Fat accumulation outside subcutaneous adipose tissue often has unfavourable effects on systemic metabolism. In addition to non-alcoholic fatty liver disease, which has received considerable attention, pancreatic fat has become an important area of research throughout the past 10 years. While a number of diagnostic approaches are available to quantify pancreatic fat, multi-echo Dixon MRI is currently the most developed method. Initial studies have shown associations between pancreatic fat and the metabolic syndrome, impaired glucose metabolism and type 2 diabetes mellitus. Pancreatic fat is linked to reduced insulin secretion, at least under specific circumstances such as prediabetes, low BMI and increased genetic risk of type 2 diabetes mellitus. This Review summarizes the possible causes and metabolic consequences of pancreatic fat accumulation. In addition, potential therapeutic approaches for addressing pancreatic fat accumulation are discussed.
A number of studies have demonstrated a link between pancreatic fat and impaired glucose metabolism, as well as between pancreatic fat and type 2 diabetes mellitus.
Possible causes of pancreatic steatosis include the metabolic syndrome, non-alcoholic fatty liver disease, alcohol consumption and specific genetic diseases.
Chronic accumulation of fat in the pancreas can lead to chronic pancreatitis, pancreatic neoplasia, disturbed glucose metabolism and impaired insulin secretion.
Different approaches, such as a hypocaloric diet, exercise, bariatric surgery and pharmacological interventions, can reduce pancreatic fat content.
Preliminary evidence shows that a reduction in pancreatic fat improves insulin metabolism, but further experimental evidence is needed to untangle the underlying mechanisms.
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Mathur, A. et al. Pancreatic steatosis promotes dissemination and lethality of pancreatic cancer. J. Am. Coll. Surg. 208, 989–994 (2009).
Zhou, J. et al. The correlation between pancreatic steatosis and metabolic syndrome in a Chinese population. Pancreatology 16, 578–583 (2016).
Olsen, T. S. Lipomatosis of the pancreas in autopsy material and its relation to age and overweight. Acta Pathol. Microbiol. Scand. A 86A, 367–373 (1978). One of the first analyses of the relationship between fatty pancreas with obesity in ~400 autopsies.
Schwenzer, N. F. et al. Quantification of pancreatic lipomatosis and liver steatosis by MRI: comparison of in/opposed-phase and spectral-spatial excitation techniques. Invest. Radiol. 43, 330–337 (2008).
Rebours, V. et al. Obesity and fatty pancreatic infiltration are risk factors for pancreatic precancerous lesions (PanIN). Clin. Cancer Res. 21, 3522–3528 (2015).
Wang, H., Maitra, A. & Wang, H. Obesity, intrapancreatic fatty infiltration, and pancreatic cancer. Clin. Cancer Res. 21, 3369–3371 (2015).
Mathur, A. et al. Nonalcoholic fatty pancreas disease. HPB 9, 312–318 (2007).
Targher, G. et al. Pancreatic fat accumulation and its relationship with liver fat content and other fat depots in obese individuals. J. Endocrinol. Invest. 35, 748–753 (2012).
Lê, K.-A. et al. Ethnic differences in pancreatic fat accumulation and its relationship with other fat depots and inflammatory markers. Diabetes Care 34, 485–490 (2011). This work describes ethnic differences in pancreatic fat and associates it with clinical features.
Smits, M. M. & van Geenen, E. J. M. The clinical significance of pancreatic steatosis. Nat. Rev. Gastroenterol. Hepatol. 8, 169–177 (2011).
Wang, C.-Y., Ou, H.-Y., Chen, M.-F., Chang, T.-C. & Chang, C.-J. Enigmatic ectopic fat: prevalence of nonalcoholic fatty pancreas disease and its associated factors in a Chinese population. J. Am. Heart Assoc. 3, e000297 (2014).
Wong, V. W.-S. et al. Fatty pancreas, insulin resistance, and β-cell function: a population study using fat-water magnetic resonance imaging. Am. J. Gastroenterol. 109, 589–597 (2014).
