The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l s

Reducing Caretaker Burden, Protecting

Young Brains and Bodies
Lynne L. Levitsky, M.D.

The year 2021 has been celebrated as the centen-
nial of the discovery of insulin, a feat that pro-
longed the lives of millions of persons with type 1
diabetes but cured none of them. In the coming
century, we can look forward to improved me-
chanical devices to mimic the actions of the
human endocrine pancreas and, potentially, to
breakthroughs in immunology and tissue engi-
neering that may lead to true cures for type 1
diabetes mellitus.
Management of type 1 diabetes remains com-
plex, technically difficult, and time-consuming.
Intensive technical treatment in adults and chil-
dren today includes the use of subcutaneous in-
sulin pumps linked to continuous subcutaneous
glucose-monitoring devices, creating a hybrid
closed-loop glucose sensor–augmented infusion
of insulin. At present, approved devices still
require user input of meal timing and carbohy-
drate content so that appropriate bolus insulin is
released to diminish postprandial glycemic ex-
cursions. In this issue of the Journal, the report
by Ware et al.1 compares use of a hybrid closed-
loop device with use of sensor-augmented insu-
lin pump therapy over periods of 16 weeks. The
trial showed improved glycemic control, as mea-
sured by the glycated hemoglobin level and the
time in range (the time over a 24-hour period
that the blood glucose level was in the normal
range), with the hybrid closed-loop system, with
little evident risk during use in young children.
Type 1 diabetes in very young children is typi-
cally associated with fluctuating glycemic con-
trol because of rapidly changing activity levels
and erratic food intake. Most young children
need others to identify hypoglycemia and treat it
appropriately. The ordinary developmental tasks
of childhood are delayed and subverted by type 1
diabetes because to maintain glycemic control,
parental involvement must be persistent and
ubiquitous. Children with type 1 diabetes and
their caretakers have decreased sleep and erratic
sleep habits, higher levels of anxiety, and stress-
filled lives because of these fluctuations in blood
glucose levels.2,3
Although the long-term microvascular and
neuropathic complications of diabetes, largely
related to chronic hyperglycemia, shorten lives
and reduce quality of life, acute hypoglycemic
complications have been the immediate concern
for most caretakers of young children with type 1
diabetes.2 For many years, it was assumed that
hypoglycemia was a major risk factor for poor
neurologic development in children with type 1
diabetes. Severe hypoglycemia in young children
with type 1 diabetes has been variably associated
with decreases in gray-matter and white-matter
volumes, but longitudinal effects on neuropsy-
chiatric function have been varied and largely
confined to children with recurrent very severe
hypoglycemia.4 However, young children who
have glycemic extremes do have subtle cognitive
decrements in areas such as processing speed.
In one cross-sectional study, young adults with
type 1 diabetes in childhood had a slightly lower
mean estimated verbal IQ score than control
participants, and some aspects of academic abil-
ity were related to greater exposure to hypergly-
cemia, not to hypoglycemia or episodes of keto-
acidosis.5

