The Time Is Right for a NewClassification System for Diabetes:Rationale and Implications of theb-Cell–Centric ClassificationSchemaDiabetes Care 2016;39:179–186 | DOI: 10.2337/dc15-1585

The current classification system presents challenges to the diagnosis andtreatment of patients with diabetes mellitus (DM), in part due to its conflictingand confounding definitions of type 1 DM, type 2 DM, and latent autoimmunediabetes of adults (LADA). The current schema also lacks a foundation that readilyincorporates advances in our understanding of the disease and its treatment. Forappropriate and coherent therapy, we propose an alternate classification system.Theb-cell–centric classification of DM is a new approach that obviates the inherentand unintended confusions of the current system. The b-cell–centric model pre-supposes that all DM originates from a final common denominatordthe abnormalpancreatic b-cell. It recognizes that interactions between genetically predisposedb-cells with a number of factors, including insulin resistance (IR), susceptibility toenvironmental influences, and immune dysregulation/inflammation, lead to therange of hyperglycemic phenotypes within the spectrum of DM. Individually or inconcert, and often self-perpetuating, these factors contribute to b-cell stress, dys-function, or loss through at least 11 distinct pathways. Available, yet underutilized,treatments provide rational choices for personalized therapies that target the in-dividual mediating pathways of hyperglycemia at work in any given patient, with-out the risk of drug-related hypoglycemia or weight gain or imposing furtherburden on theb-cells. This article issues an urgent call for the review of the currentDM classification system toward the consensus on a new, more useful system.

A CLASSIFICATION SYSTEM THAT HAS PETERED OUT?

The essential function of a classification system is as a navigation tool that helps directresearch, evaluate outcomes, establish guidelines for best practices for prevention andcare, and educate on all of the above. Diabetes mellitus (DM) subtypes as currentlycategorized, however, do not fit into our contemporary understanding of the pheno-types of diabetes (1–6). The inherent challenges of the current system, together withthe limited knowledge that existed at the time of the crafting of the current system,yielded definitions for type 1DM, type 2DM, and latent autoimmune diabetes in adults(LADA) that are not distinct and are ambiguous and imprecise.Discovery of the role played by autoimmunity in the pathogenesis of type 1 DM

created the assumption that type 1 DM and type 2 DM possess unique etiologies,disease courses, and, consequently, treatment approaches. There exists, however,overlap among even themost “typical” patient cases. Patients presentingwith otherwise

1Main Line Health, Wynnewood, PA, and Univer-sity of Pennsylvania, Philadelphia, PA2Division of Endocrinology, Diabetes and BoneDisease, Department of Medicine, Mount SinaiHospital, New York, NY3Department of Medicine, Boston UniversitySchool of Medicine, Boston, MA4Division of Human Genetics and Center forApplied Genomics, Department of Pediatrics,Perelman School of Medicine, University ofPennsylvania, Philadelphia, PA5Emory University School of Medicine, Atlanta,GA6Diabetes Nation, Sisters, OR

Corresponding author: Stanley S. Schwartz,stschwar@gmail.com.

Received 22 July 2015 and accepted 3 November2015.

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

Stanley S. Schwartz,1 Solomon Epstein,2

Barbara E. Corkey,3 Struan F.A. Grant,4

James R. Gavin III,5 and Richard B. Aguilar6

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classic insulin resistance (IR)-associatedtype 2 DM may display hallmarks oftype 1 DM. Similarly, obesity-related IRmay be observed in patients presentingwith “textbook” type 1 DM (7). The latepresentation of type 1 DM provides aparticular challenge for the current clas-sification system, in which this subtypeof DM is generally termed LADA. Lead-ing diabetes organizations have not ar-rived at a common definition for LADA(5). There has been little consensus asto whether this phenotype constitutes aform of type 2 DM with early or fast de-struction of b-cells, a late manifesta-tion of type 1 DM (8), or a distinctentity with its own genetic footprint(5). Indeed, current parameters are in-adequate to clearly distinguish any ofthe subforms of DM (Fig. 1). Discussionsand critiques of the current DM classi-fication system are found in the litera-ture (1–6).The use of IR to define type 2 DM

similarly needs consideration. The factthat many obese patients with IR donot develop DM indicates that IR is in-sufficient to cause type 2 DM withoutpredisposing factors that affect b-cellfunction (9).

CLASSIFICATION SCHEMA CANRAISE BARRIERS TO OPTIMALPATIENT CARE

The current classification schema im-poses unintended constraints on individ-ualized medicine. Patients diagnosedwith LADAwho retain endogenous insulinproduction may receive “default” insulin

therapy as treatment of choice. This de-cision is guided largely by the categoriza-tion of LADA within type 1 DM, despitethe capacity for endogenous insulinproduction. Treatment options that donot pose the risks of hypoglycemia orweight gain might be both useful andpreferable for LADA but are typicallynot considered beyond use in type 2DM (10). Incretins and sodium–glucosecotransporter 2 (SGLT-2) inhibitors areexamples of newer agents that havedemonstrated potential and are beingrigorously evaluated in the treatmentof type 1 DM and LADA (10–17).

The categorization of LADA withintype 1 DM also leads to myopia on thepart of insurers. Medications that couldbe logical choices as adjunctive or alter-native therapies to insulin for candidatepatients with LADA are not designatedas approved processes of care under thecurrent classification system and ac-cordingly are not covered by insurers.

