeFronzo, R. A. Plasma glucose concentration and prediction of future threat of type 2 diabetes. Diabetes Care32, S194– S198(2009).

  • 27

    Tabák, A. G. et al. Trajectories of glycaemia, insulin level of sensitivity, and insulin secretion prior to diagnosis of type 2 diabetes: an analysis from the Whitehall II research study. Lancet373, 2215–2221(2009).

  • 28

    Ohn, J. H. et al. 10- year trajectory of β-cell function and insulin level of sensitivity in the advancement of type 2 diabetes: a community-based prospective associate study. Lancet Diabetes Endocrinol 4, 27–34(2016).

  • 29

    DeFronzo, R. A. & Tripathy, D. Skeletal muscle insulin resistance is the primary problem in type 2 diabetes. Diabetes Care32, S157– S163(2009).

  • 30

    Petersen, K. F. et al. The function of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl Acad. Sci. U.S.A.104, 12587–12594(2007).

  • 31

    Saltiel, A. R. & Olefsky, J. M. Inflammatory systems linking obesity and metabolic illness. J. Clin. Invest 127, 1– 4 (2017).

  • 32

    Guilherme, A., Henriques, F., Bedard, A. H. & Czech, M. P. Molecular pathways linking adipose innervation to insulin action in weight problems and diabetes mellitus. Nat. Rev. Endocrinol 15, 207–225(2019).

  • 33

    Umpierrez, G. E., Smiley, D. & Kitabchi, A. E. Story evaluation: ketosis-prone type 2 diabetes mellitus. Ann. Intern. Med 144, 350–357(2006).

  • 34

    Petersen, K. F. et al. Increased occurrence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian males. Proc. Natl Acad. Sci. USA103, 18273–18277(2006).

  • 35

    Zaharia, O. P. et al. Clusters of patients with recent-onset diabetes show various danger profiles for diabetes-associated illness during a 5-year follow-up. Lancet. Diabetol. Endocrinol 7, 684–694(2019). A subgroup of people with diabetes display serious insulin resistance along with greater ectopic fat build-up and increased risk of comorbidities, which require specific attention for precise avoidance and treatment.

  • 36

    Ahlqvist, E. et al. Unique subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of 6 variables. Lancet Diabetes Endocrinol 6, 361–369(2018).

  • 37

    Udler, M. S. et al. Type 2 diabetes genetic loci informed by multi-trait associations point to disease systems and subtypes: a soft clustering analysis. PLoS Med 15, e1002654(2018).

  • 38

    Magnusson, I., Rothman, D. L., Katz, L. D., Shulman, R. G. & Shulman, G. I. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13 C nuclear magnetic resonance research study. J. Clin. Invest 90, 1323–1327(1992).

  • 39

    Krssak, M. et al. Modifications in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes53, 3048–3056(2004).

  • 40

    Rizza, R. A. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for treatment. Diabetes59, 2697–2707(2010).

  • 41

    Gastaldelli, A. et al. Impact of obesity and type 2 diabetes on gluconeogenesis and glucose output in human beings: a quantitative study. Diabetes49, 1367–1373(2000).

  • 42

    Rebrin, K., Steil, G. M., Mittelman, S. D. & Bergman, R. N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J. Clin. Invest 98, 741–749(1996).

  • 43

    Buettner, C. et al. Extreme problems in liver insulin signaling stops working to alter hepatic insulin action in conscious mice. J. Clin. Invest 115, 1306–1313(2005).

  • 44

    Cherrington, A. D. The role of hepatic insulin receptors in the regulation of glucose production. J. Clin. Invest 115, 1136–1139(2005).

  • 45

    Lu, M. et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat. Med 18, 388–395(2012).

  • 46

    O-Sullivan, I. et al. FoxO1 incorporates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat. Commun 6, 7079 (2015).

  • 47

    Titchenell, P. M., Chu, Q., Monks, B. R. & Birnbaum, M. J. Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat. Commun 6, 7078 (2015). This mouse research study showed that in the absence of FOXO1, insulin signals individually of the hepatic insulin receptor– AKT– FOXO1 axis through an intermediary extrahepatic tissue to regulate hepatic glucose production.

  • 48

    Brown, M. S. & Goldstein, J. L. Selective versus overall insulin resistance: a pathogenic paradox. Cell Metab 7, 95–96(2008).

  • 49

    Donnelly, K. L. et al. Sources of fatty acids kept in liver and secreted through lipoproteins in patients with nonalcoholic fatty liver illness. J. Clin. Invest 115, 1343–1351(2005).