Lesmana, C. R. A., Pakasi, L. S., Inggriani, S., Aidawati, M. L. & Lesmana, L. A. Prevalence of non-alcoholic fatty pancreas disease (NAFPD) and its risk factors among adult medical check-up patients in a private hospital: a large cross sectional study. BMC Gastroenterol. 15, 174 (2015).
Sepe, P. S. et al. A prospective evaluation of fatty pancreas by using EUS. Gastrointest. Endosc. 73, 987–993 (2011). This works identified pancreatic fat in a large number of patients using endoscopic ultrasonography and described a strong association with the metabolic syndrome.
Walters, M. N.-I. Adipose atrophy of the exocrine pancreas. J. Pathol. Bacteriol. 92, 547–557 (1966).
Molnar, L., Kerekes, E. & Meszaros, A. Significance of the fatty infiltration of the pancreas [Hungarian]. Orv. Hetil. 99, 1243–1246 (1958). This is one of the first systematic descriptions of fatty pancreas identified in 47% of 250 autopsies.
Rosengren, A. H. et al. Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes. Diabetes 61, 1726–1733 (2012).
Tong, X. et al. Lipid droplet accumulation in human pancreatic islets is dependent on both donor age and health. Diabetes 69, 342–354 (2020).
Ionescu-Tirgoviste, C. et al. A 3D map of the islet routes throughout the healthy human pancreas. Sci. Rep. 5, 14634 (2015).
Gerst, F. et al. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia 60, 2240–2251 (2017). This is the first evidence that fetuin-A can mediate a metabolic crosstalk between liver fat, insulin resistance and pancreatic fat exacerbating local inflammation in the pancreas and leading to decreased insulin secretion.
Wagner, R. et al. Pancreatic steatosis associates with impaired insulin secretion in genetically predisposed individuals. J. Clin. Endocrinol. Metab. 105, 3518–3525 (2020). This study demonstrates that the link between fatty pancreas and impaired insulin secretion depends on genetic risk of type 2 diabetes mellitus.
Barroso Oquendo, M. et al. Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity. Am. J. Physiol. Cell Physiol. 320, C1000–C1012 (2021).
Go, V. L. W. et al. The Pancreas: Biology, Pathobiology, and Disease (Lippincott Williams & Wilkins, 1993).
Nakamura, T. et al. Cotton rat (Sigmodon hispidus) develops metabolic disorders associated with visceral adipose inflammation and fatty pancreas without obesity. Cell Tissue Res. 375, 483–492 (2019).
Patel, S., Bellon, E. M., Haaga, J. & Park, C. H. Fat replacement of the exocrine pancreas. AJR Am. J. Roentgenol. 135, 843–845 (1980).
Murakami, R. et al. Pancreas fat and β cell mass in humans with and without diabetes: an analysis in the Japanese population. J. Clin. Endocrinol. Metab. 102, 3251–3260 (2017).
Lee, J. S. et al. Clinical implications of fatty pancreas: correlations between fatty pancreas and metabolic syndrome. World J. Gastroenterol. 15, 1869–1875 (2009).
Al-Haddad, M. et al. Risk factors for hyperechogenic pancreas on endoscopic ultrasound: a case-control study. Pancreas 38, 672–675 (2009).
Saisho, Y. et al. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes. Clin. Anat. 20, 933–942 (2007). The study provides a systematic description of changes in pancreas anatomy across the human lifespan.
Zijl, V. D. et al. Ectopic fat storage in the pancreas, liver, and abdominal fat depots: impact on β-cell function in individuals with impaired glucose metabolism. J. Clin. Endocrinol. Metab. 96, 459–467 (2011).
Heni, M. et al. Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: a nuclear magnetic resonance study. Diabetes Metab. Res. Rev. 26, 200–205 (2010). This work finds that pancreatic fat impacts insulin secretion in patients with prediabetes, but not in those with normal glucose tolerance.
Wu, W.-C. & Wang, C.-Y. Association between non-alcoholic fatty pancreatic disease (NAFPD) and the metabolic syndrome: case–control retrospective study. Cardiovasc. Diabetol. 12, 77 (2013).