We believe that there is little ratio-nale for limiting choice of therapy solelyon the current definitions of type 1 DM,type 2 DM, and LADA. We propose thatchoice of therapy should be based onthe particular mediating pathway(s) ofhyperglycemia present in each individ-ual patient, as will be discussed. Onlylarge clinical trials can fully validate thebest use of various agents across thespectrum of DM. In the interim, how-ever, an evidence-based practice ap-proach can allow for broader utility inroutine care. Metformin and pioglitazonemay be safe and efficacious adjunctive

therapies regardless of the current diag-nostic category, as may be incretins(11,15,17–23) and SGLT-2 inhibitors(14,24–26). It is reasonable that broaderuse of existing agentswould extend to themanagement ofmaturity-onset diabetes ofthe young (23,27), as well as stress-relatedand steroid-induced DM.

b-CELL–CENTRIC CONSTRUCT: APOTENTIAL MODEL FOR THECLASSIFICATION OF DM

Given the above discussion, the issue isnot “what is LADA” or any clinical pre-sentation of DM under the current sys-tem. The issue is the mechanisms andrate of destruction of b-cells at work inall DM. We present a model thatprovides a more logical approach toclassifying DM: the b-cell–centric classi-fication of DM. In this schema, the ab-normal b-cell is recognized as theprimary defect in DM. The b-cell–centricclassification system recognizes the in-terplay of genetics, IR, environmentalfactors, and inflammation/immune sys-tem on the function and mass of b-cells(Fig. 2). Importantly, this model is uni-versal for the characterization of DM.The b-cell–centric concept can be ap-plied to DM arising in genetically predis-posed b-cells, as well as in stronglygenetic IR syndromes, such as the Rabson-Mendenhall syndrome (28), which mayexhaust nongenetically predisposedb-cells. Finally, the b-cell–centric classi-fication of all DM supports best practicesin the management of DM by identifyingmediating pathways of hyperglycemiathat are operative in each patient anddirecting treatment to those specificdysfunctions.

The b-Cell: At the Root andCrossroads of Multiple MediatingPathways of HyperglycemiaThe b-cell–centric construct suggests amore logical rationale to the eight coredefects described by the ominous octet(29). Our model recognizes a total of 11interlocking pathways that contribute tohyperglycemia (Fig. 3A). These mediat-ing pathways of hyperglycemia are in-duced by the translation of geneticpredispositions to IR, susceptibility toenvironmental influences, or immunedysregulation and inflammation to ge-netically predisposed, dysfunctionalb-cells. The b-cell construct can incor-porate newly discovered pathways to

Figure 1—Qualitative illustration of the spectrum of factors associated with different forms ofDM, including the variable age at onset, lack of obesity, metabolic syndrome, genetic associa-tions, different forms of immune changes, C-peptide secretion, and the need for insulin therapy.T1DM, type 1 DM; T2DM, type 2 diabetes. Adapted with permission from Leslie et al. (1).

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dysglycemia as these evolve, such asemerging research linking osteocalcinlevels to A1C and HOMA of b-cell func-tion status (30).The mediating pathways of hypergly-

cemia that contribute to b-cell dysfunc-tion include liver, muscle, and adiposetissue (organs associated with IR) andbrain, colon, and immune dysregulation.This damage results in downstream hy-perglycemia arising from increased glu-cagon secretion, as well as a reduction ininsulin production, incretin effect, andamylin levels. Even mild hyperglycemiaresulting from b-cell dysfunction canupregulate SGLT-2 protein in the kidney,which further contributes to hypergly-cemia (31). Hyperglycemia, regardlessof its source, leads to glucotoxicity,which further impairs b-cell function.In a given patient, the specific mediatingpathways of hyperglycemia at work arevariable, though likely to involve multi-ple pathways (Fig. 3A).Three additional mediating pathways

of hyperglycemia to those of the omi-nous octet (29) have been identified.Systemic low-grade inflammation is ob-served in type 2 DM, type 1 DM, andLADA (32,33) and has been shown toaccompany the endoplasmic stress im-posed by increased metabolic demandfor insulin (34). Early studies show

incretins exert anti-inflammatory ef-fects (35,36), which may account inpart for their benefit. Inflammation isbeing clinically evaluated as a therapeu-tic target. It would be of interest if a re-cent 1-year trial reporting the ability of adipeptidyl peptidase 4 inhibitor to delaythe progression of disease in LADA pa-tients (17) proved durable and repro-ducible.

Changes in gut microbiota may con-tribute to the diabetic state (37–40).Gut microbiota has been shown to beassociated with type 1 DM, type 2 DM,and obesity and has been proposed tohelp explain the observation that only aportion of overweight individuals de-velop frank DM (38,39). Probiotics andprebiotics may address this mediator ofhyperglycemia.

Reductions in amylin production in thediabetic state are a consequence ofb-celldysfunction. Decreased amylin levels leadto accelerated gastric emptying and in-creased glucose absorption in the smallintestine, with corresponding increasesin postprandial glucose levels. Thispathway of hyperglycemia could theo-retically be addressed, at least in part,by the ability of incretins to slow gastricemptying.

A key premise is that the mediatingpathways of hyperglycemia are common

across prediabetes, type 1 DM, type 2DM, and other currently defined formsof DM. Accordingly, we believe that thecurrent antidiabetes armamentarium hasbroader applicability across the spectrumof DM than is currently utilized.

