Pathophysiology of diabetes: An overview

Abstract

Diabetes mellitus is a chronic heterogeneous metabolic disorder with complex pathogenesis. It is characterized by elevated blood glucose levels or hyperglycemia, which results from abnormalities in either insulin secretion or insulin action or both. Hyperglycemia manifests in various forms with a varied presentation and results in carbohydrate, fat, and protein metabolic dysfunctions. Long-term hyperglycemia often leads to various microvascular and macrovascular diabetic complications, which are mainly responsible for diabetes-associated morbidity and mortality. Hyperglycemia serves as the primary biomarker for the diagnosis of diabetes as well. In this review, we would be focusing on the classification of diabetes and its pathophysiology including that of its various types.

Keywords

Diabetes mellitus - endocrinopathies - gestational diabetes - maturity-onset diabetes of the young - neonatal diabetes

Publikationsverlauf

Artikel online veröffentlicht:
04. August 2021

• References

• 1 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014; 37: S81-90
• 2 American Diabetes Association. Introduction: Standards of medical care in diabetes—2018. Diabetes Care 2018; 41: S1-2
• 3 American Diabetes Association. Microvascular complications and foot care: Standards of medical care in diabetes—2018. Diabetes Care 2018; 41: S105-18
• 4 American Diabetes Association. Cardiovascular disease and risk management: Standards of medical care in diabetes—2018. Diabetes Care 2018; 41: S86-104
• 5 Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M. et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med 2017; 376: 1407-18
• 6 Blas E, Kuru A. editors Diabetes: Equity and social determinants. In: Equity, Social Determinants and Public Health Programmes. Geneva, Switzerland: World Health Organization; 2010
• 7 Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N. et al IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract 2019; 157: 107843
• 8 International Diabetes Federation. IDF Diabetes Atlas. 9th ed. Brussels, Belgium: International Diabetes Federation; 2019
• 9 American Diabetes Association. Classification and diagnosis of diabetes: Standards of medical care in diabetes—2018. Diabetes Care 2018; 41: S13-27
• 10 Knip M, Siljander H. Autoimmune mechanisms in type 1 diabetes. Autoimmun Rev 2008; 7: 550-7
• 11 Kahaly GJ, Hansen MP. Type 1 diabetes associated autoimmunity. Autoimmun Rev 2016; 15: 644-8
• 12 Taplin CE, Barker JM. Autoantibodies in type 1 diabetes. Autoimmunity 2008; 41: 11-8
• 13 Lahtela JT, Knip M, Paul R, Antonen J, Salmi J. Severe antibody-mediated human insulin resistance: Successful treatment with the insulin analog lispro. A case report. Diabetes Care 1997; 20: 71-3
• 14 Matsuyoshi A, Shimoda S, Tsuruzoe K, Taketa K, Chirioka T, Sakamoto F. et al. A case of slowly progressive type 1 diabetes with unstable glycemic control caused by unusual insulin antibody and successfully treated with steroid therapy. Diabetes Res Clin Pract 2006; 72: 238-43
• 15 Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M. et al. Latent autoimmune diabetes mellitus in adults [LADA]: The role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 1994; 11: 299-303
• 16 Naik RG, Palmer JP. Latent autoimmune diabetes in adults (LADA). Rev Endocr Metab Disord 2003; 4: 233-41
• 17 Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, di Pietro S. et al Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study Group. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non insulin requiring autoimmune diabetes (NIRAD) 4. Diabetes Care 2010; 33: 104-8
• 18 Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R. et al Action LADA Consortium. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care 2013; 36: 908-13
• 19 Hughes JW, Riddlesworth TD, DiMeglio LA, Miller KM, Rickels MR, McGill JB. T1D Exchange Clinic Network. Autoimmune diseases in children and adults with type 1 diabetes from the T1D exchange clinic registry. J Clin Endocrinol Metab 2016; 101: 4931-7