Weng, S. et al. Prevalence and factors associated with nonalcoholic fatty pancreas disease and its severity in China. Medicine 97, e11293 (2018).
Hung, C.-S. et al. Increased pancreatic echogenicity with US: relationship to glycemic progression and incident diabetes. Radiology 287, 853–863 (2018). This paper describes the relationship between ultrasound-detected fatty pancreas and diabetes mellitus in approximately 32,000 participants.
Ou, H.-Y., Wang, C.-Y., Yang, Y.-C., Chen, M.-F. & Chang, C.-J. The association between nonalcoholic fatty pancreas disease and diabetes. PLoS ONE 8, e62561 (2013).
Johnson, M. L. & Mack, L. A. Ultrasonic evaluation of the pancreas. Gastrointest. Radiol. 3, 257–266 (1978).
Lindsell, D. R. M. Ultrasound imaging of pancreas and biliary tract. Lancet 335, 390–393 (1990).
Choi, C. W. et al. Associated factors for a hyperechogenic pancreas on endoscopic ultrasound. World J. Gastroenterol. 16, 4329–4334 (2010).
Yamazaki, H. et al. Independent association between prediabetes and future pancreatic fat accumulation: a 5-year Japanese cohort study. J. Gastroenterol. 53, 873–882 (2018).
Kim, S. Y. et al. Quantitative assessment of pancreatic fat by using unenhanced CT: pathologic correlation and clinical implications. Radiology 271, 104–112 (2014).
Hong, C. W., Fazeli Dehkordy, S., Hooker, J. C., Hamilton, G. & Sirlin, C. B. Fat quantification in the abdomen. Top. Magn. Reson. Imaging 26, 221–227 (2017).
Kashiwagi, K. et al. Pancreatic fat content detected by computed tomography and its significant relationship with intraductal papillary mucinous neoplasm. Pancreas 47, 1087–1092 (2018).
Hu, H. H., Kim, H.-W., Nayak, K. S. & Goran, M. I. Comparison of fat-water MRI and single-voxel MRS in the assessment of hepatic and pancreatic fat fractions in humans. Obesity 18, 841–847 (2010).
Al-Mrabeh, A., Hollingsworth, K. G., Steven, S., Tiniakos, D. & Taylor, R. Quantification of intrapancreatic fat in type 2 diabetes by MRI. PLoS ONE 12, e0174660 (2017).
Sakai, N. S., Taylor, S. A. & Chouhan, M. D. Obesity, metabolic disease and the pancreas–quantitative imaging of pancreatic fat. Br. J. Radiol. 91, 20180267 (2018).
Dixon, W. T. Simple proton spectroscopic imaging. Radiology 153, 189–194 (1984).
Sarma, M. K. et al. Noninvasive assessment of abdominal adipose tissues and quantification of hepatic and pancreatic fat fractions in type 2 diabetes mellitus. Magn. Reson. Imaging 72, 95–102 (2020).
Heber, S. D. et al. Pancreatic fat content by magnetic resonance imaging in subjects with prediabetes, diabetes, and controls from a general population without cardiovascular disease. PLoS ONE 12, e0177154 (2017).
Hernando, D. et al. Multisite, multivendor validation of the accuracy and reproducibility of proton-density fat-fraction quantification at 1.5T and 3T using a fat-water phantom. Magn. Reson. Med. 77, 1516–1524 (2017).
Hu, H. H. et al. Linearity and bias of proton density fat fraction as a quantitative imaging biomarker: a multicenter, multiplatform, multivendor phantom study. Radiology 298, 640–651 (2021).
Meisamy, S. et al. Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology 258, 767–775 (2011).
Kukuk, G. M. et al. Comparison between modified Dixon MRI techniques, MR spectroscopic relaxometry, and different histologic quantification methods in the assessment of hepatic steatosis. Eur. Radiol. 25, 2869–2879 (2015).
Zhong, X. et al. Liver fat quantification using a multi-step adaptive fitting approach with multi-echo GRE imaging. Magn. Reson. Med. 72, 1353–1365 (2014).
