Yoshihiko Suzuki

No. B00305

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 KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA2

1HDC Atlas Clinic, Japan; 2Department of Internal Medicine, Keio University School of Medicine, Japan; 3Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; 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 whiskey) 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 (30mmx23mm), 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 Thank nuclear DNA. A high incidence of 4977-bp mtDNA deletion among alcoholic patients has been reported. Thus, 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.

No. B00306

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, Japan; 2 Department of Cardiology, Keio University School of Medicine, Japan; 3 Department of Internal Medicine, Keio University School of Medicine, Japan; 4 Department 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 delaying the occurrence of various complications. The details were r eported 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 rapidness 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 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 mitochondri al diabetes case complicated few manifestation 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.

No. B00292

Aldehyde Dehydrogenase 2 genotype and mitochondrial DNA abnormality in Asians; a new insight to understand the EMPA-REG Outcome Study

Yoshihiko SUZUKI1 *, Takashi NOMIYAMA2, Motoaki SANO3, Shigeo OHTA4, Junichiro IRIE5, Toshihide KAWAI6, Shu MEGURO5, Nobuhiro IKEMURA3

1HDC Atlas Clinic, Japan; 2 Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Japan; 3 Department of Cardiology, Keio University School of Medicine, Japan; 4 Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Japan; 5Department of Internal Medicine, Keio University School of Medicine, Japan; 6Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

We first described the association between aldehyde dehydrogenase 2 (ALDH2) genotype and mitochondrial DNA (mtDNA) abnormality in 1996 (Diabetes Care). We found that the patients with mitochondrial diabetes associated with tRNA (Leu) mutation at position 3243 (MD3243) had high percentage of chlorpropamide-alcohol flush (CPAF, Diabetes Care). Also, high percentage of them had inactive ALDH2 genotype. In contrast, MELAS patients had high percentage of active ALDH2 (Diabetologia, 1997). Then, we proposed that 3243 mtDNA (mtDNA3243) ) Abnormality in MD3243 might be acquired by some epigenetic factors like hyperglycemia and / or ALDH2 inactivity, while the 3243 mtDNA abnormality in MELAS was inherited strongly from mother, thereby letting the disease onset earlier in childhood.

Our speculation in 1990s was valuable because there has been no hypothesis to explain the different clinical pictures between MD3243 and MELAS, while their pathogenetic mtDNA mutation is the same. In 2002 (Diabetologia), Nomiyama et al. Found mtDNA3243 somatic mutation accumulates in blood accordingly with aging, and under hyperglycemia. This article supported our previous speculation in that MD3243 patients must have more acquired factor with aging, compared with MELAS.

In addition, Nomiyama et al. had interesting data as that “heteroplasmy level of mtDNA3243 is highly found in inactive ALDH2 genotype diabetes group compared with in active ALDH2 genotype diabetes group (Nomiyama and Ohta, personal communication.unpublished). This evidence strongly supports our previous first finding, namely, close association between inactive ALDH2 genotype and mtDNA3243 accumulation.

EMPA-REG Outcome study suggests the Asians are likely to have less CV-death and heart failure. In 2009 (Circ Res), we succeeded to show the evidence that ALDH2 transgenic mice had tolerance to oxidative stress in heart. Mitochondrial aldehyde stress in heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia / reperfusion. Interestingly, Asians, Chinese and Japanese, have high percentage of inactive ALDH2 genotype. Therefore, Asians are theoretically likely to have more strong tolerance to oxidative stress in heart, which might be caused by persistent negative energy balance by SGLT2 inhibitor.

We have reported that increased grip strength after SGLT2 inhibitor (Journal of Diabetes, 2016), suggesting the improvement of mitochondrial function and catabolic–anabolic balance set point change in muscle. Because of mitochondrial handicap, SGLT2 inhibitor could have stronger effect on inactive ALDH2 genotype patients of diabetes theoretically. Thus, the moderate adaptation by ALDH2 genotype could explain why Asians have superior results of cardiovascular diseases in EMPA-REG Outcome Study.