  • 50

    Albert, J. S. et al. Null anomaly in hormone-sensitive lipase gene and threat of type 2 diabetes. N. Engl. J. Med 370, 2307–2315(2014).

  • 51

    Ali, A. H., Mundi, M., Koutsari, C., Bernlohr, D. A. & Jensen, M. D. Fat totally free fatty acid storage in vivo: effects of insulin versus niacin as a control for suppression of lipolysis. Diabetes64, 2828–2835(2015).

  • 52

    Caro, J. F. et al. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J. Clin. Invest 78, 249–258(1986).

  • 53

    Abdul-Wahed, A., Guilmeau, S. & Postic, C. Sugary food sixteenth for ChREBP: established roles and future objectives. Cell Metab 26, 324–341(2017).

  • 54

    Li, S., Brown, M. S. & Goldstein, J. L. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, however not inhibition of gluconeogenesis. Proc. Natl Acad. Sci. U.S.A.107, 3441–3446(2010).

  • 55

    Herman, M. A. & Samuel, V. T. The sweet course to metabolic demise: fructose and lipid synthesis. Trends Endocrinol. Metab 27, 719–730(2016).

  • 56

    Kumashiro, N. et al. Cellular system of insulin resistance in nonalcoholic fatty liver disease. Proc. Natl Acad. Sci. U.S.A.108, 16381–16385(2011).

  • 57

    Magkos, F. et al. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology142, 1444–1446(2012).

  • 58

    Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance in clients with non-alcoholic fatty liver illness. J. Hepatol 64, 1167–1175(2016).

  • 59

    ter Horst, K. W. et al. Hepatic diacylglycerol-associated protein kinase C ε translocation links hepatic steatosis to hepatic insulin resistance in humans. J. Hepatol 64, 1167–1175(2016).

  • 60

    Ruby, M. A. et al. Human carboxylesterase 2 reverses obesity-induced diacylglycerol build-up and glucose intolerance. Cell Associate 18, 636–646(2017).

  • 61

    Apostolopoulou, M. et al. Specific hepatic sphingolipids connect to insulin resistance, oxidative tension, and inflammation in nonalcoholic steatohepatitis. Diabetes Care41, 1235–1243(2018).

  • 62

    Koliaki, C. et al. Adaptation of hepatic mitochondrial function in human beings with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 21, 739–746(2015).

  • 63

    Chaurasia, B. et al. Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science365, 386–392(2019).

  • 64

    Hammerschmidt, P. et al. CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in besity. Cell177, 1536–1552(2019).

  • 65

    Cantley, J. L. et al. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc. Natl Acad. Sci. USA110, 1869–1874(2013).

  • 66

    Hernández, E. Á. et al. Intense dietary fat intake starts alterations in basal metabolism and insulin resistance. J. Clin. Invest 127, 695–708(2017).

  • 67

    Parks, E., Yki-Järvinen, H. & Hawkins, M. Out of the frying pan: dietary saturated fat impacts nonalcoholic fatty liver disease. J. Clin. Invest 127, 454–456(2017).

  • 68

    Luukkonen, P. K. et al. Hydrogenated fat is more metabolically hazardous for the human liver than unsaturated fat or easy sugars. Diabetes Care41, 1732–1739(2018).

  • 69

    He, S. et al. Gut intraepithelial T cells calibrate metabolic process and speed up cardiovascular disease. Nature566, 115–119(2019).

  • 70

    Ussar, S. et al. Interactions in between gut microbiota, host genetics and diet plan regulate the predisposition to obesity and metabolic syndrome. Cell Metab 22, 516–530(2015).

  • 71

    Pedersen, H. K. et al. Human gut microorganisms effect host serum metabolome and insulin level of sensitivity. Nature535, 376–381(2016).

  • 72

    Hoyles, L. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic overweight women. Nat. Med 24, 1070–1080(2018).

  • 73

    Sanna, S. et al. Causal relationships among the gut microbiome, short-chain fats and metabolic illness. Nat. Genet 51, 600–605(2019).

  • 74

    Taylor, R. et al. Remission of human type 2 diabetes requires decline in liver and pancreas fat content but depends on capacity for β cell recovery. Cell Metab 28, 547–556(2018).

  • 75

    Cline, G. W. et al. Impaired glucose transportation as a reason for decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N. Engl. J. Medication 341, 240–246(1999).

  • 76

    Perseghin, G. et al. Increased glucose transport– phosphorylation and muscle glycogen synthesis after workout training in insulin-resistant subjects. N. Engl. J. Med 335, 1357–1362(1996).

  • 77

    Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in people. J. Clin. Invest 97, 2859–2865(1996).