The ideal treatment paradigm wouldbe one that uses the least number ofagents possible to target the greatestnumber of mediating pathways of hy-perglycemia operative in the given pa-tient. It is prudent to use agents that willhelp patients reach target A1C levelswithout introducing drug-related hypo-glycemia or weight gain. Despite thecapacity of insulin therapy to manageglucotoxicity, there is a concern forb-cell damage due to IR that has beenexacerbated by exogenous insulin-induced hyperinsulinemia and weightgain (41). Sulfonylureas have beenshown to induce apoptosis of b-cells inculture (42,43). In contrast, early dataon some newer agents are suggestiveof b-cell–sparing abilities. An improve-ment of early and late b-cell response toglucose load has been reported with di-peptidyl peptidase 4 inhibitor treatment(18,21). Incretins have been shown, inpreclinical evaluations, to halt apoptosis,stimulate proliferation ofb-cells, increaseinsulin availability, improve a-cell re-sponse to insulin (44–46), and, in animalstudies, preserve b-cells (47).

Genetic Influences on the b-CellThe b-cell–centric model recognizesthat the final common denominator ofDM is the genetically predisposed, dys-functional b-cell, which ultimately leadsto compromised b-cell function, loss inb-cell mass, or depleted insulin contentin the face of IR. These may includemonogenic or polygenic defects thatpredispose to hyperinsulinemia, IR,more recently understood mechanismssuch as inflammation by the immunesystem (48–51), susceptibility to envi-ronmental factors (37,51,52), or otherphysiological factors that increase de-mand on or otherwise damage b-cellssuch as elevated circulating lipids(37,53–55) (Fig. 2). As not all carriersof genes associated with DM developDM, susceptibility likely relies on com-binations of genetic abnormalities, en-vironment, and lifestyle factors toexacerbate underlying genetic predis-positions. Though research is nascent,implicated environmental factors have

Figure 2—Genetic determinants influence IR (whether centrally or peripherally induced), loss ofb-cell function and mass, environmental triggers (such as viruses, endocrine disruptors, foodadvanced glycosylation end products, gut biome), and immune modulation and inflammation.Singly or, more commonly, in various combinations, these factors converge on the geneticallysusceptible b-cell, impinge on b-cell function and biology, and orchestrate the shift from nor-moglycemia to hyperglycemia. As this process takes place regardless of subtype of DM, thedysfunctional b-cell is the final common denominator in all DM.

care.diabetesjournals.org Schwartz and Associates 181

Figure 3—b-Cell–centric construct: the egregious eleven. Dysfunction of the b-cells is the final common denominator in DM. A: Eleven currentlyknownmediating pathways of hyperglycemia are shown. Many of these contribute to b-cell dysfunction (liver, muscle, adipose tissue [shown in redto depict additional association with IR], brain, colon/biome, and immune dysregulation/inflammation [shown in blue]), and others result fromb-cell dysfunction through downstream effects (reduced insulin, decreased incretin effect, a-cell defect, stomach/small intestine via reducedamylin, and kidney [shown in green]). B: Current targeted therapies for each of the current mediating pathways of hyperglycemia. GLP-1,glucagon-like peptide 1; QR, quick release.

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included endocrine disruptors (56),food additives (52), abnormal gut bi-ome (38,39,57), and ingested advancedglycation end products (58). There isalso evidence that certain environmen-tal factors may epigenetically alter thegenotype in reproductive cells, produc-ing inheritable DM factors in future gen-erations (59,60) (Fig. 2).Clinically evident DMensues at or after

the juncture when the combined gene–environment trigger reaches a tippingpoint for sufficient b-cell compromise tobe expressed as phenotypic hyperglyce-mia. This fundamental concept appliesto all forms of DM, substantiating thatthe final common denominator in DM isat the level of the b-cell.In our model, as typical in obesity, IR

is a monogenic or, more commonly, apolygenic disorder (59). Additional con-tributing factors to IRmay include inflam-mation (48–51), changes in the gutmicrobiota (37–40), and brain-modulatedchanges in metabolism (51,61,62). Re-sulting hyperinsulinemia feeds back tothe hypothalamus to further exacerbateperipheral IR (61,62). Downstream ef-fects of IR cause detriment to b-cellfunction by mechanisms that may in-clude inflammatory cytokines, adipocy-tokines, lipotoxicity, and decreasedadiponectin, potentially representing aphysiological scenario similar to that in-duced by hyperinsulinemia (63,64).

b-CELL–CENTRIC SCHEMA ANDINDIVIDUALIZED CARE

We propose that the b-cell–centricmodel is a conceptual framework thatcould help optimize processes of carefor DM. A1C, fasting blood glucose,and postprandial glucose testing remainthe basis of DM diagnosis and monitor-ing. Precision medicine in the treatmentof DM could be realized by additionaldiagnostic testing that could includeC-peptide (1), islet cell antibodies orother markers of inflammation (1,65),measures of IR, improved assays forb-cell mass, and markers of environ-mental damage and by the developmentof markers for the various mediatingpathways of hyperglycemia.We uphold that there is, and will in-

creasingly be, a place for genotyping inDM standard of care. Pharmacoge-nomics could help direct patient-levelcare (66–69) and holds the potentialto spur on research through the

development of DM gene banks foranalyzing genetic distinctions betweentype 1 DM, LADA, type 2 DM, andmaturity-onset diabetes of the young.The cost for genotyping has become in-creasingly affordable.

