Leahy et al. recently issued a consensus statement recommending targeting b-cell function early in therapy for type 2 diabetes. The consensus is based on evidence that declining b-cell function, a key pathogenesis of type 2 diabetes, begins early and drives disease progression. Preserving b-cell function may be possible through early intervention, even in lean type 2 diabetes patients. However, more research is needed to better understand b-cell dysfunction mechanisms involving both mass reduction and functional impairment over the natural course of diabetes. Non-invasive methods to measure b-cell mass longitudinally are also critical to evaluate early intervention effects and disease progression.

1. COMMENTARY
Targeting b-cell functions in therapy for type 2
diabetes
function by early intervention is both with longer duration of diabetes than in
Recently, Leahy et al. issued a necessary and important. those with shorter duration, suggesting a
‘‘consensus statement’’ in regard to In a longitudinal study of obese Pima decrease in the capacity to compensate
targeting b-cell function in therapy Indians by Weyer et al.2, failure to aug- insulin secretion against insulin resistance
for type 2 diabetes that recommends ment b-cell function to compensate for by disease duration and that early inter-
continued multidisciplinary efforts to increased insulin demand as a result of vention might be necessary, even in lean
realign treatment of type 2 diabetes decreased insulin sensitivity, due to type 2 diabetes.
to preserve b-cell function by early weight gain for example, was found to be A previous study using streptozotocin-
intervention. This might be applicable involved in deterioration of glucose treated mini-pigs showed that b-cell func-
homeostasis in type 2 diabetes. It is tion in vivo is closely related to b-cell
not only for obese type 2 diabetes in
important to determine whether or not mass, even when only slightly reduced5.
Europe and America, but also for lean
this pathogenesis is also applicable to lean A decrease in b-cell mass in type 2 diabe-
type 2 diabetes in Asia. To establish type 2 diabetes in Asia. Sato et al.3 tes compared with that in normal subjects
evidence, development of non- showed, by a cross-sectional study using is shown by cross-sectional studies using
invasive measurements of b-cell mass the oral glucose tolerance test, that b-cells specimens of autopsies or surgical opera-
for longitudinal observation during begin to deteriorate during normoglyce- tions, but longitudinal studies are absent.
long duration of diabetes is critical. mia with a minimal elevation of fasting In a cross-sectional study using specimens
In addition, studies that clarify the plasma glucose in Japanese subjects. In derived from autopsies, b-cell mass in
development of b-cell dysfunction our previous cross-sectional study, endo- individuals showed extreme variability
with regard to both mass reduction genous insulin secretion shown by indices and markedly overlapped in normal sub-
and functional impairment are of serum C-peptide immunoreactivity jects and patients with type 2 diabetes,
required for the development of novel (CPR) levels was negatively correlated despite the significant average decrease in
with years from diagnosis, suggesting pro- b-cell mass in type 2 diabetes6. These
strategies to preserve b-cell function
gressive deterioration of b-cell function results show that measurement of b-cell
by treatment of type 2 diabetes.
over several decades of diabetes exposure mass at one time point in an individual
(J Diabetes Invest, doi: 10.1111/j.2040- in Japanese type 2 diabetes4. Interestingly, cannot predict progression to type 2 dia-
1124.2011.00117.x, 2011) body mass index (BMI) was positively betes and that longitudinal observation is
correlated with indices of CPR, suggesting necessary. Trials to find useful probes to
Leahy et al.1 recently issued a consensus that increased insulin resistance positively visualize b-cell mass in vivo continue7.
statement that recommends targeting affects endogenous insulin secretion, even Such non-invasive methods, if realized,
b-cell function for therapy in type 2 dia- in lean type 2 diabetes. However, the will be valuable to clarify the relationship
betes. The consensus is based on recent positive effect of BMI on endogenous between function and mass of b-cells dur-
studies showing that declining b-cell insulin secretion is weaker in patients ing the natural course of type 2 diabetes
function, a pathogenesis of type 2 diabe-
tes, begins early in the disease’s natural Genetic factors, environmental factors, aging, etc.
history, accelerates markedly after reach-
ing a compensatory threshold, drives the
progression of the disease and is poten-
tially reversible, particularly in the early
stages. They concluded that continued β cell mass reduction Functional impairment of individual cells
multidisciplinary effort to realign treat-
ment of type 2 diabetes to preserve b-cell
*Corresponding author. Shimpei Fujimoto Insufficient insulin secretion in vivo
Tel.: +81-75-751-3560 Fax: +81-75-751-4244
E-mail address: fujimoto@metab.kuhp.kyoto-u.ac.jp
Received 15 February 2011; accepted 20 February 2011
Figure 1 | Pathogenesis of type 2 diabetes mellitus.
178 Journal of Diabetes Investigation Volume 2 Issue 3 June 2011 ª 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd

2. Targeting b-cell function
in longitudinal studies and to evaluate the protein and a nuclear factor11,12. Interest- 5. Larsen MO, Rolin B, Wilken M, et al.
effects of early intervention. ingly, an increase in the intracellular Measurements of insulin secretory
In the consensus statement, Leahy et al. cAMP level by GLP-1 receptor agonist capacity and glucose tolerance
stressed the importance of basic research ameliorates impaired ATP production by to predict pancreatic b-cell mass
to elucidate the nature and mechanisms of suppressing endogenous ROS generation in vivo in the nicotinamide ⁄ streptozo-
b-cell failure in type 2 diabetes. Under- in diabetic b-cells, which suggests that in- tocin Go ¨ttingen minipig, a model
standing the molecular basis of b-cell pro- cretin therapy might have an important of moderate insulin deficiency and
liferation and apoptosis is required to role in recovering impaired metabolism- diabetes. Diabetes 2003; 52: 118–123.
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ª 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd Journal of Diabetes Investigation Volume 2 Issue 3 June 2011 179