  • 78

    Dresner, A. et al. Effects of complimentary fats on glucose transportation and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest 103, 253–259(1999).

  • 79

    Szendroedi, J. et al. Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Medication 4, e154(2007).

  • 80

    Kim, Y. B., Nikoulina, S. E., Ciaraldi, T. P., Henry, R. R. & Kahn, B. B. Typical insulin-dependent activation of Akt/protein kinase B, with lessened activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J. Clin. Invest 104, 733–741(1999).

  • 81

    Fazakerley, D. J., Krycer, J. R., Kearney, A. L., Hocking, S. L. & James, D. E. Muscle and fat insulin resistance: malady without system? J. Lipid Res 60, 1720–1732(2019).

  • 82

    Czech, M. P. Insulin action and resistance in obesity and type 2 diabetes. Nat. Med 23, 804–814(2017).

  • 83

    Wan, M. et al. A noncanonical, GSK3-independent path controls postprandial hepatic glycogen deposition. Cell Metab 18, 99–105(2013).

  • 84

    Bouskila, M. et al. Allosteric guideline of glycogen synthase manages glycogen synthesis in muscle. Cell Metab 12, 456–466(2010).

  • 85

    von Wilamowitz-Moellendorff, A. et al. Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a crucial function in hepatic glycogen synthesis. Diabetes 62,4070–4082(2013).

  • 86

    Musi, N. et al. AMP-activated protein kinase (AMPK) is triggered in muscle of subjects with type 2 diabetes throughout exercise. Diabetes50, 921–927(2001).

  • 87

    Rabøl, R., Petersen, K. F., Dufour, S., Flannery, C. & Shulman, G. I. Reversal of muscle insulin resistance with workout minimizes postprandial hepatic de novo lipogenesis in insulin resistant people. Proc. Natl Acad. Sci. U.S.A.108, 13705–13709(2011).

  • 88

    Ruegsegger, G. N., Creo, A. L., Cortes, T. M., Dasari, S. & Nair, K. S. Modified mitochondrial function in insulin-deficient and insulin-resistant states. J. Clin. Invest 128, 3671–3681(2018).

  • 89

    Petersen, K. F. et al. Mitochondrial dysfunction in the senior: possible role in insulin resistance. Science300, 1140–1142(2003).

  • 90

    Kraja, A. T. et al. Associations of mitochondrial and nuclear mitochondrial variants and genes with seven metabolic traits. Am. J. Hum. Genet 104, 112–138(2019).

  • 91

    Kacerovsky-Bielesz, G. et al. Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of human beings with type 2 diabetes. Diabetes58, 1333–1341(2009).

  • 92

    Holloszy, J. O. “Shortage” of mitochondria in muscle does not cause insulin resistance. Diabetes62, 1036–1040(2013).

  • 93

    Pospisilik, J. A. et al. Targeted removal of AIF decreases mitochondrial oxidative phosphorylation and secures from weight problems and diabetes. Cell131, 476–491(2007).

  • 94

    Koh, J. H. et al. TFAM boosts fat oxidation and attenuates high fat diet plan induced insulin resistance in skeletal muscle. Diabetes68, 1552–1564(2019).

  • 95

    Lotta, L. A. et al. Integrative genomic analysis links limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat. Genet 49, 17–26(2017).

  • 96

    Knowles, J. W. et al. Recognition and recognition of N– acetyltransferase 2 as an insulin level of sensitivity gene. J. Clin. Invest 125, 1739–1751(2015).

  • 97

    Chennamsetty, I. et al. Nat1 deficiency is connected with mitochondrial dysfunction and exercise intolerance in mice. Cell Representative 17, 527–540(2016).

  • 98

    Maurya, S. K. et al. Sarcolipin signaling promotes mitochondrial biogenesis and oxidative metabolism in skeletal muscle. Cell Associate 24, 2919–2931(2018).

  • 99

    Latva-Rasku, A. et al. A partial loss-of-function variation in AKT2 is connected with decreased insulin-mediated glucose uptake in several insulin-sensitive tissues: a genotype-based callback positron emission tomography research study. Diabetes67, 334–342(2018).

  • 100

    Hussain, K. et al. An activating anomaly of AKT2 and human hypoglycemia. Science334, 474 (2011).

  • 101

    Dash, S. et al. A truncation mutation in TBC1D4 in a household with acanthosis nigricans and postprandial hyperinsulinemia. Proc. Natl Acad. Sci. U.S.A.106, 9350–9355(2009).

  • 102

    Moltke, I. et al. A typical Greenlandic TBC1D4 variant gives muscle insulin resistance and type 2 diabetes. Nature512, 190–193(2014).