No. A00173

Clinical Pictures Associated with Borderline Heteroplasmy Rate of 3243 Mitochondrial tRNALeu (UUR) mutation in Type 2 Diabetes

Yoshihiko SUZUKI1 *, Junichiro IRIE2, Shigeo OHTA3, Motoaki SANO4, Toshihide KAWAI5, Shu MEGURO2, Nobuhiro IKEMURA4

1HDC Atlas Clinic, Japan; 2 Department of Internal Medicine, Keio University School of Medicine, Japan; 3 Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Japan; 4 Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; 5 Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

Approximately 0.5-2.8% of Japanese diabetic patients population is estimated to have mitochondrial DNA (mtDNA) mutation at position 3243 in the blood. However, the cut-off limitation for detecting the mutation in blood differs depending upon the judgments of researchers. In general A new technology using real-time PCR with a TaqMan Probe was introduced, which can quantify as little as 0.001% of the 3243 mtDNA By using this method, we examined the association of low borderline heteroplasmic rate with clinical pictures in cross sectional study of type 2 diabetes.

189 patients with type 2 diabetic were subjected. The profile of the 189 subjects was 142 males and 47 females. Their ages were 59.4 ± 10.2 years and diabetes duration was 12.1 ± 7.9 years. BMI 22.9 ± 4.0 and HbA1c 8.2 ± 1.3% (mean) ± SD)

In result, the heteroplasmy rates were about six times higher than the healthy controls (aged 20 – 60 years, n = 186). In all the type 2 diabetes subjects, the mathematical mean and SD of heteroplasmy rate was 0.041 ± 0.018%. When logarithmically converted, the data were seemingly distributed normally. By the data, the mean was –1.408, and SD was 0.142.'Mean + 2SD' was -1.124, which corresponds to 0.075% of the heteroplasmy rate. Therefore, we regarded the patients with over 0.075% heteroplasmic rate as having a high level among type 2 diabetes patients.

As the result, five patients were positioned over 0.075%. Interestingly, all the five had clinical pictures associated with mitochondrial dysfunction, such as juvenile cataract (Subject-1: 0.090% of heteroplasmy rate), ophthalmoplegia and lipoma (Subject-2: 0.102) %) and high lactate levels in the blood (Subject-3: 0.172% and Subject-4: 0.115%). Subject 5 (heteroplasmy rate: 0.127%) had a maternal inheritance of diabetes and cerebellar atrophy. The details of Subjects 1 and 2 have been described in Diabetologia 2004 and Diab.Res.Clin, Prac. 2004 63 (3): 225-9

Thus, when we define the upper-borderline level of heteroplasmy rate to be 0.075% among type 2 diabetes patients, five patients were found to have a high heteroplasmy rate. Interestingly, the five patients had one or two mitochondria-associated characteristics. They did not have hearing loss.

Therefore, we propose that clinicians should not overlook the important features of mitochondrial diabetes, even when the result of examination for 3243 mtDNA mutation is negative by ordinary PCR method and even when hearing loss is absent.

No. B00297

Gain of muscle strength in mitochondrial diabetes treated with SGLT2 inhibitors

Yoshihiko SUZUKI1 *, Junichiro IRIE2, Motoaki SANO3, Toshihide KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA3

1HDC Atlas Cliniv, Japan; 2 Department of Internal Medicine, Keio University School of Medicine, Japan; 3 Department of Cardiology, Keio University School of Medicine, Japan; 4 Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

In 1996, we reported the first identified case of mitochondrial diabetes caused by a T-to-C transition at position 3271. The proband was a 58-year-old male. Heteroplasmy of the 3271 mutation, strongly maternal inheritance of diabetes and other evidences associated with mitochondrial dysfunction suggested this 3271 mutation to be pathogenic.

During a 20 year follow-up, in 2014, he received SGLT2 inhibitor (Sodium glucose transporter 2 inhibitor: SGLT2i), first ipragliflozin 50mg / day for 6 weeks, subsequently luseogliflozin 2.5mg / day for 4 weeks, dapagliflozin 10mg / day for 4 The four different products of SGLT2i seemingly had similar effect on weight loss and the decrease of HbA1c. Then, he lost weight and achieved improvement of glycemic. Control with HbA1c from 6.5% to 6.3%. Concurrently, the dose of glimepiride was adjusted to decrease from 6 mg to 1 mg daily. Body weight decreased from 64.7 kg to 58.7 kg within three months (height 174 cm. BMI: from 21.4 to 19.4) . These phenomena suggested that he relieved insulin resistance.

