and of non‐alcoholic fatty liver disease were highest in the first and third cluster, respectively. This latter cluster also had the highest risk of chronic kidney disease [54]. HOMA measures have significant limitations and poor predictive value for progression to diabetes [55] – although in fairness the investigators used C‐peptide rather than insulin to estimate β‐cell function. Whether this will help guide therapeutic interventions and improve outcomes in individual patients remains to be ascertained.
Another approach to characterizing different sub‐types of diabetes is based on common genetic variation and its influence on quantitative traits such as glucose tolerance in response to a standardized challenge. For example, Dimas et al. identified 5 clusters of genetic risk loci that altered glycemic traits [56]. In this study examining data from ~58 000 non‐diabetic subjects, one cluster altered insulin sensitivity. A second cluster altered fasting glucose while a third cluster altered the ratio of proinsulin to insulin in the fasting state. Another cluster was primarily characterized by defects in post‐challenge insulin secretion. The final cluster of risk loci did not alter glycemic traits. While this exercise has certainly helped understand the effect of genotype on phenotype, the effect size of each risk allele on a given phenotypic trait is so small as be unhelpful in terms of predicting individual clinical behavior.
Pharmacogenomics has also held promise as a way of classifying diabetes. This hope was reinforced by the discovery that the target for thiazolidinediones and sulfonylureas are risk loci for type 2 diabetes. Unfortunately, their effect on response to therapy is difficult to discern at an individual level and genotype at PPARG and KCNJ11 should not alter therapeutic choices in type 2 diabetes [57, 58].
Conclusions
Multiple roads lead to the pathophysiologic defects that cause hyperglycemia. While autoimmune diabetes can be characterized quite readily in many patients, the remaining patients are far more heterogeneous. Efforts to reinvent the classification, at least to date, have not appreciably changed, or guided, the management of individual patients – the notable exception being monogenic forms of diabetes. Nevertheless, appreciating the underlying defects as well as the limitations of autoantibody and β‐cell function testing should help improve the care of patients with unclear classification and with associated comorbidities.
Bibliography
1 1. Gale EA. Declassifying diabetes. Diabetologia. 2006; 49:1989–1995.
2 2. Kaestner KH, Powers AC, Naji A, Consortium H, Atkinson MA. NIH Initiative to Improve Understanding of the Pancreas, Islet, and Autoimmunity in Type 1 Diabetes: The Human Pancreas Analysis Program (HPAP). Diabetes. 2019; 68:1394–1402.
3 3. Hattersley AT, Pearson ER. Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta‐cell physiology, and genetics in diabetes. Endocrinology. 2006; 147:2657–2663.
4 4. Smushkin G, Vella A. What is type 2 diabetes? Medicine (Baltimore). 2010; 38:597–601.
5 5. Vella A, Camilleri M, Rizza RA. The gastrointestinal tract and glucose tolerance. Curr Opin Clin Nutr Metab Care. 2004; 7:479–484.
6 6. Cobelli C, Dalla Man C, Toffolo G, Basu R, Vella A, Rizza R. The oral minimal model method. Diabetes. 2014; 63:1203–1213.
7 7. Haataja L, Manickam N, Soliman A, Tsai B, Liu M, Arvan P. Disulfide mispairing during proinsulin folding in the endoplasmic reticulum. Diabetes. 2016;.
8 8. Sun J, Cui J, He Q, Chen Z, Arvan P, Liu M. Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. Mol Aspects Med 2015; 42:105–118.
9 9. Smushkin G, Vella A. Genetics of type 2 diabetes. Curr Opin Clin Nutr Metab Care. 2010; 13:471–477.
