Researchers have defined key
characteristics that enable some
obese individuals to remain free from
type 2 diabetes and other metabolic
disorders.
“It has been known for some time that
some obese individuals seem to stay meta-
bolically healthy,” said A/Prof Jerry Green-
field of Sydney’s St Vincent’s Hospital and
the Garvan Institute of Medical Research.
“However, there has been no consensus
about how to define ‘metabolically healthy’
obesity – so it has not been easy to under-
stand what underpins these individuals’
apparent protection from disease.”
Greenfield’s research, published in theJournal
of Clinical Endocrinology and Metabolism
(tinyurl.com/onm9cvw), examined “whether or not
obese individuals also have... a resistance to the
hormone insulin, which regulates the level of sugar in the
blood after a meal. We consider that obese individuals
who are not insulin-resistant, but instead remain sensi-
tive to insulin, can be thought of as being metaboli-
cally healthy.”
In people with insulin resistance, the body’s tissues
become progressively less responsive to insulin.
Muscle cells become sluggish at removing glucose
from the bloodstream, and liver cells are less able
to halt their release of glucose into the blood.
As a result, the insulin-production machinery
is overworked and ultimately becomes
exhausted, leading to type 2 diabetes.Greenfield’s team measured the response of insulin
to blood glucose levels in 64 individuals. “We were
intrigued to find that some participants were sensitive
to insulin at muscle but were resistant at liver – whilst
others had the opposite profile,” said study co-author Dr
Dorit Samocha-Bonet. “So, we now know it’s not
enough to label an individual as ‘insulin-resistant’ or
‘insulin-sensitive’. Instead, they can be insulin-resistant
at liver, at muscle, at both sites, or at neither.”
The researchers next tested how each participant’s
insulin response profile related to other key readouts
of metabolic health. “What we found,” said Samocha-
Bonet, “is that obese individuals who are sensitive to
insulin in muscle only or liver only are metabolically
healthier in many respects than the group that is insulin-
resistant at both sites.
“Not only do they have lower blood pressure, but
they also have less deep abdominal fat and less fat within
the liver. In fact, judging by these criteria, the metabolic
health of these people is similar to that of individuals who
are insulin-sensitive at both muscle and liver.”
Greenfield added that “being insulin-sensitive at
either muscle or liver conferred as much metabolic
protection as being insulin-sensitive at both sites... The
findings suggest that there are different drivers of insulin
action at liver and muscle that may be determined by
specific genetic pathways.
“The demonstration that insulin sensitivity in the
liver and muscle may occur independently in humans
potentially paves the way for earlier detection and indi-
vidualised treatment of people at risk of developing
metabolic disease.”The Paradox of Healthy Obesity
6 | JAN/FEB 2016A new technique has demonstrated how genetically repaired stem cells
can be derived from patient skin cells in as little as 2 weeks, compared
with conventional multi-step approaches that take more than 3 months.
The key to the advance, published inStem Cell Reports
(tinyurl.com/plhzruf), is to combine two essential steps when preparing
cells for potential therapy. First, adult cells must be reprogrammed to
an embryonic cell-like state in order to be differentiated into the cells
of therapeutic interest. The cells then need to undergo a sophisticated
gene-editing process to correct the disease-causing mutation.
Dr Sara Howden of the Murdoch Childrens Research Institute
successfully combined these two steps in skin cells derived from an
adult patient with retinal degeneration as well as an infant patient with
severe immunodeficiency. “The method developed in our study could
potentially advance transplant medicine by making gene-corrected
cells available to patients in a much more timely manner, and at a lower
cost,” Howden says.
Howden says the faster process, using Cas9/CRISPR technology,
also means the cell culture period is greatly reduced, potentially
minimising the risks associated with culturing cells outside of the
human body, such as genome instability or other epigenetic changes.Induced pluripotent cells (iPS cells) hold great promise for medical
research because they can essentially be derived from any individual
and are capable of becoming any of the 220 types of cells in the human
body. The ability to efficiently and precisely modify the DNA in these
cells offers enormous potential for the development of personalised
stem cell therapies that benefit people with many different types of
genetic disorders.
Howden says one potential next step is to adapt the protocol to work
with blood samples. Not only is a blood sample less invasive than a skin
biopsy, it also could further reduce the time to obtain genetically
repaired iPS cells. Skin cells need to be expanded for several weeks
before initiating reprogramming.
Howden says this “fast-tracked process” could be most influential in
cases where urgent medical intervention is needed. One example is
severe combined immunodeficiency, where children typically die within
the first few years of life.
However, Howden says that scientists still need to derive a long-term
source of blood cells from pluripotent stem cells before such
treatments are viable.Gene Editing of Stem Cells Hastened
BROWSE
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