Hollingsworth, K. G., Al-Mrabeh, A., Steven, S. & Taylor, R. Pancreatic triacylglycerol distribution in type 2 diabetes. Diabetologia 58, 2676–2678 (2015).
Fukui, H. et al. Evaluation of fatty pancreas by proton density fat fraction using 3-T magnetic resonance imaging and its association with pancreatic cancer. Eur. J. Radiol. 118, 25–31 (2019).
Yoon, J. H. et al. Pancreatic steatosis and fibrosis: quantitative assessment with preoperative multiparametric MR imaging. Radiology 279, 140–150 (2016).
Hakim, O. et al. Associations between pancreatic lipids and β-cell function in black African and white European men with type 2 diabetes. J. Clin. Endocrinol. Metab. 104, 1201–1210 (2019).
Kato, S. et al. Three-dimensional analysis of pancreatic fat by fat-water magnetic resonance imaging provides detailed characterization of pancreatic steatosis with improved reproducibility. PLoS ONE 14, e0224921 (2019).
Tushuizen, M. E. et al. Pancreatic fat content and β-cell function in men with and without type 2 diabetes. Diabetes Care 30, 2916–2921 (2007). This is one of the first reports of the potential detrimental impact of fatty pancreas on β-cell function.
Machann, J. et al. Morning to evening changes of intramyocellular lipid content in dependence on nutrition and physical activity during one single day: a volume selective 1H-MRS study. MAGMA 24, 29–33 (2011).
Colgan, T. J., Van Pay, A. J., Sharma, S. D., Mao, L. & Reeder, S. B. Diurnal variation of proton density fat fraction in the liver using quantitative chemical shift encoded MRI. J. Magn. Reson. Imaging 51, 407–414 (2020).
Machann, J. et al. Short-term variability of proton density fat fraction in pancreas and liver assessed by multi-echo chemical-shift encoding-based MRI at 3 T. medRxiv https://doi.org/10.1101/2021.06.08.21257560 (2021).
Staaf, J. et al. Pancreatic fat is associated with metabolic syndrome and visceral fat but not beta-cell function or body mass index in pediatric obesity. Pancreas 46, 358–365 (2017).
Yamazaki, H. et al. Association between pancreatic fat and incidence of metabolic syndrome: a 5-year Japanese cohort study. J. Gastroenterol. Hepatol. 33, 2048–2054 (2018).
Lingvay, I. et al. Noninvasive quantification of pancreatic fat in humans. J. Clin. Endocrinol. Metab. 94, 4070–4076 (2009).
Rossi, A. P. et al. Predictors of ectopic fat accumulation in liver and pancreas in obese men and women. Obesity 19, 1747–1754 (2011).
Jaghutriz, B. A. et al. Metabolomic characteristics of fatty pancreas. Exp. Clin. Endocrinol. Diabetes 128, 804–810 (2020).
Maggio, A. B. R. et al. Increased pancreatic fat fraction is present in obese adolescents with metabolic syndrome. J. Pediatr. Gastroenterol. Nutr. 54, 720–726 (2012).
Patel, N. S. et al. Insulin resistance increases MRI-estimated pancreatic fat in nonalcoholic fatty liver disease and normal controls. Gastroenterol. Res. Pract. 2013, 498296 (2013).
Hannukainen, J. C. et al. Liver and pancreatic fat content and metabolism in healthy monozygotic twins with discordant physical activity. J. Hepatol. 54, 545–552 (2011).
van Geenen, E.-J. M. et al. Nonalcoholic fatty liver disease is related to nonalcoholic fatty pancreas disease. Pancreas 39, 1185–1190 (2010).
Milovanovic, T. et al. Ultrasonographic evaluation of fatty pancreas in Serbian patients with non alcoholic fatty liver disease–a cross sectional study. Medicina 55, 697 (2019).
Taylor, R. Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia 51, 1781–1789 (2008).
Taylor, R. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab. 28, 547–556.e3 (2018). This study demonstrates that fatty pancreas is reversible by a hypocaloric diet.