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 The n e w e ng l a n d j o u r na l
Studies from the DirecNet group (Diabetes
Research in Children Network) have shown that
slower growth of the hippocampus, as studied
on structural magnetic resonance imaging, cor-
related with increased exposure to hyperglyce-
mia as well as with greater glycemic variability.
In addition, decreases in total-brain, gray-matter,
and white-matter volumes, as well as small de-
creases in full-scale and verbal IQ scores, corre-
lated with exposure to hyperglycemia.6 These
findings are not entirely surprising given that
hyperglycemia is recognized to be associated
with epigenetic and other modifications that
have long-lasting effects for the brain and other
tissues.7
The trial by Ware et al. offers hope that major
problematic areas of diabetes management in
young children can be resolved with appropriate
technology. These changes include decreases in
the number and severity of hypoglycemic epi-
sodes with sensor-augmentation systems alone,
as well as increases in periods of normoglycemia
with hybrid closed-loop management. Such treat-
ment strategies are likely to lead to decreased
parental stress and sleep deprivation and to less
interference with developmental tasks of child-
hood because of increased potential for autonomy.
One hopes that despite complexity, the use of
hybrid closed-loop devices will persist. In a pre-
vious study of continuous glucose monitoring in
adolescents and adults, there was a decrease in
use over a period of 6 months, which might
erode further with time.8 In addition, large-scale
adoption of hybrid closed-loop devices will de-
pend on the availability and affordability of
these devices within our current variable health
care reimbursement schemas.
Finally, all these devices, even when they lead
to superb glycemic control, do not fully solve the
Targeting HER2-Mutant NSCLC — The Light Is On
Antonio Passaro, M.D., Ph.D., and Solange Peters, M.D., Ph.D.
The identification of human epidermal growth
factor receptor 2 (HER2, also known as ErbB2 or
HER2/neu) generated high expectations for the
treatment of different cancers carrying HER2
aberrations, including non–small-cell lung can-
286 n engl j med 386;3  nejm.org  January 20, 2022
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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
problem of long-term diabetes complications.
They all create peripheral hyperinsulinism, which
in itself may increase the risk of macrovascular
disease.9,10 The prevention of diabetes complica-
tions is likely to require both excellent glycemic
control and an insulin supply that is physiologi-
cally available to the hepatoportal circulation
before release at lower levels into the peripheral
circulation.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Department of Pediatrics, Harvard Medical School,
and the Division of Pediatric Endocrinology, Massachusetts
General Hospital, Boston.
1. Ware J, Allen JM, Boughton CK, et al. Randomized trial of
closed-loop control in very young children with type 1 diabetes.
N Engl J Med 2022;​386:​209-19.
2. Herbert LJ, Monaghan M, Cogen F, Streisand R. The impact
of parents’ sleep quality and hypoglycemia worry on diabetes
self-efficacy. Behav Sleep Med 2015;​13:​308-23.
3. Jaser SS, Foster NC, Nelson BA, et al. Sleep in children with
type 1 diabetes and their parents in the T1D Exchange. Sleep
Med 2017;​39:​108-15.
4. Nevo-Shenker M, Shalitin S. The impact of hypo- and hyper-
glycemia on cognition and brain development in young children
with type 1 diabetes. Horm Res Paediatr 2021;​94:​115-23.
5. Semenkovich K, Patel PP, Pollock AB, et al. Academic abili-
ties and glycaemic control in children and young people with
type 1 diabetes mellitus. Diabet Med 2016;​33:​668-73.
6. Mauras N, Buckingham B, White NH, et al. Impact of type 1
diabetes in the developing brain in children: a longitudinal
study. Diabetes Care 2021;​44:​983-92.
7. Singh R, Chandel S, Dey D, et al. Epigenetic modification
and therapeutic targets of diabetes mellitus. Biosci Rep 2020;​
40(9):​BSR20202160.
8. Laffel LM, Kanapka LG, Beck RW, et al. Effect of continuous
glucose monitoring on glycemic control in adolescents and
young adults with type 1 diabetes: a randomized clinical trial.
JAMA 2020;​323:​2388-96.
9. Gregory JM, Cherrington AD, Moore DJ. The peripheral per-
il: injected insulin induces insulin insensitivity in type 1 diabe-
tes. Diabetes 2020;​69:​837-47.
10. Lee AS, Twigg SM, Flack JR. Metabolic syndrome in type 1
diabetes and its association with diabetes complications. Diabet
Med 2021;​38(2):​e14376.
DOI: 10.1056/NEJMe2119915
Copyright © 2022 Massachusetts Medical Society.
cer (NSCLC).1 Across cancer types, HER2 muta-
tions and amplification and HER2 overexpres-
sion represent biologically distinct alterations
that can harbor driver oncogenic properties.
HER2 amplification is recognized as a frequent