Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

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source. Especially, d-3-hydroxybutyrate (3OHB) is an alterna-
tive energy substrate for the brain during hypoglycemia.
Therefore, we speculate that above two cases are unlikely to
notice hypoglycemia, thanks to the protection of minimal
ketosis, which could prevent the brain energy depletion and
contribute to the unawareness of hypoglycemia.
In contrast, normal MtDM patients under insulin therapy have
experience of hypoglycemia usually. We speculate that,
because the capacity and limits of 3OHB to compensate
cerebral glucose depletion during hypoglycemia is important
for its potential clinical use, non-appropriate insulin supple-
mental treatment might block the ketone production from
liver, which disturbs the exportation of ketone to brain for use
as an energy source, thereby inducing the actually subjective
hypoglycemia.
Conclusion: although only two case reports are not enough to
have a robust conclusion, to confirm our speculation, further
other parameters associated with subjective hypoglycemia
unawareness should be considered with more number of
various MtDM patients without insulin therapy.
PB-17
A case of diabetes with severe peripheral neuropathy who had
negligible level of mitochondrial tRNA Leu (UUR) mutation at
position 3243
Yoshihiko SUZUKI1*, Junichiro IRIE2, Motoaki SANO3,
Toshihide KAWAI 4, Shu MEGURO2, Nobuhiro IKEMURA2. 1HDC
Atlas Clinic, 2Department of Internal Medicine, Keio University School
of Medicine, 3Department of Cardiology, Keio University School of
Medicine, 4Department of Internal Medicine, Saiseikai Central
Hospital, Tokyo, Japan
We previously reported that the mitochondrial tRNA Leu(UUR)
mutation at position 3243mutation was found with higher
frequency (9.8%) in diabetics with symptomatic neuropathy
than in those without it (1.1%). To evaluate it, the ratio of
heteroplasmy was screened among 195 type 2 diabetes
patients by using the new technique. In result, mean ± SD of
Log (heteroplasmy ratio %) was – 1.364 ± 0.43. A diabetic patient
whose heteroplasmy level was the lowest, almost negligible
level (0.001%, − 3.0 by Logarithm transormation).
The case was 59 y/o man with diabetes onset 41 y/o. Since
age 18, he has continued to drink alcohol (half bottle of
whisky) every day. After nine years of diabetes ’ diagnosis, he
developed bilateral leg pain and foot numbness. He then
had progressive weakness, wasting and sensory loss in both
legs, and became unable to walk, being confined to a wheel
chair.
At age 51, physical examination showed distal upper limb
weakness, mild to moderate proximal and moderate to severe
distal lower limb weakness. The legs were markedly wasted
and weak diffusely, more severely distally. Pinprick sensation
and vibration sensation were impaired below the low thigh.
Tendon reflexes were absent in both arms and legs. Hands ’
muscles were markedly wasting and weak. Nerve conduction
motor studies showed combinations of conduction slowing
and block, prolongation of distal latencies. Motor nerve
conduction velocity of median nerve was 8.09 m/sec and of
tibial nerve was not evoked. On sural nerve biopsy, marked
loss of myelinated fibers was seen on light microscopy.
Proliferation of Schwann cells and degeneration like Onion
Bulbs were found in electron-microscopy. Foot ulcer and
gangrane often appeared. At age 62, giant lipoma appeared at
neck (30 × 23 mm), a manifestation found sometimes in
patients with mtDNA deletions or mutations.
This case suggests that heteroplasmy level of mtDNA
mutation is not always related to the severity of diabetes
polyneuropathy. Interestingly, he was a very heavy drinker.
Acetaldehyde is a highly reactive and mutagenic substance,
and mtDNA is 10 –16 times more prone to oxidative damage
than nuclear DNA. A high incidence of 4977-bp mtDNA
deletion among alcoholic patients has been reported. Hence,
it is plausible that he have a certain factor, such as mtDNA
deletion, which prohibits the accumulation of 3243 mtDNA
mutation. And, the certain factor impairs the mitochondrial
function of nerves or Schwann cells, thereby developing severe
peripheral neuropathy.
PB-18
A case of mitochondrial diabetes associated with 3243 bp
tRNA Leu (UUR) mutation, who suffered from the rapid
appearance of “mitochondriopathies”
Yoshihiko SUZUKI1*, Motoaki SANO2, Junichihro IRIE3,
Toshihide KAWAI4, Shu MEGURO3, Nobuhiro IKEMURA2. 1HDC
Atlas Clinic, 2Department of Cardiology, Keio University School of
Medicine,3Department of Internal Medicine, Keio University School of
Medicine, 4Department of Internal Medicine, Saiseikai Central
Hospital, Tokyo, Japan
His diabetes was diagnosed at age 38. Although he was found
to have mitochondrial diabetes associated with 3243 bp tRNA
(Leu (UUR)) mutation, he had few complications despite the
long duration of the disease. The heteroplasmy ratio was
10% in blood and 59% in muscle. At age 54 y/o., we reported
that, despite long duration of glucose intolerance and high
heteroplasmy rate in blood and muscle, he had been free from
diabetic complications. Serum lactate was normal. There were
no hallmarks of MELAS (mitochondrial encephalopathy,
myopathy, lactic acidosis and stroke-like episodes). In this
case, respiratory chain enzyme activities of mitochondria
in biceps brachii muscle were over three times higher than
the normal range. While ragged red fibers were found,
focal cytochrome c oxidase deficiency was absent. We then
speculated that he may have a compensative mechanism by
up-regulating respiratory chain system activity, thereby delay-
ing the occurrence of various complications. The details were
reported previously in literature (Diabetes Res Clin Pract.
69:309–10, 2005).
However, after around 60 y/o, he noticed to suffer severe
hearing loss. He gradually developed heart failure. At age
65 y/o, he suffered from severe hepatic and renal dysfunction.
The acute renal-hepatic failure appeared abruptly, the rapid-
ness of which was as like the stroke-like episode in MELAS.
After several times of hospitalization, he died by unexplained
progressive multisystem disorders.
Discussion: Mitochondriopathies (MCPs) are either due to
sporadic or inherited mutations in nuclear or mitochondrial
DNA located genes (primary MCPs), or due to exogenous
factors (secondary MCPs). MCPs usually show a chronic,
slowly progressive course and present with multiorgan
involvement with varying onset between birth and late
adulthood. Apart from well-recognized syndromes, MCP
should be considered in any patient with unexplained
progressive multisystem disorder. Although there is actually
no specific therapy and cure for MCP, many secondary
problems require specific treatment. This case suggests that
the mitochondrial diabetes does not always progress step by
step. Even when the associated phenomena were seemingly
light in the beginning, the various systematic disorders can
appear abruptly at any time.
Conclusion: Diabetologists should be aware of the high risk of
progression from simple mild stage of mitochondrial diabetes
into the serious stage of MCP. Because this mitochondrial
diabetes case complicated fewmanifestation during long time,
rapid worsening at the end stage was a big surprise.
We hope the increasing understanding of MCPs may further
facilitate the diagnostic approach and open perspectives to
future, possibly causative therapies.
Poster Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S65–S211 S81