Al-Mrabeh, A. et al. Hepatic lipoprotein export and remission of human type 2 diabetes after weight loss. Cell Metab. 31, 233–249.e4 (2020). This study shows that changes in pancreatic fat are related to changes in β-cell function after weight loss.
Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).
Yadav, D. & Whitcomb, D. C. The role of alcohol and smoking in pancreatitis. Nat. Rev. Gastroenterol. Hepatol. 7, 131–145 (2010).
Apte, M. V., Pirola, R. C. & Wilson, J. S. Mechanisms of alcoholic pancreatitis. J. Gastroenterol. Hepatol. 25, 1816–1826 (2010).
Crane, J. D. et al. ELBW survivors in early adulthood have higher hepatic, pancreatic and subcutaneous fat. Sci. Rep. 6, 31560 (2016).
Curhan Gary, C. et al. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 94, 3246–3250 (1996).
Raeder, H. et al. Pancreatic lipomatosis is a structural marker in nondiabetic children with mutations in carboxyl-ester lipase. Diabetes 56, 444–449 (2007).
Kashyap, S. et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52, 2461–2474 (2003).
Quiclet, C. et al. Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice. Metabolism 97, 9–17 (2019). This is a study in mice that suggests that intermittent fasting prevents fatty pancreas.
Kleinert, M. et al. Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 14, 140–162 (2018).
Engjom, T. et al. Sonographic pancreas echogenicity in cystic fibrosis compared to exocrine pancreatic function and pancreas fat content at Dixon-MRI. PLoS ONE 13, e0201019 (2018).
Feigelson, J. et al. Imaging changes in the pancreas in cystic fibrosis: a retrospective evaluation of 55 cases seen over a period of 9 years. J. Pediatr. Gastroenterol. Nutr. 30, 145–151 (2000).
Soyer, P. et al. Cystic fibrosis in adolescents and adults: fatty replacement of the pancreas–CT evaluation and functional correlation. Radiology 210, 611–615 (1999).
Tham, R. T. et al. Cystic fibrosis: MR imaging of the pancreas. Radiology 179, 183–186 (1991).
Toiviainen-Salo, S. et al. Magnetic resonance imaging findings of the pancreas in patients with Shwachman-Diamond syndrome and mutations in the SBDS gene. J. Pediatr. 152, 434–436 (2008).
Argyropoulou, M. I. et al. Liver, bone marrow, pancreas and pituitary gland iron overload in young and adult thalassemic patients: a T2 relaxometry study. Eur. Radiol. 17, 3025–3030 (2007).
Midiri, M. et al. MR imaging of pancreatic changes in patients with transfusion-dependent beta-thalassemia major. Am. J. Roentgenol. 173, 187–192 (1999).
Papakonstantinou, O. et al. The pancreas in β-thalassemia major: MR imaging features and correlation with iron stores and glucose disturbances. Eur. Radiol. 17, 1535–1543 (2007).
Pfeifer, C. D. et al. Pancreatic iron and fat assessment by MRI-R2* in patients with iron overload diseases. J. Magn. Reson. Imaging 42, 196–203 (2015).
Katz, D. et al. Using CT to reveal fat-containing abnormalities of the pancreas. Am. J. Roentgenol. 172, 393–396 (1999).
Tirkes, T. et al. Association of pancreatic steatosis with chronic pancreatitis, obesity, and type 2 diabetes mellitus. Pancreas 48, 420–426 (2019).
Fujii, M., Ohno, Y., Yamada, M., Kamada, Y. & Miyoshi, E. Impact of fatty pancreas and lifestyle on the development of subclinical chronic pancreatitis in healthy people undergoing a medical checkup. Environ. Health Prev. Med. 24, 10 (2019).
Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127, 1–4 (2017).
Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).
Stefan, N. & Häring, H.-U. Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat. Med. 19, 394–395 (2013). This study describes the interaction of fetuin-A and fatty acids on insulin resistance in humans.
Siegel-Axel, D. I. et al. Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells. Diabetologia 57, 1057–1066 (2014).