Lifestyle modification is the startingpoint for intervention in prediabetes andDM as is normalization of dyslipidemia,given the links of prolonged lipid exposurewith b-cell dysfunction (9,53–55). Our ap-proach advocates intervention early in theprocess of b-cell dysfunction. It is intui-tively obvious that the constellation ofmediating pathways of hyperglycemia infrank DM is likely the same as those inprediabetes. Pharmacotherapy for predi-abetes should be considered if lifestyleapproaches do not produce normoglyce-mia. Preferential use of agents withproven or strong evidence for b-cell pres-ervation is logical (70).

The optimal strategy is to use theleast number of agents to target thegreatest number of mediating pathwaysof hyperglycemia operative in the givenpatient. It would use regimens that sta-bilize hyperglycemia across multiplecauses, act synergistically to reduce car-diovascular and other risk factors, andpreserve b-cells. Figure 3B illustratesthe mediating pathways of hyperglyce-mia addressed by various availableagents and provides a logic for the se-lection of complementary modes of ac-tion in combination therapy.

Our approach for using combinationtherapy is consistent with the recom-mendations within the 2015 AmericanDiabetes Association (71) and 2015American Association of Clinical Endo-crinologists (72) guidelines. We advo-cate the introduction of combinationtherapy early in the pharmacologicalmanagement of the disease. Critically,we avoid stratifying first-, second-, andthird-line treatment sequencing. Thisstratification establishes undue competi-tion between classes, which should morerightly be viewed as complementary op-tions rather than salvage therapy after in-evitable treatment failure (19,73).

The ideal treatment regimens shouldnot be potentially detrimental to thelong-term integrity of the b-cells. Spe-cifically, sulfonylureas and glinidesshould be ardently avoided. Any bene-fits associated with sulfonylureas andglinides (including low cost) are not en-during and are far outweighed by their

attendant risks (and associated treat-ment costs) of hypoglycemia and weightgain, high rate of treatment failure andsubsequent enhanced requirements forantihyperglycemic management, poten-tial for b-cell exhaustion (42), increasedrisk of cardiovascular events (74), andpotential for increased risk of mortality(75,76). Fortunately, there are a largenumber of classes now available thatdo not pose these risks. Empagliflozinhas been recently shown to reduce car-diovascular outcomes and mortality intype 2 DM, while reducing weight andposing a low risk for hypoglycemia (24).

Newer agents present alternatives toinsulin therapy, including in patientswith “advanced” type 2 DM with resid-ual insulin production. Insulin therapyinduces hypoglycemia, weight gain,and a range of adverse consequencesof hyperinsulinemia with both short-and long-term outcomes (77–85). Newerantidiabetes classes may be used to de-lay insulin therapy in candidate patientswith endogenous insulin production(19). In patients requiring basal insulin,clinical research on novel combinationsof classes, such as pramlintide (86) andincretins (19,22), may reduce or elim-inate the need for bolus insulin. Bolusinsulin accounts for most of the hypo-glycemia seen with basal–bolus insulintherapy (87). When insulin therapy isneeded, we suggest it be incorporatedas add-on therapy rather than as sub-stitution for noninsulin antidiabetesagents. Outcomes research is neededto fully evaluate various combina-tion therapeutic approaches, as well asthe potential of newer agents to addressdrivers of b-cell dysfunction and loss.

The principles of the b-cell–centricmodel provide a rationale for adjunctivetherapy with noninsulin regimens in pa-tients with type 1 DM (7,12–16). Thiazo-lidinedione (TZD) therapy in patientswith type 1 DM presenting with IR, forexample, is appropriate and can be ben-eficial (17). Clinical trials in type 1 DMshow that incretins (20) or SGLT-2 inhi-bitors (25,88) as adjunctive therapy toexogenous insulin appear to reduceplasma glucose variability.

FURTHER EXPERIMENTAL ANDTRANSLATIONAL RESEARCH

This article highlights the need to replotthe classification of DM, recognizing theb-cell as the final common denominator

care.diabetesjournals.org Schwartz and Associates 183

of glucose dysregulation and the medi-ating pathways of hyperglycemia sur-rounding the b-cell as the basis fortreatment decisions. A b-cell–focusedschema can integrate knowledge todate and incorporate new discoveries.It can provide sage advice for preferen-tial use of pharmacological interven-tions that address the mechanisms ofhyperglycemia operative in an individ-ual patient, avoid hypoglycemia andweight gain, and appear to be b-cellsparing. Preferred therapies will bethose that affect multiple mediators ofhyperglycemia. Novel anti-inflammationagents currently in phase 2 and 3 clinicaldevelopment should be evaluated forsafety and efficacy, and we should fur-ther explore suggestions that this ap-proach could effectively treat, reverse,or even prevent DM with an inflamma-tory component (89).The b-cell–centric classification

schema was envisioned as a stimulusto guide basic research, as well as clini-cal and translational research. It ishoped to help direct research on thegenes involved in DM, the functionsthat these genes serve, the mechanismsthat lead to b-cell damage, the down-stream effects of reduced b-cell function,and any novel mechanisms of b-cell path-ophysiology. Also needed is research to-ward improved diagnostic markers forthe development of DM.The b-cell–centric model can be

readily retrofitted into the terminologyof the existing classification system.However, we submit that an entirelynew nomenclature may likely best fulfillthe imperative of bringing the classifica-tion in line with the known etiology anddisease course.