The patients with sarcopenia have been believed to suffer from loss of muscle power and frailty. Therefore, it is noteworthy that, in this patient, his grip strength (GS) and back strength (BS) got stronger despite robust weight loss. Before SGLT2i treatment , GS was 37.6 kg in right hand and 30.5 kg in left hand, respectively. BS was 82 kg. After three months of SGLT2i, GS of right hand grew stronger to 39.4 kg (+ 1.8 kg) and left hand to 32.2 kg (+1.7) kg). BS also grew stronger to 105 kg (+ 23 kg).

Thus the case provides a novel information in diabetes treatment and the role of mitochondria. Caloric restriction that reduces oxidative damage improves mitochondrial function. In our previous study, defective insulin secretion as well as insulin resistance is a salient feature of mitochondria diabetes (1). Reduced glucose flux in muscles with SGLT2i treatment possibly mitigates insulin resistance via decreased oxidative stress. Insulin resistance is one of risk factors of sarcopenia. Thus, the recovery of muscle strength after SGLT2i treatment in our patient is attributed to regained energy from restored mitochondria.

Conclusion: SGLT2i upon the patient of mitochondrial diabetes could induce remarkable weight loss within short time and decrease of insulin resistance, which seemingly compensated genetic deficit of mitochondrial DNA. This supports our previous published study (2).

Ref: 1) Metabolism 46: 1019-23, 1997 and 2) Journal of Diabetes, 2016, April

No. K00159

Increased Grip Strength with SGLT2 inhibitors: Sub-Analysis by BMI, A new insight to EMPA-REG OUTCOME STUDY

Yoshihiko SUZUKI1 *, Motoaki SANO2, Shu MEGURO3, Toshihide KAWAI4, Junichiro IRIE3, Nobuhiro IKEMURA2

1HDC Atlas Clinic, Japan; 2Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; 3Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 4Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

Maximal hand grip strength measurement could be a method for cardiovascular risk stratification among patients with type 2 diabetes.

Materials and methods: We examined the change in maximal hand grip strength before and after sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment. The study included 92 men and 20 women with type 2 diabetes in Japanese. The patients were treated with ipragliflozin 50 mg , luseogliflozin 2.5 mg, or dapagliflozin 5 mg or 10 mg daily for at least 4 weeks.

The results showed that both the men and women had increased grip strength in both hands (P <0.01, paired T test). In the sub-analysis, in men, grip strength (GS) of patients whose BMI over 25 (n = 49) ) Was 32.1 ± 1.1 kg (Mean ± SEM) in right hand and 30.5 ± 1.0 kg in left hand at baseline. After SGLT2i, GS of right hand increased to 34.3 ± 1.1 kg (p <0.01), and GS of left hand increased to 32.0 ± 1.1kg (p <0.01). GS of patients whose BMI below 25 (n = 43) was 28.6 ± 1.1kg in right hand and 28.1 ± 1.2kg in left hand at baseline. After SGLT2i, GS of right hand increased to 29.5 + 1.2 kg (ns), but GS of left hand was almost the same as 28.2 ± 1.1 kg (ns).

In women, GS of patients whose BMI over 25 (n = 11) was 18.5 ± 1.2 kg in right hand and 17.2 ± 1.0 kg in left hand at baseline. After SGLT2i, GS of right hand increased to 20.6 ± 1.6 kg (ns) ), And GS of left hand increased to 18.3 ± 1.2 kg (ns). GS of patients whose BMI below 25 (n = 9) was 17.5 ± 1.2 kg in right hand and 17.2 ± 0.9 kg in left hand at baseline. After SGLT2i , GS of right hand increased to 20.0 ± 1.5 kg (ns), and GS of left hand increased to 18.3 ± 1.4 kg (ns). Thus, in women, because the number of subjects was small, the difference was non-significant statistically ..

Conclusion: The results suggest that, in Japanese, obese men over BMI 25 are likely to have an increased GS than lean men. But, in the EMPA-REG OUTCOME Study, obese subjects whose BMI was over 35 were more unlikely to have the benefit This difference will give a new insight to understand the difference of races. The putative mechanisms responsible was already described in reference 1.

