For decades, aged population has been increasing in developed countries and geriatric medicine or anti-aging medicine has attracted attention [1]. Among them, medical problems of atherosclerotic cardiovascular disease (ASCVD) have been in focus including hypertension, type 2 diabetes (T2D), dyslipidemia, cerebral vascular accident (CVA), coronary heart disease (CHD), and peripheral artery disease (PAD) [2]. Furthermore, clinically crucial problems include dementia and mild cognitive impairment (MCI) for elderly people with various diseases [3]. From mentioned above, recent topics include the mutual relationship between T2D and cognitive dysfunction, where the background of them seems to have common pathophysiology [4].

In contrast, recent topics are in discussion that T2D would be involved in MCI or dementia associated with impaired zinc function. For human body, zinc has crucial role for tissues, fluids and component of several enzymes [5]. From pathophysiological point of view, overlapping metabolic dysfunction would be present for the combination of T2D and Alzheimer's disease (AD) [6]. If zinc homeostasis would be disturbed in human brain, memory and synaptic deficits will be found. Various perspectives are argued for the association among AD, zinc function, and CMI/dementia [7].

Authors’ medical group has continued clinical practice for various cases with elderly, T2D, ASCVD, metabolic syndrome (MetS) and so on [8]. As adequate nutritional treatment, low carbohydrate diet (LCD) was initiated in Japan by our group, in which petite, standard and super LCD were proposed as practical use [9].We have developed Japan LCD promotion association (JLCDPA) and planned to inform LCD usefulness broadly in various opportunities [10]. Recently, we experienced a meaningful elderly female patient with some medical problems. Her general progress and its perspectives are described in current article.

History and Physicals

Formerly, she was diagnosed with diabetes in her early 60s. After that, she was provided by oral hypoglycemic agents (OHAs). Her diabetic control was rather stable with HbA1c around 6.5-7.0%. At the age of 80, her physical activity and also communication situation have been rather exacerbated. Then, she often ate various snacks at home, and then glucose control became aggravation. She was introduced to our diabetic clinic in 2021. Physical examination at first contact showed in the following: consciousness alert, conversation and speech are normal in the room of the out-clinic. Vitals are within normal limits, with normal SpO₂. There were no remarkable abnormalities in lung, heart, abdomen and neurological exams.

Several Examinations

Biochemistry data was summarized in Table 1. She showed hyperglycemia and elevated HbA1c as 8.8%. Other biochemical results were unremarkable for liver function, renal, lipids and complete blood count (CBC). Among them, ALP (IFCC) value that is related to liver, bone and zinc metabolism showed low level, where normal range was 38-113 U/L. Chest -ray was unremarkable, and Electrocardiogram (ECG) showed pulse 80/min, ordinary sinus rhythm (OSR), and no remarkable ST-T changes. Urinalysis showed the results as urobilinogen (+/-), protein (-), glucose (+++), occult blood (+/-)), pH 6.0, ketone bodies (-), and bilirubin (-).

Table 1: Progress of Biochemistry Data.

She underwent the examination of pulse wave velocity (PWV) (Figure 1). As a result, Cardio-Ankle Vascular Index (CAVI) revealed 9.8/9.8 (right/left), which were more than standard range as 7.9 +/- 0.7. However, the data were situated as almost borderline when the applicant is 80s for age. The value of ankle-brachial index (ABI) was 0.98/0.94 (right/left), as normal range of 0.91-1.40. Then, the results showed adequate degree for 80s for age.

Figure 1: Clinical Progress Concerning HbA1c and Medical Treatment.

Clinical Progress and Medical Problems

She has been treated in our hospital, and her general medial situation has been evaluated in detail. By the OHA of imeglimin (Twymeeg) 2000mg per day, her glucose variability has been improved associated with stable HbA1c around 6.5-6.9%. She has some clinical problems which were almost controlled in satisfactory condition. Furthermore, she has developed some symptoms of mild cognitive impairment (MCI) to dementia and then she has recently visited neurosurgery department.

Her medical problems can be summarized for 2022-2025 as follows. They are #1 T2D: this is the main problem for long. Her nutritional treatment was not so satisfactory because of MCI development (#2). #2: MCI-dementia: she has developed several signs and symptoms of MCI-dementia for a few years, associated with taking memantine 5 mg/day. Her daily condition has been almost stable. #3: Dyslipidemia: She has shown dyslipidemia and fatty liver, and then she was formerly provided anti-hyperlipidemia. #4 Hypertension: she has given anti-hypertensive agent (AHA), and then her blood pressure has been controlled well. #5 Cerebral vascular accident (CVA) may be present, associated with possible lacunar infarct. Consequently, she is provided cilostazol (Pletal) so far. #6: Zinc deficiency: She developed T2D and MCI, in which her blood concentration of Zinc was studied. As a result, serum value of Zinc was 52 µg/dL, where standard normal range was 80-130 µg/dL. Consequently, she was given zinc acetate hydrate (Novelzin) in the neurosurgery department.