A CALL TO ACTION

For all the above-stated reasons, weurge that the time is right to convene acommittee of diabetes community lead-ers and researchers to reevaluate thecurrent outmoded DM classification sys-tem. Members of the American Diabe-tes Association, American Association ofClinical Endocrinologists, European As-sociation for the Study of Diabetes, In-ternational Diabetes Federation, andWorld Health Organization shouldcome together to address this immense,but vital, task toward delivering state-of-the-art, optimal patient care and di-recting future research.

Acknowledgments. The authors acknowledgeDr. Mary E. Herman, Montclair State University,Montclair, NJ, for her editorial assistance in thecrafting of the manuscript.Funding. S.S.S. and S.F.A.G. are partially sup-ported by National Institutes of Health (NIH)grant R01 DK085212. S.F.A.G. holds the DanielB. Burke Endowed Chair for Diabetes Research.B.E.C. is partially supported by NIH grantsDK99618, DK56690, DK74778, and DK35914.No funding was received by any of authors forthe work in the manuscript.Duality of Interest. S.S.S. is a speaker andadvisor toNovoNordisk,Merck, Takeda, Johnson& Johnson, AstraZeneca/Bristol-Myers Squibb,Eli Lilly and Co., and Boehringer Ingelheim/EliLilly and Co. and is a speaker for Eisai andGlaxoSmithKline. J.R.G. has received consul-tant fees from Abbott Diabetes Care, IntarciaPharmaceuticals, AstraZeneca, and NovoNordisk; has served on the advisory boardsof Janssen Pharmaceuticals and AstraZeneca;and has served on the speakers’ bureaus ofAstraZeneca, Janssen Pharmaceuticals, andBoehringer Ingelheim/Eli Lilly and Co. R.B.A.sits on the advisory board and speakers’ bu-reaus of Eli Lilly and Co., Boehringer Ingelheim,Janssen Pharmaceuticals, and Takeda. No otherpotential conflicts of interest relevant to thisarticle were reported.Author Contributions. S.S.S. conceived theb-cell–centric concept and crafted the first draftof the manuscript. S.E., B.E.C., S.F.A.G., J.R.G.,and R.B.A. critically reviewed, provided incisiveinput, edited, and approved the final version ofthe manuscript. B.E.C., in particular, lent impor-tant critical analysis of the concept. R.B.A. addi-tionally contributed graphic design.

References1. Leslie RD, Palmer J, Schloot NC, Lernmark A.Diabetes at the crossroads: relevance of diseaseclassification to pathophysiology and treat-ment. Diabetologia. 24 October 2015 [Epubahead of print]2. Grant SFA, Hakonarson H, Schwartz S. Canthe genetics of type 1 and type 2 diabetesshed light on the genetics of latent autoim-mune diabetes in adults? Endocr Rev 2010;31:183–1933. Rolandsson O, Palmer JP. Latent autoim-mune diabetes in adults (LADA) is dead: longlive autoimmune diabetes! Diabetologia 2010;53:1250–12534. Redondo MJ. LADA: time for a new defini-tion. Diabetes 2013;62:339–3405. Basile KJ, Guy VC, Schwartz S, Grant SFA.Overlap of genetic susceptibility to type 1 dia-betes, type 2 diabetes, and latent autoimmunediabetes in adults. Curr Diab Rep 2014;14:5506. Thomas CC, Philipson LH. Update on diabe-tes classification. Med Clin North Am 2015;99:1–167. Polsky S, Ellis SL. Obesity, insulin resistance,and type 1 diabetes mellitus. Curr Opin Endo-crinol Diabetes Obes 2015;22:277–2828. Guy VC, Chesi A, Hawa M, et al. The role ofGWAS-implicated type 1 and type 2 diabetesloci in the pathogenesis of latent autoimmunediabetes in adults (LADA) (Abstract) Diabetes2015;64(Suppl. 1):A80

