Level of Micronutrients Affects Pathophysiology of Diabetes Mellitus: A Scoping Review

Currently, 463 million adults across the globe are living with diabetes. If undeterred, this figure is projected to rise to 700 million by 2045. About 79% of adult diabetics live in Africa; majority of whom are undiagnosed. Several interventions are already available, but the disease prevalence seems steady on an upward trajectory. The economic cost of managing diabetes is overwhelming considering that type II cases have overly and audaciously continues to rise. This underpins the need for exploration of more feasible and relatively inexpensive interventions. We profiled the role of micronutrients in the pathophysiology of diabetes mellitus (DM). Findings from 10 studies published in highly refereed journals and indexed in Research Gate, PubMed, and Elsevier were synthesized, collated, and reported. Guidelines such as year of publication, conflict of interest, type of journal, research design among others, informed the process of study selection. The level of Selenium (Se) and Copper (Cu) was higher when HBA1C was higher. Further, the level of Mg, P, K, & Vitamin D correlated inversely with HBA1C. Some studies reported increased levels of Zinc (Zn) in DM subjects while others reported a decrease. Diabetes mellitus subjects should reduce intake of Se and Cu and increase intake of Mg, P, K, & Vitamin D.


I. INTRODUCTION
Diabetes Mellitus (DM) continues to represent a significant public health concern across the world [1]. While the bigger burden of DM has for a long time been a problem among developed countries, it seems to be steadily shifting focus to Africa as well as other economically underprivileged regions. Worse still, the bulk of global mortality cases are currently occurring in the latter [2]. For instance, there are 463 million cases of diabetes in the world today. If unchecked, this figure is likely to rise to 700 million by 2045. Out of the projected increase, 63 million, 49 million and 47 million will occur in North America, South & Central America and Africa, respectively. While the capacity to diagnose is poor and non-exhaustive, the African continent is projected to represent the greatest increase of global cases at 143% [3]. These figures are enormous and epitomize a genuine cause for priority concern.
Data regarding the cumulative economic cost of managing diabetes are increasingly becoming available. Evidently, governments and individuals alike spend colossal amounts of money in an effort to improve disease prognosis and prolong life. To achieve better treatment outcomes, a diabetes patient spends in excess of $9600 every year. This amount is up to 2.3 times higher than what a non-diabetic spends on healthcare over a similar period [4]. Globally, over $727 billion is injected into management of diabetes yearly.
Unfortunately, this figure is projected to rise to $776 billion by 2045 [5]. With an already emaciated economy, Africa spent $3.4 billion in 2015 and this figure will rise to $5.5 billion in 2040 as the burden of diabetes is surely on a skyrocketing trajectory [3], [6]. Excluding diabetes management, Kenya spends an average of 4.6% of her Gross Domestic Product (GDP) on healthcare [7]. With such arrangement and with the projected upsurge in the prevalence of diabetes, the risk of poverty and non-compliance is at alltime high. Interventions, feasible enough to reverse these worrying statistics must be immediately explored.
Over time, several interventions to manage diabetes have been exploited [8]. They comprise dietary intervention, consistent physical activity, health education and intake of medication [9]. While medication constitutes the most important intervention, patient purchasing power has remained a significant hindrance [10]. Consequently, the case fatality rate has become higher especially for subjects living in low-and middle-income countries. One would wonder why people in these regions have yet to consider deliberate physical activity as it represents an easy to perform, likely effective and relatively affordable alternative. However, the lack of and costs necessary to accessing modern and safe training stadia and gymnasia could be prohibitive. As such, dietary management though inadequately explored seems to be the most promising and viable way forward. Wide-ranging paucity of data regarding the role of macro nutrients in the dynamics of diabetes is a fundamental setback to effective management [11]. Of greater importance is the lack of adequate knowledge on the role of micronutrients in the pathogenesis of diabetes [12].
Against this background, we reviewed published articles in order to provide clear information on the role of micronutrients in the kinetics of DM.

A. Protocol and Registration
This review was carried out according to guidelines by Vrabel [13].

B. Eligibility Criteria
Several eligibility criteria regarding selection of systematic review articles were considered. All articles included satisfied the following rationale: i. Published after January, 2012; ii. Involves role of micronutrients in management of diabetes; iii. Published in English language or has a current valid translation and; iv. Published in highly refereed and peer reviewed journals.

C. Information Sources
Three medical databases were searched for articles that meet the set criteria. They include Research Gate, PubMed and Elsevier. The databases were accessed between 28 th June 2021 and 26 th July 2021. Corresponding authors were contacted to clarify any information that appeared vague to the study review team.

D. Search Criteria
Relevant medical subject headings were used to search for articles in the selected databases using Google Scholar as the search engine. This included the following:

F. Data Collection Process & Synthesis of Results
The process of data collection was done as follows: 1. Each member of the review team individually synthesized results for each of the selected articles. 2. The entire team jointly analyzed synthesized results from each team member. 3. Congruent results were represented in a matrix table (Table I).

G. Data Items
Synthesis of results from the selected articles was guided by the following items: 1. The title of the study; 2. Research design and implementation; 3. Objectives of the study; 4. Results obtained; 5. Discussion; 6. Sources of funding and; 7. The institutional affiliation of the author

H. Risk of Bias in Individual Studies
The study methodology for the selected articles reviewed was assessed to guarantee that the design used does not in any way introduce a possibility of bias. Only results that entailed collection & analysis of empirical data were assessed.