• 20 Triolo TM, Armstrong TK, McFann K, Yu L, Rewers MJ, Klingensmith GJ. et al. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011; 34: 1211-3
• 21 Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661-78
• 22 Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V. et al Genetics of Type 1 Diabetes in Finland; Wellcome Trust Case Control Consortium. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39: 857-64
• 23 Undlien DE, Lie BA, Thorsby E. HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet 2001; 17: 93-100
• 24 Park Y. Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes. Diabetes Res Clin Pract 2007; 77: S110-5
• 25 Chistiakov DA, Voronova NV, Chistiakov PA. The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. Immunol Lett 2008; 118: 1-5
• 26 Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med 2000; 342: 301-7
• 27 Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res 2005; 36: 197-209
• 28 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88: 787-835 ix
• 29 Muoio DM, Newgard CB. Mechanisms of disease:molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9: 193-205
• 30 Umpierrez G, Korytkowski M. Diabetic emergencies—ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol 2016; 12: 222-32
• 31 Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: Data from the FDA adverse event reporting system. Diabetologia 2017; 60: 1385-9
• 32 Frayling TM. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007; 8: 657-62
• 33 Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T. et al Wellcome Trust Case Control Consortium. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008; 40: 638-45
• 34 Fujimoto WY. The importance of insulin resistance in the pathogenesis of type 2 diabetes mellitus. Am J Med 2000; 108: 9S-14S
• 35 Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840-6
• 36 Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999–2005. Diabetes Care 2008; 31: 899-904
• 37 Yuen L, Wong VW. Gestational diabetes mellitus: Challenges for different ethnic groups. World J Diabetes 2015; 6: 1024-32
• 38 Hedderson MM, Darbinian JA, Ferrara A. Disparities in the risk of gestational diabetes by race-ethnicity and country of birth. Paediatr Perinat Epidemiol 2010; 24: 441-8
• 39 Cosson E. Diagnostic criteria for gestational diabetes mellitus. Diabetes Metab 2010; 36: 538-48
• 40 Kim C. Gestational diabetes: Risks, management, and treatment options. Int J Womens Health 2010; 2: 339-51
• 41 Noctor E, Crowe C, Carmody LA, Saunders JA, Kirwan B, O’Dea A. et al ATLANTIC-DIP Investigators. Abnormal glucose tolerance post-gestational diabetes mellitus as defined by the international association of diabetes and pregnancy study groups criteria. Eur J Endocrinol 2016; 175: 287-97
• 42 Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: A systematic review. Diabetes Care 2002; 25: 1862-8
• 43 Aroda VR, Christophi CA, Edelstein SL, Zhang P, Herman WH, Barrett-Connor E. et al Diabetes Prevention Program Research Group. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: The Diabetes Prevention Program outcomes study 10-year follow-up. J Clin Endocrinol Metab 2015; 100: 1646-53
• 44 Gardner DS, Tai ES. Clinical features and treatment of maturity onset diabetes of the young [MODY]. Diabetes Metab Syndr Obes 2012; 5: 101-8
• 45 Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): How many cases are we missing?. Diabetologia 2010; 53: 2504-8
• 46 Kim SH. Maturity-onset diabetes of the young: What do clinicians need to know?. Diabetes Metab J 2015; 39: 468-77
• 47 Hattersley AT, Greeley SAW, Polak M, Rubio-Cabezas O, Njølstad PR, Mlynarski W. et al. ISPAD clinical practice consensus guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2018; 19: 47-63
• 48 Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 2008; 29: 254-64
• 49 Froguel P, Velho G. Molecular genetics of maturity-onset diabetes of the young. Trends Endocrinol Metab 1999; 10: 142-6
• 50 García-Herrero CM, Rubio-Cabezas O, Azriel S, Gutierrez-Nogués A, Aragonés A, Vincent O. et al. Functional characterization of MODY2 mutations highlights the importance of the fine-tuning of glucokinase and its role in glucose sensing. PLoS One 2012; 7: e30518