9. Corkey BE. Diabetes: have we got it allwrong? Insulin hypersecretion and food addi-tives: cause of obesity and type 2 diabetes? Di-abetes Care 2012;35:2432–243710. Guglielmi C, Palermo A, Pozzilli P. Latentautoimmune diabetes in the adults (LADA) inAsia: from pathogenesis and epidemiology totherapy. Diabetes Metab Res Rev 2012;28(Suppl. 2):40–4611. Ghazi T, Rink L, Sherr JL, Herold KC. Acutemetabolic effects of exenatide in patients withtype 1 diabetes with and without residual insu-lin to oral and intravenous glucose challenges.Diabetes Care 2014;37:210–21612. Lebovitz HE. Adjunct therapy for type 1 di-abetes mellitus. Nat Rev Endocrinol 2010;6:326–33413. Munir KM, Davis SN. The treatment oftype 1 diabetes mellitus with agents approvedfor type 2 diabetes mellitus. Expert Opin Phar-macother 2015;16:2331–234114. Perkins BA, Cherney DZ, Partridge H, et al.Sodium-glucose cotransporter 2 inhibition andglycemic control in type 1 diabetes: results of an8-week open-label proof-of-concept trial. Dia-betes Care 2014;37:1480–148315. Renukuntla VS, Ramchandani N, Trast J,Cantwell M, Heptulla RA. Role of glucagon-likepeptide-1 analogue versus amylin as an adju-vant therapy in type 1 diabetes in a closedloop setting with ePID algorithm. J DiabetesSci Technol 2014;8:1011–101716. Tafuri KS, Godil MA, Lane AH, Wilson TA.Effect of pioglitazone on the course of new-onset type 1 diabetes mellitus. J Clin Res PediatrEndocrinol 2013;5:236–23917. Zhao Y, Yang L, Xiang Y, et al. Dipeptidylpeptidase 4 inhibitor sitagliptin maintainsb-cell function in patients with recent-onset la-tent autoimmune diabetes in adults: one yearprospective study. J Clin Endocrinol Metab2014;99:E876–E88018. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4inhibitor saxagliptin in drug-naive patients withtype 2 diabetes. Diabetes Obes Metab 2008;10:376–38619. Abdul-Ghani MA, Puckett C, Triplitt C, et al.Initial combination therapy with metformin,pioglitazone and exenatide is more effectivethan sequential add-on therapy in subjectswith new-onset diabetes. Results from the Effi-cacy and Durability of Initial Combination Ther-apy for Type 2 Diabetes (EDICT): a randomizedtrial. Diabetes Obes Metab 2015;17:268–27520. Arnolds S, Dellweg S, Clair J, et al. Furtherimprovement in postprandial glucose controlwith addition of exenatide or sitagliptin to com-bination therapy with insulin glargine and met-formin: a proof-of-concept study. Diabetes Care2010;33:1509–151521. Nonaka K, Kakikawa T, Sato A, et al. Efficacyand safety of sitagliptin monotherapy in Japa-nese patients with type 2 diabetes. Diabetes ResClin Pract 2008;79:291–29822. Schwartz S. Evidence-based practice use ofincretin-based therapy in the natural history ofdiabetes. Postgrad Med 2014;126:66–8423. Schwartz SS, DeFronzo RA, Umpierrez GE.Practical implementation of incretin-basedtherapy in hospitalized patients with type 2 di-abetes. Postgrad Med 2015;127:251–257

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24. Zinman B, Wanner C, Lachin JM, et al.;EMPA-REGOUTCOME Investigators. Empagliflozin,cardiovascular outcomes, and mortality intype 2 diabetes. N Engl J Med 2015;373:2117–212825. Henry RR, Rosenstock J, Edelman S, et al.Exploring the potential of the SGLT2 inhibitordapagliflozin in type 1 diabetes: a randomized,double-blind, placebo-controlled pilot study.Diabetes Care 2015;38:412–41926. Wilding JP, Woo V, Rohwedder K, Sugg J,Parikh S; Dapagliflozin 006 Study Group.Dapagliflozin in patients with type 2 diabetesreceiving high doses of insulin: efficacy andsafety over 2 years. Diabetes Obes Metab2014;16:124–13627. Anık A, Çatlı G, Abacı A, Bober E. Maturity-onset diabetes of the young (MODY): an update.J Pediatr Endocrinol Metab 2015;28:251–26328. Longo N, Wang Y, Pasquali M. Progressivedecline in insulin levels in Rabson-Mendenhallsyndrome. J Clin Endocrinol Metab 1999;84:2623–262929. Defronzo RA. Banting Lecture. From the tri-umvirate to the ominous octet: a new paradigmfor the treatment of type 2 diabetes mellitus.Diabetes 2009;58:773–79530. Kunutsor SK, Apekey TA, Laukkanen JA. As-sociation of serum total osteocalcin with type 2diabetes and intermediate metabolic pheno-types: systematic review and meta-analysis ofobservational evidence. Eur J Epidemiol 2015;30:599–61431. DeFronzo RA, Davidson JA, Del Prato S. Therole of the kidneys in glucose homeostasis: anew path towards normalizing glycaemia. Dia-betes Obes Metab 2012;14:5–1432. Pietropaolo M, Barinas-Mitchell E, KullerLH. The heterogeneity of diabetes: unravelinga dispute: is systemic inflammation relatedto islet autoimmunity? Diabetes 2007;56:1189–119733. Subauste A, Gianani R, Chang AM et al. Isletautoimmunity identifies a unique pattern of im-paired pancreatic beta-cell function, markedlyreduced pancreatic beta cell mass and insulinresistance in clinically diagnosed type 2 diabe-tes. PLoS One 2014;9:e10653734. Oslowski CM, Hara T, O’Sullivan-Murphy B,et al. Thioredoxin-interacting protein mediatesER stress-induced b cell death through initia-tion of the inflammasome. Cell Metab 2012;16:265–27335. Chaudhuri A, Ghanim H, Vora M, et al. Ex-enatide exerts a potent antiinflammatory ef-fect. J Clin Endocrinol Metab 2012;97:198–20736. Makdissi A, Ghanim H, Vora M, et al. Sita-gliptin exerts an antinflammatory action. J ClinEndocrinol Metab 2012;97:3333–334137. Kahn SE, Cooper ME, Del Prato S. Patho-physiology and treatment of type 2 diabetes:perspectives on the past, present, and future.Lancet 2014;383:1068–108338. Allin KH, Nielsen T, Pedersen O. Mecha-nisms in endocrinology: gut microbiota in pa-tients with type 2 diabetes mellitus. Eur JEndocrinol 2015;172:R167–R17739. Tai N, Wong FS, Wen L. The role of gut mi-crobiota in the development of type 1, type 2diabetes mellitus and obesity. Rev EndocrMetab Disord 2015;16:55–65