10 10. Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, Lyssenko V, Bouatia‐Naji N, Dupuis J, Jackson AU, Kao WH, Li M, Glazer NL, Manning AK, Luan J, Stringham HM, Prokopenko I, Johnson T, Grarup N, Boesgaard TW, Lecoeur C, Shrader P, O'Connell J, Ingelsson E, Couper DJ, Rice K, Song K, Andreasen CH, Dina C, Kottgen A, Le Bacquer O, Pattou F, Taneera J, Steinthorsdottir V, Rybin D, Ardlie K, Sampson M, Qi L, van Hoek M, Weedon MN, Aulchenko YS, Voight BF, Grallert H, Balkau B, Bergman RN, Bielinski SJ, Bonnefond A, Bonnycastle LL, Borch‐Johnsen K, Bottcher Y, Brunner E, Buchanan TA, Bumpstead SJ, Cavalcanti‐Proenca C, Charpentier G, Chen YD, Chines PS, Collins FS, Cornelis M, G JC, Delplanque J, Doney A, Egan JM, Erdos MR, Firmann M, Forouhi NG, Fox CS, Goodarzi MO, Graessler J, Hingorani A, Isomaa B, Jorgensen T, Kivimaki M, Kovacs P, Krohn K, Kumari M, Lauritzen T, Levy‐Marchal C, Mayor V, McAteer JB, Meyre D, Mitchell BD, Mohlke KL, Morken MA, Narisu N, Palmer CN, Pakyz R, Pascoe L, Payne F, Pearson D, Rathmann W, Sandbaek A, Sayer AA, Scott LJ, Sharp SJ, Sijbrands E, Singleton A, Siscovick DS, Smith NL, Sparso T, Swift AJ, Syddall H, Thorleifsson G, Tonjes A, Tuomi T, Tuomilehto J, Valle TT, Waeber G, Walley A, Waterworth DM, Zeggini E, Zhao JH, Illig T, Wichmann HE, Wilson JF, van Duijn C, Hu FB, Morris AD, Frayling TM, Hattersley AT, Thorsteinsdottir U, Stefansson K, Nilsson P, Syvanen AC, Shuldiner AR, Walker M, Bornstein SR, Schwarz P, Williams GH, Nathan DM, Kuusisto J, Laakso M, Cooper C, Marmot M, Ferrucci L, Mooser V, Stumvoll M, Loos RJ, Altshuler D, Psaty BM, Rotter JI, Boerwinkle E, Hansen T, Pedersen O, Florez JC, McCarthy MI, Boehnke M, Barroso I, Sladek R, Froguel P, Meigs JB, Groop L, Wareham NJ, Watanabe RM. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet. 2010; 42:142–148.
11 11. Bock G, Dalla Man C, Campioni M, Chittilapilly E, Basu R, Toffolo G, Cobelli C, Rizza R. Pathogenesis of pre‐diabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance. Diabetes. 2006; 55:3536–3549.
12 12. Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet. 1975; 1:14–16.
13 13. Faerch K, Vistisen D, Pacini G, Torekov SS, Johansen NB, Witte DR, Jonsson A, Pedersen O, Hansen T, Lauritzen T, Jorgensen ME, Ahren B, Holst JJ. Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. Diabetes. 2016; 65:3473–3481.
14 14. Sharma A, Varghese RT, Shah M, Man CD, Cobelli C, Rizza RA, Bailey KR, Vella A. Impaired insulin action is associated with increased glucagon concentrations in non‐diabetic humans. J Clin Endocrinol Metab. 2018; 103:314–319.
15 15. Ashcroft FM, Rorsman P. K(ATP) channels and islet hormone secretion: new insights and controversies. Nature Reviews. 2013; 9:660–669.
16 16. Karanth S, Adams JD, Serrano MLA, Quittner‐Strom EB, Simcox J, Villanueva CJ, Ozcan L, Holland WL, Yost HJ, Vella A, Schlegel A. A hepatocyte FOXN3‐alpha cell glucagon axis regulates fasting glucose. Cell Rep. 2018; 24:312–319.
17 17. Shah M, Varghese RT, Miles JM, Piccinini F, Dalla Man C, Cobelli C, Bailey KR, Rizza RA, Vella A. TCF7L2 Genotype and alpha‐cell function in humans without diabetes. Diabetes. 2016; 65:371–380.
18 18. Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. American Journal of Physiology Endocrinology and Metabolism. 2005; 288:E1047–1054.
19 19. Urbanek M, Legro RS, Driscoll D, Strauss JF, 3rd, Dunaif A, Spielman RS. Searching for the polycystic ovary syndrome genes. J Pediatr Endocrinol Metab. 2000; 13 Suppl 5:1311–1313.
20 20. Vella A, Camilleri M. The gastrointestinal tract as an integrator of mechanical and hormonal response to nutrient ingestion. Diabetes. 2017; 66:2729–2737.
21 21. Ikramuddin S, Korner J, Lee WJ, Thomas AJ, Connett JE, Bantle JP, Leslie DB, Wang Q, Inabnet WB, 3rd, Jeffery RW, Chong K, Chuang LM, Jensen MD, Vella A, Ahmed L, Belani K, Billington CJ. Lifestyle intervention and medical management with vs without Roux‐en‐Y Gastric Bypass and control of hemoglobin A1c, LDL cholesterol, and systolic blood pressure at 5 years in the Diabetes Surgery Study. JAMA. 2018; 319:266–278.
22 22. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, Aminian A, Pothier CE, Kim ES, Nissen