• 51 Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M. et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996; 384: 455-8
• 52 Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A. et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998; 338: 226-30
• 53 Matschinsky F, Liang Y, Kesavan P, Wang L, Froguel P, Velho G. et al. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest 1993; 92: 2092-8
• 54 Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S. et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat 2009; 30: 1512-26
• 55 Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013; 34: 669-85
• 56 Bacon S, Kyithar MP, Schmid J, Rizvi SR, Bonner C, Graf R. et al. Serum levels of pancreatic stone protein (PSP)/reg1a as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward. BMC Endocr Disord 2012; 12: 13
• 57 Stoffel M, Duncan SA. The maturity-onset diabetes of the young [MODY1] transcription factor HNF4α regulates expression of genes required for glucose transport andmetabolism. Proc Natl Acad Sci U S A 1997; 94: 13209-14
• 58 Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM. et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 2005; 115: 1006-15
• 59 Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med 2009; 26: 437-41
• 60 Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003; 362: 1275-81
• 61 Edghill EL, Bingham C, Ellard S, Hattersley AT. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet 2006; 43: 84-90
• 62 Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN. et al. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 1997; 17: 384-5
• 63 Barbacci E, Reber M, Ott MO, Breillat C, Huetz F, Cereghini S. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 1999; 126: 4795-805
• 64 Bingham C, Ellard S, Allen L, Bulman M, Shepherd M, Frayling T. et al. Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta. Kidney Int 2000; 57: 898-907
• 65 Bingham C, Bulman MP, Ellard S, Allen LI, Lipkin GW, Hoff WG. et al. Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 2001; 68: 219-24
• 66 Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, Ellard S. et al. Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: Support for a critical role of HNF-1beta in human pancreatic development. Diabet Med 2006; 23: 1301-6
• 67 Bellanné-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S. et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med 2004; 140: 510-7
• 68 Kavvoura FK, Owen KR. Maturity onset diabetes of the young: Clinical characteristics, diagnosis and management. Pediatr Endocrinol Rev 2012; 10: 234-42
• 69 Bingham C, Ellard S, van’t Hoff WG, Simmonds HA, Marinaki AM, Badman MK. et al. Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation. Kidney Int 2003; 63: 1645-51
• 70 Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 1997; 17: 138-9
• 71 Stoffers DA, Thomas MK, Habener JF. Homeodomain protein IDX-1: A master regulator of pancreas development and insulin gene expression. Trends Endocrinol Metab 1997; 8: 145-51
• 72 Kim SK, Selleri L, Lee JS, Zhang AY, Gu X, Jacobs Y. et al. Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. Nat Genet 2002; 30: 430-5
• 73 Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A. et al. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab 2003; 88: 4398-406
• 74 Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 1998; 12: 1763-8
• 75 Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T. et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999; 23: 323-8
• 76 Gonsorcíková L, Průhová S, Cinek O, Ek J, Pelikánová T, Jørgensen T. et al. Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation in NEUROD1. Pediatr Diabetes 2008; 9: 367-72
• 77 Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes 2010; 59: 2326-31
• 78 Lomberk G, Grzenda A, Mathison A, Escande C, Zhang JS, Calvo E. et al. Krüppel-like factor 11 regulates the expression of metabolic genes via an evolutionarily conserved protein interaction domain functionally disrupted in maturity onset diabetes of the young. J Biol Chem 2013; 288: 17745-58
• 79 Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 2006; 38: 54-62