Ref: 1) Sano M, Meguro S, Kawai T, Suzuki Y. Increased Grip Strength with SGLT2 inhibitors. Journal of Diabetes. April, 2016.

No. B00300

Mitochondrial Diabetes and Subjective Hypoglycemia Unawareness

Yoshihiko SUZUKI1 *, Junichiro IRIE2, Motoaki SANO3, Toshihide KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA3

1HDC Atlas Clinic, Japan; 2Department of Internal Medicine, Keio University School of Medicine, Japan; 3Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; 4Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

Mitochondrial diabetes (MtDM) usually lacks endocrinal insulin secretion from pancreas. Therefore, most patients are on insulin injection therapy. Thus, among MtDM, rare patients are free of insulin injection. We experienced two MtDM patients without insulin therapy, both of whom had never noticed subjective hypoglycemia.

Case 1: 26 y / o. Women (at 2006). She was diagnosed as having diabetes at age 12 y / o. During 14 years observation, she never noticed hypoglycemia under sulfonylurea treatment. As examination, we injected rapid insulin to induce absolute hypoglycemia. In result, she never noticed symptoms even when the plasma glucose level became lower than 30 mg / dl. She was afterward diagnosed to have mitochondrial DNA (mitDNA) mutation at position 3243. Her detailed profile are described already (Diabetologia 47: 592) -3, 2004)

Case 2: 59 y / o. Men (at 2018). He was diagnosed as having MtDM diabetes at age 33 y / o. During 26 years observation, he never noticed hypoglycemia. Though he was under glimepiride 6 mg daily treatment, he had never experience of hypoglycemia. His detailed profile are already described (Diabetes Care 19: 1304-1305, 1996)

Discussion; Some cases of Kearns-Sayre syndrome (KSS), resulting from a mitochondrial DNA deletion, associated with diabetes that presented with hyperosmolar hyperglycemia with minimal ketosis were reported. Some cases of MtDM and MELAS were reported with ketoacidosis in literature.

Ketone bodies are produced in liver, mainly from the oxidation of fatty acids, and exported to peripheral tissues for use as an energy source. They are particularly important for the brain, which has no other substantial non-glucose-derived energy source. Especially, d-3-hydroxybutyrate (3OHB) is an alternative 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 supplemental treatment might block the ketone production from liver, which disturbs the exportation of glucose 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.

No. B00167

Mitochondrial Diabetes associated with tRNALeu (UUR) Mutation at Position 3271 and Two Times of GAD antibody Negative Conversion

Yoshihiko SUZUKI1 *, Junichiro IRIE2, Motoaki SANO3, Toshihide KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA3

1HDC Atlas Clinic, Japan; 2Department of Internal Medicine, Keio University School of Medicine, Japan; 3Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; 4Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

The proband has been followed up as a patient of mitchondrial diabetes associated with tRNA Leu (UUR) mutation at position 3271 for over 20 years. We first reported this case in 1996 (ref.1). We report here that this case has had phenomena of GAD antibody positive-negative conversion two times in his life.

1. First episode:

When he was 54 y / o, his GAD antibody became positive, glycemic control got worse. It was transient phenomena, then, GAD antibody became negative and glycemic control improved. The etiology was unknown. To our knowledge, only seven cases were reported as mitochondrial diabetes having GAD antibody. However, among them, this case is the first as having negatively-converted GAD with insulin independent state. (Ref.3 and 4)

When we started sitaglipitin, DPP4-inhibitor, 50 mg / day and observed 9 months, HbA1c improved remarkably and oral glucose tolerance test showed increase of early phase insulin secretion and suppression of postprandial hyperglycemia.

2. Second episode:

When he was 59 y / o, his GAD antibody became positive after the start of 6 months of SGLT2 inhibitor treatment. In addition, Serum amylase was elevated together with rise of CA19-9, elastase-I, lipase, trysin and IgG4. The reassessment of the radiological diagnosis has not identified pancreatic mass as a manifestation of focal pancreatitis. Because of high IgG4, he was tentatively diagnosed as having had autoimmune pancreatitis (AIP).