  • 103

    Sylow, L. et al. Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes62, 1865–1875(2013).

  • 104

    Kahn, C. R. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a required distinction. Metabolism27, 1893–1902(1978).

  • 105

    Freidenberg, G. R., Reichart, D., Olefsky, J. M. & Henry, R. R. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Impact of weight-loss. J. Clin. Invest 82, 1398–1406(1988).

  • 106

    Kahn, B. B. & Flier, J. S. Weight problems and insulin resistance. J. Clin. Invest 106, 473–481(2000).

  • 107

    Bódis, K. & Roden, M. Energy metabolism of white fat and insulin resistance in human beings. Eur. J. Clin. Invest 48, e13017(2018).

  • 108

    Scherer, P. E. The numerous secret lives of adipocytes: ramifications for diabetes. Diabetologia62, 223–232(2019).

  • 109

    Zeng, X. et al. Innervation of thermogenic adipose tissue by means of a calsyntenin 3β– S100 b axis. Nature569, 229–235(2019).

  • 110

    McQuaid, S. E. et al. Downregulation of adipose tissue fat trafficking in weight problems: a driver for ectopic fat deposition? Diabetes60, 47–55(2011).

  • 111

    Manning, A. K. et al. A genome-wide approach accounting for body mass index recognizes hereditary variants affecting fasting glycemic characteristics and insulin resistance. Nat. Genet 44, 659–669(2012).

  • 112

    Shungin, D. et al. New hereditary loci connect adipose and insulin biology to body fat distribution. Nature518, 187–196(2015).

  • 113

    Camporez, J. P. et al. System by which arylamine N– acetyltransferase 1 ablation triggers insulin resistance in mice. Proc. Natl Acad. Sci. U.S.A.114, E11285– E11292(2017).

  • 114

    Orozco, L. D. et al. Epigenome-wide association in fat from the METSIM mate. Hum. Mol. Genet 27, 1830–1846(2018).

  • 115

    Lee, Y. S. et al. Increased adipocyte O 2 intake sets off HIF-1α, triggering inflammation and insulin resistance in weight problems. Cell157, 1339–1352(2014).

  • 116

    Seo, J. B. et al. Knockdown of ANT2 decreases adipocyte hypoxia and improves insulin resistance in weight problems. Nat. Metab 1, 86–97(2019). Utilizing mouse models, this study shows that adipocyte oxygen need instead of oxygen supply or angiogenesis is the key factor of intracellular hypoxia, which might be the initial occasion leading to adipose tissue swelling.

  • 117

    Kratz, M. et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in fat macrophages. Cell Metab 20, 614–625(2014).

  • 118

    Sartipy, P. & Loskutoff, D. J. Monocyte chemoattractant protein 1 in weight problems and insulin resistance. Proc. Natl Acad. Sci. U.S.A.100, 7265–7270(2003).

  • 119

    Ying, W. et al. Fat B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling. J. Clin. Invest 127, 1019–1030(2017).

  • 120

    Lee, B.-C. et al. Adipose natural killer cells manage adipose tissue macrophages to promote insulin resistance in weight problems. Cell Metab 23, 685–698(2016).

  • 121

    Wensveen, F. M. et al. NK cells connect obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol 16, 376–385(2015).

  • 122

    Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the avoidance and management of diabetes. J. Am. Coll. Cardiol71,2392–2401(2018).

  • 123

    Oral, E. A. et al. Inhibition of IKKε and TBK1 enhances glucose control in a subset of clients with type 2 diabetes. Cell Metab 26, 157–170(2017).

  • 124

    Samuel, V. T. et al. Inhibition of protein kinase Cε avoids hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest 117, 739–745(2007).

  • 125

    Nishimura, S. et al. CD8 effector T cells add to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med 15, 914–920(2009).

  • 126

    Strissel, K. J. et al. Adipocyte death, fat renovation, and weight problems issues. Diabetes56, 2910–2918(2007).

  • 127

    Thomou, T. et al. Adipose-derived distributing miRNAs control gene expression in other tissues. Nature542, 450–455(2017).

  • 128

    Kullmann, S. et al. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol. Rev 96, 1169–1209(2016).

  • 129

    Jais, A. & Brüning, J. C. Hypothalamic inflammation in obesity and metabolic illness. J. Clin. Invest 127, 24–32(2017).

  • 130

    Thaler, J. P. et al. Obesity is connected with hypothalamic injury in rodents and human beings. J. Clin. Invest 122, 153–162(2012).