Gerst, F. et al. What role do fat cells play in pancreatic tissue? Mol. Metab. 25, 1–10 (2019).
Michaud, D. S. et al. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 286, 921–929 (2001).
Maisonneuve, P. Epidemiology and burden of pancreatic cancer. La. Presse Méd. 48, e113–e123 (2019).
Takahashi, M. et al. Fatty pancreas: a possible risk factor for pancreatic cancer in animals and humans. Cancer Sci. 109, 3013–3023 (2018).
Yu, D.-Y. et al. Clinical significance of pancreatic intraepithelial neoplasia in resectable pancreatic cancer on survivals. Ann. Surg. Treat. Res. 94, 247–253 (2018).
Chang, H.-H. et al. Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice. PLoS ONE 12, e0184455 (2017).
Kashiwagi, K. et al. Pancreatic fat content may increase the risk of imaging progression in low-risk branch duct intraductal papillary mucinous neoplasm. J. Dig. Dis. 20, 557–562 (2019).
Stolzenberg-Solomon, R. Z. et al. Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 294, 2872–2878 (2005).
Bao, Y. et al. A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. J. Natl Cancer Inst. 105, 95–103 (2013).
Roshani, R., McCarthy, F. & Hagemann, T. Inflammatory cytokines in human pancreatic cancer. Cancer Lett. 345, 157–163 (2014).
Wisse, B. E. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. JASN 15, 2792–2800 (2004).
Gaborit, B. et al. Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int. J. Obes. 39, 480–487 (2015).
Lu, T. et al. Pancreatic fat content is associated with β-cell function and insulin resistance in Chinese type 2 diabetes subjects. Endocr. J. 66, 265–270 (2019).
Chin, S. O. et al. Pancreatic fat accumulation is associated with decreased β-cell function and deterioration in glucose tolerance in Korean adults. Diabetes Metab. Res. Rev. https://doi.org/10.1002/dmrr.3425 (2020).
Kühn, J.-P. et al. Pancreatic steatosis demonstrated at MR imaging in the general population: clinical relevance. Radiology 276, 129–136 (2015).
Yamazaki, H. et al. Lack of independent association between fatty pancreas and incidence of type 2 diabetes: 5-year Japanese cohort study. Diabetes Care 39, 1677–1683 (2016).
Yamazaki, H. et al. Longitudinal association of fatty pancreas with the incidence of type-2 diabetes in lean individuals: a 6-year computed tomography-based cohort study. J. Gastroenterol. 55, 712–721 (2020). This study demonstrates that fatty pancreas predicts future type 2 diabetes mellitus in lean people.
Begovatz, P. et al. Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans. Diabetologia 58, 1646–1655 (2015).
Roh, E. et al. Comparison of pancreatic volume and fat amount linked with glucose homeostasis between healthy Caucasians and Koreans. Diabetes Obes. Metab. 20, 2642–2652 (2018).
Nowotny, B. et al. Circulating triacylglycerols but not pancreatic fat associate with insulin secretion in healthy humans. Metab. Clin. Exp. 81, 113–125 (2018).
Szczepaniak, L. S. et al. Pancreatic steatosis and its relationship to β-cell dysfunction in humans: racial and ethnic variations. Diabetes Care 35, 2377–2383 (2012).
Ahlqvist, E. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 6, 361–369 (2018). This study characterizes sub-phenotypes of type 2 diabetes mellitus and their clinical relevance.
Wagner, R. & Fritsche, A. Reclassification of diabetes mellitus based on pathophysiologic and genetic features [German]. Dtsch. Med. Wochenschr. 145, 601–608 (2020).
Wagner, R. et al. Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nat. Med. 27, 49–57 (2021). This study characterizes sub-phenotypes of people at risk of type 2 diabetes mellitus and their prospective clinical value.
Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).
Perea, A., Clemente, F., Martinell, J., Villanueva-Peñacarrillo, M. L. & Valverde, I. Physiological effect of glucagon in human isolated adipocytes. Horm. Metab. Res. 27, 372–375 (1995).
