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DC 151585
DC 151585
PERSPECTIVES IN CARE
b-Cell–Centric Classification
Schema
classic insulin resistance (IR)-associated therapy as treatment of choice. This de- therapies regardless of the current diag-
type 2 DM may display hallmarks of cision is guided largely by the categoriza- nostic category, as may be incretins
type 1 DM. Similarly, obesity-related IR tion of LADA within type 1 DM, despite (11,15,17–23) and SGLT-2 inhibitors
may be observed in patients presenting the capacity for endogenous insulin (14,24–26). It is reasonable that broader
with “textbook” type 1 DM (7). The late production. Treatment options that do use of existing agents would extend to the
presentation of type 1 DM provides a not pose the risks of hypoglycemia or management of maturity-onset diabetes of
particular challenge for the current clas- weight gain might be both useful and the young (23,27), as well as stress-related
sification system, in which this subtype preferable for LADA but are typically and steroid-induced DM.
of DM is generally termed LADA. Lead- not considered beyond use in type 2
ing diabetes organizations have not ar- DM (10). Incretins and sodium–glucose b-CELL–CENTRIC CONSTRUCT: A
rived at a common definition for LADA cotransporter 2 (SGLT-2) inhibitors are POTENTIAL MODEL FOR THE
(5). There has been little consensus as examples of newer agents that have CLASSIFICATION OF DM
to whether this phenotype constitutes a demonstrated potential and are being Given the above discussion, the issue is
form of type 2 DM with early or fast de- rigorously evaluated in the treatment not “what is LADA” or any clinical pre-
Figure 3—b-Cell–centric construct: the egregious eleven. Dysfunction of the b-cells is the final common denominator in DM. A: Eleven currently
known mediating pathways of hyperglycemia are shown. Many of these contribute to b-cell dysfunction (liver, muscle, adipose tissue [shown in red
to depict additional association with IR], brain, colon/biome, and immune dysregulation/inflammation [shown in blue]), and others result from
b-cell dysfunction through downstream effects (reduced insulin, decreased incretin effect, a-cell defect, stomach/small intestine via reduced
amylin, 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.
care.diabetesjournals.org Schwartz and Associates 183
included endocrine disruptors (56), development of DM gene banks for attendant risks (and associated treat-
food additives (52), abnormal gut bi- analyzing genetic distinctions between ment costs) of hypoglycemia and weight
ome (38,39,57), and ingested advanced type 1 DM, LADA, type 2 DM, and gain, high rate of treatment failure and
glycation end products (58). There is maturity-onset diabetes of the young. subsequent enhanced requirements for
also evidence that certain environmen- The cost for genotyping has become in- antihyperglycemic management, poten-
tal factors may epigenetically alter the creasingly affordable. tial for b-cell exhaustion (42), increased
genotype in reproductive cells, produc- Lifestyle modification is the starting risk of cardiovascular events (74), and
ing inheritable DM factors in future gen- point for intervention in prediabetes and potential for increased risk of mortality
erations (59,60) (Fig. 2). DM as is normalization of dyslipidemia, (75,76). Fortunately, there are a large
Clinically evident DM ensues at or after given the links of prolonged lipid exposure number of classes now available that
the juncture when the combined gene– with b-cell dysfunction (9,53–55). Our ap- do not pose these risks. Empagliflozin
environment trigger reaches a tipping proach advocates intervention early in the has been recently shown to reduce car-
point for sufficient b-cell compromise to process of b-cell dysfunction. It is intui- diovascular outcomes and mortality in
be expressed as phenotypic hyperglyce- tively obvious that the constellation of type 2 DM, while reducing weight and
of glucose dysregulation and the medi- 9. Corkey BE. Diabetes: have we got it all
ating pathways of hyperglycemia sur- Acknowledgments. The authors acknowledge wrong? Insulin hypersecretion and food addi-
Dr. Mary E. Herman, Montclair State University, tives: cause of obesity and type 2 diabetes? Di-
rounding the b-cell as the basis for Montclair, NJ, for her editorial assistance in the abetes Care 2012;35:2432–2437
treatment decisions. A b-cell–focused crafting of the manuscript. 10. Guglielmi C, Palermo A, Pozzilli P. Latent
schema can integrate knowledge to Funding. S.S.S. and S.F.A.G. are partially sup- autoimmune diabetes in the adults (LADA) in
date and incorporate new discoveries. ported by National Institutes of Health (NIH) Asia: from pathogenesis and epidemiology to
It can provide sage advice for preferen- grant R01 DK085212. S.F.A.G. holds the Daniel therapy. Diabetes Metab Res Rev 2012;28
B. Burke Endowed Chair for Diabetes Research. (Suppl. 2):40–46
tial use of pharmacological interven- B.E.C. is partially supported by NIH grants 11. Ghazi T, Rink L, Sherr JL, Herold KC. Acute
tions that address the mechanisms of DK99618, DK56690, DK74778, and DK35914. metabolic effects of exenatide in patients with
hyperglycemia operative in an individ- No funding was received by any of authors for type 1 diabetes with and without residual insu-
ual patient, avoid hypoglycemia and the work in the manuscript. lin to oral and intravenous glucose challenges.
Duality of Interest. S.S.S. is a speaker and Diabetes Care 2014;37:210–216
weight gain, and appear to be b-cell
advisor to Novo Nordisk, Merck, Takeda, Johnson 12. Lebovitz HE. Adjunct therapy for type 1 di-
sparing. Preferred therapies will be & Johnson, AstraZeneca/Bristol-Myers Squibb, abetes mellitus. Nat Rev Endocrinol 2010;6:
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