  • 131

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

  • 132

    Pocai, A. et al. Hypothalamic K ATP channels control hepatic glucose production. Nature434, 1026–1031(2005).

  • 133

    Inoue, H. et al. Function of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab 3, 267–275(2006).

  • 134

    Gelling, R. W. et al. Insulin action in the brain adds to glucose lowering throughout insulin treatment of diabetes. Cell Metab 3, 67–73(2006).

  • 135

    Scherer, T. et al. Brain insulin manages fat lipolysis and lipogenesis. Cell Metab 13, 183–194(2011).

  • 136

    Ramnanan, C. J., Edgerton, D. S. & Cherrington, A. D. Evidence against a physiologic role for acute modifications in CNS insulin action in the rapid policy of hepatic glucose production. Cell Metab 15, 656–664(2012). This perspective goes over the proof that the brain can sense insulin and control hepatic glucoregulatory enzyme expression, although the action of cerebral insulin is not necessary for the quick insulin-mediated suppression of glucose production.

  • 137

    Winnick, J. J. et al. Hepatic glycogen can manage hypoglycemic counterregulation via a liver– brain axis. J. Clin. Invest 126, 2236–2248(2016).

  • 138

    Gancheva, S. et al. Intranasal insulin lowers hepatic fat accumulation and enhances energy metabolism in people. Diabetes64, 1966–1975(2015).

  • 139

    Kishore, P. et al. Activation of K ATP channels suppresses glucose production in human beings. J. Clin. Invest 121, 4916–4920(2011).

  • 140

    Esterson, Y. B. et al. Main policy of glucose production might suffer in type 2 diabetes. Diabetes65, 2569–2579(2016).

  • 141

    Kimura, K. et al. Central insulin action activates Kupffer cells by suppressing hepatic vagal activation by means of the nicotinic alpha 7 acetylcholine receptor. Cell Associate 14, 2362–2374(2016).

  • 142

    Perreault, L. et al. Intracellular localization of diacylglycerols and sphingolipids affects insulin level of sensitivity and mitochondrial function in human skeletal muscle. JCI Insight 3, e96805(2018).

  • 143

    Brandon, A. E. et al. Protein kinase C epsilon removal in adipose tissue, but not in liver, enhances glucose tolerance. Cell Metab 29, 183–191(2019).

  • 144

    Gancheva, S. et al. Dynamic changes of muscle insulin level of sensitivity after metabolic surgical treatment. Nat. Commun 10, 4179 (2019).

  • 145

    Parker, B. L. et al. An integrative systems hereditary analysis of mammalian lipid metabolic process. Nature567, 187–193(2019).

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    Recognitions

    This research study is supported by grants from the German Federal Ministry of Health and Ministry of Culture and Science of the state North Rhine-Westphalia to DDZ, the German Federal Ministry of Education and Research Study to DZD, European Funds for Regional Development (EFRE-0400191), EUREKA Eurostars-2 (E! 113230 DIA-PEP) and the German Science Foundation (CRC/SFB 1116/ 2 B12) (to M.R.) and by grants from the United States Public Health Service (R01 DK-113984, R01 DK114793, R01 DK116774, R01 DK119968, P30 DK-045735) (to G.I.S.). The content is exclusively the obligation of the authors and does not necessarily represent the official views of the NIH.

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    1. Division of Endocrinology and Diabetology, Medical Professors, Heinrich-Heine University, Düsseldorf, Germany

      • Michael Roden
    2. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research Study at Heinrich-Heine University, Düsseldorf, Germany

      • Michael Roden
    3. German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany

      • Michael Roden
    4. Departments of Internal Medicine and Cellular and Molecular Physiology, Yale Diabetes Proving Ground, Yale School of Medicine, New Sanctuary, CT, USA

      • Gerald I. Shulman

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    M.R. and G.I.S. wrote the manuscript.

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    Michael Roden or Gerald I. Shulman.

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    M.R. is on the clinical advisory boards of Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, NovoNordisk, Servier Laboratories, Target Pharmasolutions and Terra Firma and receives investigator-initiated support from Boehringer Ingelheim, Nutricia/Danone and Sanofi– Aventis. G.I.S. is on the scientific boards of advisers of Merck, NovoNordisk, Gilead Sciences, AstraZeneca, Aegerion, iMBP, Janssen Research study and Advancement and receives investigator-initiated assistance from Gilead Sciences, Merck and AstraZeneca.

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    Roden, M., Shulman, G.I. The integrative biology of type 2 diabetes.
    Nature576, 51–60(2019) doi: 10.1038/ s41586 -019-1797 -8

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    • https://doi.org/101038/ s41586 -019-1797 -8

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