Heni, M. et al. Insulin action in the hypothalamus increases second-phase insulin secretion in humans. Neuroendocrinology 110, 929–937 (2020). This work demonstrates that the brain is able to modulate insulin secretion in humans.
Thorens, B. Neural regulation of pancreatic islet cell mass and function. Diabetes Obes. Metab. 16, 87–95 (2014).
Wagner, R. et al. Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans. Diabetes 62, 2106–2111 (2013).
Rodríguez, A., Ezquerro, S., Méndez-Giménez, L., Becerril, S. & Frühbeck, G. Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism. Am. J. Physiol. Endocrinol. Metab. 309, E691–E714 (2015).
Solimena, M. et al. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes. Diabetologia 61, 641–657 (2018).
Man, Z. W. et al. Impaired beta-cell function and deposition of fat droplets in the pancreas as a consequence of hypertriglyceridemia in OLETF rat, a model of spontaneous NIDDM. Diabetes 46, 1718–1724 (1997).
Winzell, M. S., Ström, K., Holm, C. & Ahrén, B. Glucose-stimulated insulin secretion correlates with β-cell lipolysis. Nutr. Metab. Cardiovasc. Dis. 16, S11–S16 (2006).
Nolan, C. J. et al. Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling. Diabetologia 49, 2120–2130 (2006).
Cantley, J. et al. Deletion of PKCε selectively enhances the amplifying pathways of glucose-stimulated insulin secretion via increased lipolysis in mouse β-cells. Diabetes 58, 1826–1834 (2009).
Mulder, H., Yang, S., Winzell, M. S., Holm, C. & Ahrén, B. Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion. Diabetes 53, 122–128 (2004). This work describes the impact of β-cell lipid metabolism on insulin secretion.
Fex, M. et al. A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis. Diabetologia 52, 271–280 (2009).
Beysen, C. et al. Interaction between specific fatty acids, GLP-1 and insulin secretion in humans. Diabetologia 45, 1533–1541 (2002).
Eitel, K. et al. Protein kinase C δ activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells. Diabetes 52, 991–997 (2003).
Lupi, R. et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that β-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51, 1437–1442 (2002).
Latour, M. G. et al. GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo. Diabetes 56, 1087–1094 (2007).
Schmitz-Peiffer, C. & Biden, T. J. PKCδ blues for the β-cell. Diabetes 59, 1–3 (2010).
Hennige, A. M. et al. Overexpression of kinase-negative protein kinase Cδ in pancreatic β-cells protects mice from diet-induced glucose intolerance and β-cell dysfunction. Diabetes 59, 119–127 (2010).
Ranta, F. et al. Protein kinase C delta (PKCδ) affects proliferation of insulin-secreting cells by promoting nuclear extrusion of the cell cycle inhibitor p21Cip1/WAF1. PLoS ONE 6, e28828 (2011).
Steven, S. et al. Weight loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care 39, 158–165 (2016).
Lim, E. L. et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54, 2506–2514 (2011).
Heiskanen, M. A. et al. Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial. Diabetologia 61, 1817–1828 (2018).
Dutour, A. et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes. Metab. 18, 882–891 (2016).
Vanderheiden, A. et al. Mechanisms of action of liraglutide in patients with type 2 diabetes treated with high-dose insulin. J. Clin. Endocrinol. Metab. 101, 1798–1806 (2016).
Kuchay, M. S. et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial). Diabetologia 63, 2434–2445 (2020).
Yki-Järvinen, H. Thiazolidinediones. N. Engl. J. Med. 351, 1106–1118 (2004).
Gastaldelli, A. et al. Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients. Am. J. Physiol. Endocrinol. Metab. 297, E225–E230 (2009).
Eldor, R., DeFronzo, R. A. & Abdul-Ghani, M. In vivo actions of peroxisome Proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care 36, S162–S174 (2013).
Lupi, R. et al. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARγ2 in the modulation of insulin secretion. Am. J. Physiol. Endocrinol. Metab. 286, E560–E567 (2004).
Matsui, J. et al. Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-γ-deficient mice on a high-fat diet. Diabetes 53, 2844–2854 (2004).