• 80 Biason-Lauber A, Boehm B, Lang-Muritano M, Gauthier BR, Brun T, Wollheim CB. et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4: Possible link to beta cell regenerative capacity. Diabetologia 2005; 48: 900-5
• 81 Molven A, Ringdal M, Nordbø AM, Raeder H, Støy J, Lipkind GM. et al Norwegian Childhood Diabetes Study Group. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 2008; 57: 1131-5
• 82 Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B. et al Neonatal Diabetes International Collaborative Group. Insulin mutation screening in 1,044 patients with diabetes: Mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 2008; 57: 1034-42
• 83 Borowiec M, Liew CW, Thompson R, Boonyasrisawat W, Hu J, Mlynarski WM. et al. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc Natl Acad Sci U S A 2009; 106: 14460-5
• 84 Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH, Paisey R. et al. Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia 2012; 55: 123-7
• 85 Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T. et al. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 2004; 89: 3932-5
• 86 Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Akazawa Y. et al. The C42R mutation in the kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab 2005; 90: 3174-8
• 87 Prudente S, Jungtrakoon P, Marucci A, Ludovico O, Buranasupkajorn P, Mazza T. et al. Loss-of-function mutations in APPL1 in familial diabetes mellitus. Am J Hum Genet 2015; 97: 177-85
• 88 Iafusco D, Massa O, Pasquino B, Colombo C, Iughetti L, Bizzarri C. et al Early Diabetes Study Group of ISPED. Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births. Acta Diabetol 2012; 49: 405-8
• 89 Polak M, Cavé H. Neonatal diabetes mellitus: A disease linked to multiple mechanisms. Orphanet J Rare Dis 2007; 2: 12
• 90 Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev 2008; 29: 265-91
• 91 von Mühlendahl KE, Herkenhoff H. Long-term course of neonatal diabetes. N Engl J Med 1995; 333: 704-8
• 92 Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20-1
• 93 Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000; 25: 406-9
• 94 Ozbek MN, Senée V, Aydemir S, Kotan LD, Mungan NO, Yuksel B. et al. Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Pediatr Diabetes 2010; 11: 279-85
• 95 Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K. et al Neonatal Diabetes International Collaborative Group. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab 2009; 94: 4162-70
• 96 Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y. et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330: 962-8
• 97 Gruppuso PA, Gorden P, Kahn CR, Cornblath M, Zeller WP, Schwartz R. Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin. N Engl J Med 1984; 311: 629-34
• 98 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev 2012; 33: 981-1030
• 99 Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM. et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 1976; 294: 739-45
• 100 Taylor SI. Lilly lecture: Molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 1992; 41: 1473-90
• 101 Garg A. Lipodystrophies. Am J Med 2000; 108: 143-52
• 102 Vigouroux C, Magré J, Vantyghem MC, Bourut C, Lascols O, Shackleton S. et al. Lamin A/C gene: Sex-determined expression of mutations in dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy. Diabetes 2000; 49: 1958-62
• 103 Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004; 350: 1220-34
• 104 Magré J, Delépine M, Khallouf E, Gedde-Dahl Jr T, Van Maldergem L, Sobel E. et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nature Genetics 2001; 28: 365-70
• 105 Krook A, Kumar S, Laing I, Boulton AJ, Wass JA, O’Rahilly S. Molecular scanning of the insulin receptor gene in syndromes of insulin resistance. Diabetes 1994; 43: 357-68
• 106 Resmini E, Minuto F, Colao A, Ferone D. Secondary diabetes associated with principal endocrinopathies: The impact of new treatment modalities. Acta Diabetol 2009; 46: 85-95
• 107 Biering H, Knappe G, Gerl H, Lochs H. Prevalence of diabetes in acromegaly and Cushing syndrome. Acta Med Austriaca 2000; 27: 27-31