40. Carvalho BM, Saad MJ Influence of gut mi-crobiota on subclinical inflammation and insulinresistance. Mediators Inflamm 2013;2013:98673441. Del Prato S. Role of glucotoxicity and lipo-toxicity in the pathophysiology of type 2 diabe-tes mellitus and emerging treatment strategies.Diabet Med 2009;26:1185–119242. Maedler K, Carr RD, Bosco D, Zuellig RA,Berney T, Donath MY. Sulfonylurea inducedbeta-cell apoptosis in cultured human islets.J Clin Endocrinol Metab 2005;90:501–50643. Iwakura T, Fujimoto S, Kagimoto S, et al.Sustained enhancement of Ca(2+) influx byglibenclamide induces apoptosis in RINm5Fcells. Biochem Biophys Res Commun 2000;271:422–42844. Reimer MK, Holst JJ, Ahren B. Long-terminhibition of dipeptidyl peptidase IV improvesglucose tolerance and preserves islet functionin mice. Eur J Endocrinol 2002;146:717–72745. Mu J, Woods J, Zhou YP, et al. Chronic in-hibition of dipeptidyl peptidase-4 with a sita-gliptin analog preserves pancreatic beta-cellmass and function in a rodent model of type 2diabetes. Diabetes 2006;55:1695–170446. Chen J, Couto FM, Minn AH, Shalev A. Ex-enatide inhibits beta-cell apoptosis by decreas-ing thioredoxin-interacting protein. BiochemBiophys Res Commun 2006;346:1067–107447. Shimoda M, Kanda Y, Hamamoto S, et al.The human glucagon-like peptide-1 analogueliraglutide preserves pancreatic beta cells viaregulation of cell kinetics and suppression ofoxidative and endoplasmic reticulum stressin a mouse model of diabetes. Diabetologia2011;54:1098–110848. Donath MY. Targeting inflammation in thetreatment of type 2 diabetes: time to start. NatRev Drug Discov 2014;13:465–47649. Roep BO, Tree TI. Immune modulation inhumans: implications for type 1 diabetes melli-tus. Nat Rev Endocrinol 2014;10:229–24250. Rossetti L, Hawkins M, Chen W, Gindi J,Barzilai N. In vivo glucosamine infusion inducesinsulin resistance in normoglycemic but not inhyperglycemic conscious rats. J Clin Invest 1995;96:132–14051. Straub RH. Insulin resistance, selfish brain,and selfish immune system: an evolutionarilypositively selected program used in chronic in-flammatory diseases. Arthritis Res Ther 2014;16(Suppl. 2):S452. Simmons AL, Schlezinger JJ, Corkey BE.What are we putting in our food that is makingus fat? Food additives, contaminants, and otherputative contributors to obesity. Curr Obes Rep2014;3:273–28553. Erion KA, Berdan CA, Burritt NE, Corkey BE,Deeney JT. Chronic exposure to excess nutrientsleft-shifts the concentration dependence ofglucose-stimulated insulin secretion in pancreaticbeta cells. J Biol Chem 2015;290:16191–1620154. Halban PA, Polonsky KS, Bowden DW, et al.b-Cell failure in type 2 diabetes: postulatedmechanisms and prospects for prevention andtreatment. Diabetes Care 2014;37:1751–175855. Stahli BE, Gebhard C, Tardif JC. Lipid effectsand cardiovascular disease risk associated withglucose-lowering medications. Curr Cardiol Rep2015;17:608

56. Chevalier N, Fenichel P. Endocrinedisruptors:new players in the pathophysiology oftype 2 diabetes? Diabetes Metab 2015;41:107–11557. Escobedo G, Lopez-Ortiz E, Torres-Castro I.Gut microbiota as a key player in triggering obe-sity, systemic inflammation and insulin resis-tance. Rev Invest Clin 2014;66:450–45958. Biswas SK, Mohtarin S, Mudi SR, et al. Re-lationship of soluble RAGE with insulin resis-tance and beta cell function during developmentof type 2 diabetes mellitus. J Diabetes Res 2015;2015:15032559. Raciti GA, Longo M, Parrillo L, et al. Under-standing type 2 diabetes: from genetics toepigenetics. Acta Diabetol 2015;52:821–82760. Zhao M, Wang Z, Yung S, Lu Q. Epigeneticdynamics in immunity and autoimmunity. Int JBiochem Cell Biol 2015;67:65–7461. Schlaich M, Straznicky N, Lambert E,Lambert G. Metabolic syndrome: a sympatheticdisease? Lancet Diabetes Endocrinol 2015;3:148–15762. Coomans CP, van den Berg SA, Lucassen EA,et al. The suprachiasmatic nucleus controls cir-cadian energy metabolism and hepatic insulinsensitivity. Diabetes 2013;62:1102–110863. Mandrup-Poulsen T. IAPP boosts islet mac-rophage IL-1 in type 2 diabetes. Nat Immunol2010;11:881–88364. Evans JL, Goldfine ID, Maddux BA, GrodskyGM. Are oxidative stress-activated signalingpathways mediators of insulin resistance andbeta-cell dysfunction? Diabetes 2003;52:1–865. Gottlieb PA. What defines disease in an ageof genetics and biomarkers? Curr Opin Endocri-nol Diabetes Obes 2015;22:296–29966. Groop L, Storm P, Rosengren A. Can genet-ics improve precision of therapy in diabetes?Trends Endocrinol Metab 2014;25:440–44367. Zhou K, Donnelly L, Yang J, et al.; WellcomeTrust Case Control Consortium 2. Heritability ofvariation in glycaemic response to metformin: agenome-wide complex trait analysis. LancetDiabetes Endocrinol 2014;2:481–48768. Tuomi T, Santoro N, Caprio S, CaiM,Weng J,Groop L. The many faces of diabetes: a diseasewith increasing heterogeneity. Lancet 2014;383:1084–109469. Wherrett DK, Chiang JL, Delamater AM,et al.; Type 1 Diabetes TrialNet Study Group.Defining pathways for development of disease-modifying therapies in children with type 1diabetes: a consensus report. Diabetes Care2015;38:1975–198570. Armato J, DeFronzo RA, Abdul-Ghani M,Ruby R. Successful treatment of prediabetesin clinical practice: targeting insulin resistanceand b-cell dysfunction. Endocr Pract 2012;18:342–35071. Inzucchi SE, Bergenstal RM, Buse JB, et al.Management of hyperglycaemia in type 2 dia-betes, 2015: a patient-centered approach. Up-date to a position statement of the AmericanDiabetes Association and the European Associ-ation for the Study of Diabetes. Diabetologia2015;58:429–44272. Garber AJ, AbrahamsonMJ, Barzilay JI, et al.AACE/ACE comprehensive diabetes manage-ment algorithm 2015. Endocr Pract 2015;21:438–447