Nissen, S. E. The rise and fall of rosiglitazone. Eur. Heart J. 31, 773–776 (2010).
Honka, H. et al. The effects of bariatric surgery on pancreatic lipid metabolism and blood flow. J. Clin. Endocrinol. Metab. 100, 2015–2023 (2015). This work shows the effect of bariatric surgery on pancreatic fat and a possible link to improved glucose metabolism.
Umemura, A. et al. Pancreas volume reduction and metabolic effects in Japanese patients with severe obesity following laparoscopic sleeve gastrectomy. Endocr. J. 64, 487–498 (2017).
Hui, S. C. N. et al. Observed changes in brown, white, hepatic and pancreatic fat after bariatric surgery: evaluation with MRI. Eur. Radiol. 29, 849–856 (2019).
Slentz, C. A. et al. Effects of exercise training intensity on pancreatic β-cell function. Diabetes Care 32, 1807–1811 (2009).
Solomon, T. P. J. et al. Pancreatic β-cell function is a stronger predictor of changes in glycemic control after an aerobic exercise intervention than insulin sensitivity. J. Clin. Endocrinol. Metab. 98, 4176–4186 (2013).
Cen, J., Sargsyan, E. & Bergsten, P. Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms. Nutr. Metab. 13, 59 (2016).
Dasgupta, S. et al. NF-κB mediates lipi d-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance. Biochem. J. 429, 451–462 (2010).
We thank S. Hülskämper (University of Tübingen) for artistic support in preparation of the first drafts of the figures. The authors acknowledge support (grant no. 01GI0925) from the Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD). The authors also acknowledge the support from JSPS KAKENHI (grant no. 19K16978).
Since January 2020, B.A.J. has been an employee and shareholder of Eli Lilly and Company. Outside the current work, R.W. reports lecture fees from Novo Nordisk and Sanofi, and travel grants from Eli Lilly. R.W. served on an advisory board for Akcea Therapeutics and Daiichi Sankyo. In addition to his current work, A.L.B. reports lecture fees from AstraZeneca, Boehringer Ingelheim and Novo Nordisk. A.L.B. served on advisory boards for AstraZeneca, Boehringer Ingelheim and Novo Nordisk. Besides his current work, A.F. reports lecture fees from and advisory board membership for Sanofi, Novo Nordisk, Eli Lilly and AstraZeneca. In addition to his current work, M.H. reports research grants from Boehringer Ingelheim and Sanofi (both to the University Hospital of Tübingen) and lecture fees from Sanofi, Novo Nordisk, Boehringer Ingelheim, Eli Lilly and Merck Sharp & Dohme. He also served on an advisory board for Boehringer Ingelheim. The other authors declare no competing interests.
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The ability of a surface to reflect ultrasound in ultrasonography.
The radiological absorption of X-rays.
- Hounsfield units
(HU). Units for quantitatively describing the radiodensity of different body tissues and materials, standardized in relation to the attenuation coefficients of air (−1,000 HU) and distilled water (0 HU), named after the developer of CT, Sir Godfrey Hounsfield.
- Dixon method
An MR imaging technique that enables separation of fat and water by the inherent chemical shift difference of protons bound to lean tissues and lipids, named after the American physicist and developer W. Thomas Dixon.
- Proton density fat fraction
The proton density fat fraction is a non-invasive and accurate measure of the percentage of fat infiltration in organs calculated from multi-echo Dixon images.
An effective transverse relaxation time resulting from the inherent transverse relaxation time T2 and microscopic magnetic field inhomogenities in MR gradient echo images.
A unit of magnetic field strength. Typical clinical MR scanners work with field strengths between 1.5 T and 3 T.
Describes the relationship between the measured signal and concentration/amount of the assessed substance, e.g. amount of lipids within the pancreas.
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Wagner, R., Eckstein, S.S., Yamazaki, H. et al. Metabolic implications of pancreatic fat accumulation. Nat Rev Endocrinol 18, 43–54 (2022). https://doi.org/10.1038/s41574-021-00573-3
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