3. Discrepancy: Interestingly, during the first episode, glycemic control got abruptly worse according to the elevation of GAD antibody titer. GAD antibody titer and HbA1c elevation had seemingly close relationship. In contrast, during the second episode, glycemic control was stable, seemingly having no relationship between GAD antibody titer and HbA1c level. While the difference of two times episodes was apparent, true aetiology was unknown.

In conclusion, this is the first case report of mitochondrial diabetes, in which GAD antibodies were detected once positive and soon after became negative two times in life. The aetiology and pathophysiology are not fully elucidated.

References

1. Suzuki Y et al. Clinical picture of a case of diabetes with mitochondrial tRNA mutation at position 3271. Diabetes Care 19: 1304-1305, 1996

2. Suzuki Y et al. Diabetes Care 25: 407-408, 2002

3. Suzuki Y et al. GAD antibody in mitochondrial diabetes associated with tRNA Leu (UUR) mutation at position 3271. Diabetes Care 25: 1097-1098, 2002

4. Suzuki Y, Shimada A, Sano M, Ohta S. Mitochondrial Diabetes Associated with a tRNA Leu (UUR) Mutation at Position 3271: Over a 15-year Follow-up Observation, J.Japan Diab.Soc. 56 (3) : 173-176, 2013 (in Japanese)

No. B00322

Two times elevation of CA19-9 in Mitochondrial diabetes associated with tRNA (Leu) at position 3271

Yoshihiko SUZUKI1 *, Junichiro IRIE2, Motoaki SANO3, Toshihide KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA3

1HDC Atlas Clinic, Japan; 2Department of Internal Medicine, Keio University School of Medicine, Japan; 3Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; 4Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan;

We first reported a case of mitochondrial diabetes associated with a tRNA Leu (UUR) mutation (Mt-DM) at position 3271 (1). So far, the case has shown several important findings in practice (2,3). He has a strong inheritance of type 2 diabetes but no hearing loss. His mother and ten relatives in maternal side had diabetes without hearing loss, suggesting the clear different expression from Mt-DM at position 3243 (hearing loss is often complicated).

In 2012, at age 57-y / o, within weeks of stopping smoking, CA19-9 was elevated up to 221 U / ml, five times higher than the normal value (normal: less than 37.0 U / ml). He noticed dull back pain. Some change in the lung's tissue level associated with emphysema was diagnosed as a plausible cause (FEV: 73.2% on spirometry and on CT). But, latent pancreatitis are also plausible, because he had a back pain, a sign of pancreatitis ..

We started taurine treatment (3.06g / day), which was conducted in clinical trial for mitochondrial diseases. Interestingly, after taurine treatment, back pain disappeared. And remarkable improvement of emphysema was noted functionally (FEV: improved to 83.4%). Accordingly, CA19-9 returned to be normal.

We previously reported that patients of Mt-DM at position 3243 are likely to have posttreatment painful neuropathy. Therefore, we speculate that Mt-DM is likely to cause ischaemia / reperfution damage, triggered by rapid environmental change as like rapid glycemic control or stop- smoking.

Recently, at age 59 y / o. (At 2016), he suffered from autoimmune pancreatitis with elevation of CA19-9 (55.3u / ml). After six months of sodium glucose cotransporter 2 inhibitor (SGLT2i) treatment, CA19-9 was elevated together with elevation of p-amylase, elastase I, and IgG4. Even after stopping SGLT2i treatment, CA19-9 was still high.

Thus, two times elevation of CA19-9 suggests that Mt-DM patients are likely to suffer from lung or pancreatic damage after the rapid change of environmental or habitual conditions. However, question whether these phenomena are reproducible in other Mt-DM patients remains to be a problem. Additionally, hereditary pancreatitis (HP) is a rare, heterogeneous familial disease. HP usually appears with an acute, a recurrent acute, and a chronic phase. Therefore, two times elevation of CA19-9 could be a reflection of a recurrent acute pancreatitis. The possibility of mitochondrial DNA abnormality as a cause of HP is the first finding in literature.

References

1. Suzuki Y et al. Diabetes Care 19: 1304-1305, 1996

2. Suzuki Y et al. Diabetes Care 25: 407-408, 2002

3. Suzuki Y et al. Diabetes Care 25: 1097-1098, 2002