• 108 Krejs GJ, Orci L, Conlon JM, Ravazzola M, Davis GR, Raskin P. et al. Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N Engl J Med 1979; 301: 285-92
• 109 Nestler JE, McClanahan MA. Diabetes and adrenal disease. Baillieres Clin Endocrinol Metab 1992; 6: 829-47
• 110 Price S, Cole D, Alcolado JC. Diabetes due to exocrine pancreatic disease—a review of patients attending a hospital-based diabetes clinic. Q J Med 2010; 103: 759-63
• 111 Bartosch-Härlid A, Andersson R. Diabetes mellitus in pancreatic cancer and the need for diagnosis of asymptomatic disease. Pancreatology 2010; 10: 423-8
• 112 Frohnert BI, Ode KL, Moran A, Nathan BM, Laguna T, Holme B. et al. Impaired fasting glucose in cystic fibrosis. Diabetes Care 2010; 33: 2660-4
• 113 Williams JA, Goldfine ID. The insulin-pancreatic acinar axis. Diabetes 1985; 34: 980-6
• 114 Karjalainen J, Knip M, Hyöty H, Leinikki P, Ilonen J, Käär ML. et al. Relationship between serum insulin autoantibodies, islet cell antibodies and coxsackie-B4 and mumps virus-specific antibodies at the clinical manifestation of type 1 (insulin-dependent) diabetes. Diabetologia 1988; 31: 146-52
• 115 Pak CY, Eun HM, McArthur RG, Yoon JW. Association of cytomegalovirus infection with autoimmune type 1 diabetes. Lancet 1988; 2: 1-4
• 116 Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG. et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003; 125: 1695-704
• 117 Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592-9
• 118 Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA 2001; 286: 1945-8
• 119 Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: A quantitative review. Hypertension 2006; 48: 219-24
• 120 Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018; 359: 1350-5
• 121 Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23-34
• 122 Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373: 1627-39
• 123 Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A. et al KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375: 1823-33
• 124 Ferris RL, Blumenschein Jr G, Fayette J, Guigay J, Colevas AD, Licitra L. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375: 1856-67
• 125 Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L. et al KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376: 1015-26
• 126 Cheema A, Makadia B, Karwadia T, Bajwa R, Hossain M. Autoimmune diabetes associated with pembrolizumab: A review of published case reports. World J Oncol 2018; 9: 1-4
• 127 World Health Organization. Report of a WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications.1. Diagnosis and Classification of Diabetes Mellitus. Geneva, Switzerland: WHO; 1999
• 128 Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: Understanding of electrophysiological and immunological processes. Muscle Nerve 2012; 45: 623-34
• 129 Lupsa BC, Chong AY, Cochran EK, Soos MA, Semple RK, Gorden P. Autoimmune forms of hypoglycemia. Medicine 2009; 88: 141-53
• 130 Taylor SI, Barbetti F, Accili D, Roth J, Gorden P. Syndromes of autoimmunity and hypoglycemia. Autoantibodies directed against insulin and its receptor. Endocrinol Metab Clin North Am 1989; 18: 123-43
• 131 Uchigata Y, Eguchi Y, Takayama-Hasumi S, Omori Y. Insulin autoimmune syndrome (Hirata disease): Clinical features and epidemiology in Japan. Diabetes Res Clin Pract 1994; 22: 89-94
• 132 Balasubramanyam A, Garza G, Rodriguez L, Hampe CS, Gaur L, Lernmark A. et al. Accuracy and predictive value of classification schemes for ketosis-prone diabetes. Diabetes Care 2006; 29: 2575-9
• 133 Sobngwi E, Mauvais-Jarvis F, Vexiau P, Mbanya JC, Gautier JF. Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus. Diabetes Metab 2002; 28: 5-12
• 134 Khurshid Ahmad Khan JA. South Asian version of Flatbush diabetes mellitus—a case report and review article. Int J Med Med Sci 2009; 1: 347-52
• 135 Tan KC, Mackay IR, Zimmet PZ, Hawkins BR, Lam KS. Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus. Diabetes Care 2000; 23: 335-8
• 136 Banerji MA, Chaiken RL, Huey H, Tuomi T, Norin AJ, Mackay IR. et al. GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4. Flatbush diabetes. Diabetes 1994; 43: 741-5