care.diabetesjournals.org Schwartz and Associates 185

73. DeFronzo RA, Eldor R, Abdul-Ghani M.Pathophysiologic approach to therapy in pa-tients with newly diagnosed type 2 diabetes.Diabetes Care 2013;36(Suppl. 2):S127–S13874. Federal Drug Administration. Code of Fed-eral Regulations Title 21. Sec. 310.517: Labelingfor oral hypoglycemic drugs of the sulfonylureaclass, 49 FR 14331, 11 April 1984. Available fromhttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.517. Ac-cessed 20 September 201575. Evans JM, Ogston SA, Emslie-Smith A,Morris AD. Risk of mortality and adverse car-diovascular outcomes in type 2 diabetes: acomparison of patients treated with sulfonyl-ureas and metformin. Diabetologia 2006;49:930–93676. Margolis DJ, Hoffstad O, Strom BL. Associ-ation between serious ischemic cardiac out-comes and medications used to treatdiabetes. Pharmacoepidemiol Drug Saf 2008;17:753–75977. Currie CJ, Johnson JA. The safety profileof exogenous insulin in people with type 2diabetes: justification for concern. DiabetesObes Metab 2012;14:1–478. Nathan DM, Cleary PA, Backlund JY,et al.; Diabetes Control and ComplicationsTrial/Epidemiology of Diabetes Interventions

and Complications (DCCT/EDIC) Study ResearchGroup. Intensive diabetes treatment and car-diovascular disease in patients with type 1 di-abetes. N Engl J Med 2005;353:2643–265379. Draznin B. Mechanism of the mitogenic in-fluence of hyperinsulinemia. Diabetol MetabSyndr 2011;3:1080. Karlstad O, Starup-Linde J, Vestergaard P,et al. Use of insulin and insulin analogs andrisk of cancer - systematic review and meta-analysis of observational studies. Curr Drug Saf2013;8:333–34881. Yarchoan M, Arnold SE. Repurposing dia-betes drugs for brain insulin resistance inAlzheimer disease. Diabetes 2014;63:2253–226182. Gallagher EJ, LeRoith D. Obesity and diabe-tes: the increased risk of cancer and cancer-related mortality. Physiol Rev 2015;95:727–74883. Kelly CT, Mansoor J, Dohm GL, ChapmanWH 3rd, Pender JR 4th, Pories WJ. Hyperinsuli-nemic syndrome: the metabolic syndrome isbroader than you think. Surgery 2014;156:405–41184. Kleinridders A, Ferris HA, Cai W, Kahn CR.Insulin action in brain regulates systemic me-tabolism and brain function. Diabetes 2014;63:2232–2243

85. Muntoni S, Muntoni S. Insulin resistance:pathophysiology and rationale for treatment.Ann Nutr Metab 2011;58:25–3686. Riddle M, Frias J, Zhang B, et al. Pramlin-tide improved glycemic control and reducedweight in patients with type 2 diabetes usingbasal insulin. Diabetes Care 2007;30:2794–279987. Garber AJ, King AB, Del Prato S, et al.;NN1250-3582 (BEGIN BB T2D) Trial Investigators.Insulin degludec, an ultra-longacting basal in-sulin, versus insulin glargine in basal-bolus treat-ment with mealtime insulin aspart in type 2diabetes (BEGIN Basal-Bolus Type 2): a phase 3,randomised, open-label, treat-to-target non-inferiority trial . Lancet 2012;379:1498–150788. Matthews D, Fulcher G, Perkovic V, et al.Efficacy and safety of canagliflozin, an inhibitorof sodium glucose co-transporter 2, added on toinsulin therapy with or without oral agents intype 2 diabetes. Poster presented at the 48thAnnual Meeting of the European Association forthe Study of Diabetes, 1–5 October 2012, Berlin,Germany89. Larsen CM, Faulenbach M, Vaag A, et al.Interleukin-1-receptor antagonist in type 2diabetes mellitus. N Engl J Med 2007;356:1517–1526

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