For recent situation, she has been stable physically and psychologically with several oral medicine. They include metformin, alogliptin and imeglimin for T2D, amlodipine for hypertension, and memantine for MCI and dementia, and Novelzin for Zn deficiency. Although she has MCI / dementia, she has regular happy lives with her families from family medicine point of view.

Ethical Standards

This study complied with the guideline for Helsinki Declaration [11]. In addition, the comment is along with the standard protection for personal information. The principle is based on the ethical rules in the clinical practice and research on human subjects. Certain guidelines are from Ministry of Health, Labour and Welfare, and Ministry of Education, Culture, Sports, Science Technology in Japan. The authors and co-researchers established ethical committee in Sakamoto Hospital. It included the director, doctors, registered nurse, pharmacist and legal personnel. All members have discussed enough for current case, agreed research protocol and obtained informed consent.

This case was characteristic for her several medical problems. They are summarized for i) improvement of T2D by the combination of OHAs, ii) adequate control of MCI/dementia by medicine, and iii) administration of Novelzin for Zn deficiency. Among them, related perspectives are described in the following.

First, she showed clinical improvement for glucose variability by the combination of OHAs, including metformin 500mg, alogliptin 25mg, and imeglimin 2000mg per day. Imeglimin (Twymeeg) was recently developed, and it has been known to have both effects of stimulating insulin secretion from the pancreas and lowering insulin resistance [12,13]. It can be used safely with clinical efficacy for aged T2D cases [14]. Imeglimin has been also known for add-on therapy with other OHAs. Large clinical studies were conducted internationally for various usage of imeglimin. They are Trials of IMeglimin for Efficacy and Safety (TIMES) 1,2 and 3. Clinical efficacy were investigated for monotherapy and combined therapy in TIMES 2 [15]. The degree of HbA1c decrease was compared, where 0.46% in monotherapy, 0.92% of DPP4-i, 0.67% for biguanides, 0.85% for alfa-GI, and 0.57% for SGLT2i. Furthermore, impressive data were revealed in TIMES 3 [16], in which GLP-1RA of subcutaneous injection showed combination of efficacy as only 0.12%. Certain route may exist for this phenomena, other than mitochondrial pathway, in the light of pharmaco-physiological aspect.

Second, she underwent MMSE (Mini-Mental State Examination) and also Japanese HDS-R (Hasegawa's Dementia Scale-Revised) [17]. She was satisfactory controlled by the memantine and tiapride for daily stable life style. Concerning the relationship between Alzheimer disease (AZ) and T2D, the odds ratio (OR) of risk would be 3.48, where T2D case tends to show neuropsychiatric early AZ symptoms more than 3-times [18]. Correlation between Diabetes and AZ has attracted attention [19]. AZ has been recently recognized as type 3 diabetes mellitus (T3DM), since impaired glucose metabolism is almost related to decreased insulin signaling and insulin resistance [20].

Third, current case showed zinc deficiency and took Novelzin 25mg/day for years. AZ tends to show lower value of zinc that is called as syndrome of Alzheimer's-plus with low zinc (APLZ) [21]. T2D and AD are both amyloidogenic, chronic aged disease, and their onset would be linked by glucose hypometabolism, altered insulin signaling and dyslipidemia [19]. AD is characterized for its deposition of β-amyloid (Aβ) and tau protein, which leads to formation of neurofibrillary tangles (NFTs) [22]. For the association of metal ions, Zn²+, Cu²+, and Fe³+ have been recognized for increasing Aβ aggregation rate and amyloid plaques with higher concentrations [23].

Certain limitations may exist for this report. This case revealed clinical efficacy of imeglimin, memantine and Novelzin for T2D, dementia and zinc deficiency. However, other factors or markers are possibly involved in the pathophysiology of this patients. She has been at present stable condition medically with her family, and future careful following-up will be required.

In summary, 85-year-old aged female case was described for several medical problems. Related discussion was added for current situation and progress. This report becomes hopefully useful reference for diabetic and geriatric medicine in the future.

The authors declare no conflict of interest.

Funding

There was no funding received for this paper.

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