I. Risk of Bias Across all Studies
The GRADE system of imprecision/bias analysis according to [14] was used. This GRADE system recommended that findings be summarized in brief, transparent and enlightening tables that showed quality of evidence and the degree of relative and absolute influence for each key outcome.    o There was a significant positive association between selenium intake and diabetes (p for trend =0.03); o There was a significant positive association between selenium intakes and diabetes among the sub-group with BMI <25 (P for trend = 0.02); o There was minor positive association between selenium intake and diabetes among the male subgroup (P for trend = 0.09) and; o There was no significant positive association between selenium intake and diabetes in the following subgroups:

III. DISCUSSION
Micronutrients (MNs) play a crucial role in the kinetics of diabetes mellitus (DM). Their upsurge or decrease can either be detrimental or favorable to the prognosis of the disease. For instance, [15] reported an increase in levels of Copper (Cu), Zinc (Zn) and Selenium (Se) as well as a decrease in the level of Magnesium (Mg) among type II diabetic patients. Further, the study documented a direct correlation between the former and increased age, body mass index (BMI) greater than 30, and elevated Systolic & Diastolic Blood Pressure. According to [25], Cu contains anti-oxidant properties. As such, it plays an integral role in the elimination of free radicals which are pre-cursors for a range of conditions including diabetes and malignancies. Moreover, Cu regulates the level of cholesterol and triglycerides in the body. The two are quite fundamental in the dynamics of blood pressure and heart-rate which have a strong kinship with development of DM. Reference [26] associated Cu-water with a more efficient digestion process and nutrient absorption stature. The former and the latter constitute critical events in the management process of DM.
Interestingly, unlike [15], most other studies have reported reduced levels of Zn among DM subjects. For example, [27] attributes the decrease in levels of Zn among DM subjects to increased loss through micturition while [28] documents deficient Zn levels and consequently, poor glycemic control among DM subjects. According to [29], Zn is responsible for physiological efficiency of over 300 enzymes as well as the integrity of key immunological cells like Natural Killer cells (NK-cells) and Neutrophils. Findings of [15] regarding Zn are therefore inconsistent with most other studies including [22] and may underpin the need for further methodological interrogation. While it is a clear shift from what is expected, the position of [15] seems consistent with that of [23]. Selenium (Se) is a crucial component in the process of development of antioxidant enzymes which play a pivotal role in the prevention of cell damage. It is associated with increased production of antibodies as well as improved performance of T-helper cells (Th-cells), cytotoxic T-cells (CTLs) and NK-cells. However, Se is only needed by the body in trace amounts as increased in-take may increase the risk of heart, liver, and kidney damage [30]. The role of Se in the pathogenesis of DM is yet to be clearly profiled. Reference [21] citing [31]- [33] reported that high level of serum Se may either increase or reduce the risk of DM. Obviously, this needs to be urgently studied and the actual role of Se in DM be accurately documented. According to [18], [21], the level of Se is likely to be higher in males of increased age and BMI than in females. These points to a possibility that it may be associated with increased odds of developing or poor DM prognosis.
According to [15], [17], [19], [20], the level of Magnesium (Mg), Phosphorous (P), Potassium (K) and Vitamin D among DM subjects reduced. Reference [34], reports that Mg regulates blood sugar levels. The study further documents that hypomagnesemia is often consistent with DM subjects and it is associated with elevated insulin resistance. On the same note, [35] postulates that insulin and glucose are pivotal to efficient metabolism of Mg. Cumulatively, Mg constitutes a bedrock of multiple biochemical reactions, supports optimal physiology of the immune system, and helps maintain a steady heartbeat. Low level of Mg among DM subjects may therefore be justifiably consistent with poor disease prognosis. Phosphorus has a nexus with how the body utilizes fats and carbohydrates. Further, it optimizes the functioning of the kidney as well as help maintain a normal heartbeat. References [36], [37] associates' consumption of phosphorus (P) with a reduction in postprandial glucose and insulin at minute 60. Reference [38] correlates low level of K with reduced production of insulin. Low production of insulin is often consistent with poor glycemic control & an increased likelihood of unfavorable disease outcome. Further, Potassium (K) enhances entry of nutrients into cells and ejection of waste matter out of cells. The element also counters negative effects of Sodium (Na) on blood pressure & significantly lowers the risk of development of DM. Vitamin D enhances sensitivity of the body to insulin and accordingly diminishes chances of insulin resistance. Moreover, it plays a fundamental role in the process of metabolism; help reduce cellular damage while optimizing cell physiology. These events underpin favorable management of DM.
References [23], [24] reported a decrease in the level of 25-hydroxyvitamin D3 (25(OH) D3) and Bromide (Br) respectively. The former reported an inverse relationship between 25(OH) D3 and HBA1C while the latter directly reported low level Br in DM subjects. According to [39], Br accelerates diabetes wound healing by inhibiting inflammatory responses and reducing oxidative stress. However, in the letter to the editor, [40], reported that Br has a long half-life and may be slightly toxic (bromism).

A. Review Limitations
This review involved papers published in specific databases. It is therefore possible that further or different information may be available in study papers published elsewhere.

B. Conclusion(s)
1. Increased serum/plasma level of Se & Cu is consistent with unfavorable prognosis of DM; 2. Reduced serum/plasma level of Mg, P, K, & Vitamin D correlates with favorable prognosis of DM and; 3. The role of Zn in the pathogenesis of DM remains unclear