Metformin for diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a common complication
of diabetes.
DPN presents primarily with sensory neuropathy, but can also be associated with autonomic neuropathy and impaired
motor function.
About 30% of DPN patients have pain symptoms, including tingling, burning, spontaneous pain, abnormal pain, and hyperalgesia
.
However, the treatment of painful diabetic peripheral neuropathy (PDPN) has been unsatisfactory, with less than 30%
of PDPN patients receiving satisfactory analgesics as a result of treatment.

Metformin is an antihyperglycemic drug widely used in patients with type 2 diabetes mellitus (T2DM) and has been reported to have analgesic potential
.
Studies have shown that metformin can relieve neuropathic pain caused by diabetes or chemotherapy drugs, low back pain, osteoarthritis, postoperative pain, and inflammatory pain
by activating adenosine 5′ monophosphate-activated protein kinase (AMPK).
Metformin also has the ability to remove methylglyoxal (MGO), a related metabolite
of PDPN.
However, metformin has one case in clinical use – it may reduce serum vitamin B12 levels, thereby worsening nerve damage
.

Recently, the Journal of Diabetes published a review from the research team of Jia Shushan from Yantai Affiliated Hospital of Binzhou Medical College, which summarized the research status and mechanism
of metformin in the treatment of DPN by analyzing basic and clinical studies.
Data have been shown that metformin may be a very promising drug for remission of DPN, and more clinical studies are needed to evaluate its efficacy and safety
.

01.
Effect and mechanism of metformin on PDPN

Metformin works in a variety of ways, including inhibition of mitochondrial respiration and gluconeogenesis, activation of AMPK, increased insulin sensitivity, antagonistic effects of glucagon, and increased fatty acid oxidation
.
It was previously thought that high blood sugar was the main cause of PDPN, but this view has recently been challenged
.
In one study, rats fed 15% fructose solution for 16 weeks caused generalized tactile pain and hyperalgesia without significant elevation in blood glucose levels, suggesting that fructose's effect on pain may be due to insulin resistance rather than hyperglycemia
.
Metformin can reverse dysphonia and hyperalgesia in fructose-treated rats, suggesting that its antihyperalgesic effects are not entirely dependent on hypoglycemic effects
.
Metformin also reversed the reduction in mechanical withdrawal threshold in high-fat diet/streptozotocin rats without alteration in plasma glucose and insulin
.
The mechanism by which metformin remission of DPN is shown in Figure 2, in which the AMPK pathway plays a significant role, which is detailed
in the next section.

Fig.
2 Mechanism of remission of DPN by metformin

02.
Metformin and AMPK pathway

AMPK is a ubiquitous energy-sensitive kinase consisting of
two regulatory subunits (β and γ) and one catalytic subunit (α).
When the AMP/ATP ratio increases, AMP junctions with γ subunits, while Thr172 phosphorylation of α subunits by Ca21/calmodulin-dependent protein kinase or liver kinase B1 (LKB1) leads to indirect activation
of AMPK.
AMPK can also be directly activated
by phosphorylation of α subunits by certain drugs, such as O304.

Metformin activates AMPK primarily by inhibiting mitochondrial respiratory chain complex 1 and inhibiting ATP production, and acts
in a LKB1-dependent manner.
Damage to AMPK is associated with a number of pathological conditions, including obesity, exercise or metabolic syndrome, and inflammation
.
Recent studies have shown that downregulation of AMPK is strongly associated with pain symptoms, and metformin can relieve pain by activating AMPK, as summarized in
Table 1.

Table 1 Study on the neuroprotective effect of metformin in DPN model

03.
Adverse reactions in the clinical application of metformin

Based on current clinical experience and data, metformin has few serious safety concerns
.
By adjusting the dose and dosage form, rare and mild side effects such as hypoglycemia, gastrointestinal side effects (usually nausea, vomiting or diarrhea), impaired liver and kidney function, and heart failure
can be effectively avoided.
However, it is worth noting that metformin affects the status of vitamin B1, vitamin B12, vitamin D, folic acid and magnesium, and affects the intestinal flora
.
Among them, vitamin B12 deficiency can cause neurological dysfunction (such as peripheral and autonomic neuropathy, painful neuropathy) and accelerate the progression of
diabetic neuropathy.
Therefore, the authors focused on the effects
of metformin and vitamin B12 on the nervous system.

Since vitamin B12 malabsorption in metformin diabetics was first reported in 1971, numerous clinical trials and meta-analyses have confirmed the association
between metformin and low vitamin B12 levels.
Vitamin B12 is present in food in protein-bound form, enters the digestive tract and is released
under the action of gastric acid pepsin and trypsin.
The free vitamin B12 then binds to intrinsic factors (IF, glycosylated proteins secreted by parietal cells of the stomach) to form the IF-vitamin B12 complex, which is eventually absorbed
in the ileum.

The main mechanisms by which metformin causes vitamin B12 deficiency are:

(1) bacterial overgrowth caused by changes in small intestinal motility;

(2) decreased vitamin B12 absorption due to changes in IF levels;

(3) Inhibit the absorption
of vitamin B12-IF complex in the terminal ileum.

In addition, anemia is also a potential consequence of vitamin B12 deficiency, which occurs much
later than neuropathy.
Anemia is not the primary goal of most DPN studies, and metformin exposure is not prolonged enough to reveal a significant association
between metformin use and anaemia.
However, a long-term study showed that the prevalence of anemia was significantly higher in patients at high risk of diabetes taking metformin for 5 years than in patients
who did not take metformin.
In the future, we need more long-term studies to explain the association
between anaemia and metformin use.

04.
Gender differences in metformin for pain

Numerous studies have shown that men and women respond differently to pain and to pharmacological pain
interventions.
There is no difference in the prevalence of DPN between sexes, but women may have a greater
probability of developing PDPN.
In some mouse models of pain, the pain relief effect of metformin also varies by sex
.
Metformin reduced sparing nerve injury-induced mechanical hypersensitivity and cold-induced mechanical hypersensitivity and reversed microglial activation in the spinal cord of male rather than female mice
.
In addition, the researchers observed that metformin reduced incision-induced mechanical hypersensitivity and blocked the initiation
of hyperalgesia only in male mice.

These differences may be caused by
sex hormones.
Metformin is a water-soluble drug that requires the help of an organic cation transporter (OCT2) to cross cell membranes
.
OCT2 exhibits sex-differentiated expression in many tissues of many species, with higher expression in males, which is associated
with androgen regulation.
Inyang et al.
argue that sex differences cannot be explained by metformin pharmacokinetics because metformin levels in the plasma and brain of female mice are higher than in male mice
.
Metformin is an AMPK activator with sex-specific effects, which may be due to links
in the AMPK pathway.
However, there are also researchers who take the opposite view, and they found that metformin had the same effect on male and female mice after lumbar disc puncture, although the mechanical pain was more severe
in female mice before treatment.

In summary, whether there is a sex difference in the analgesic effect of metformin requires further investigation
.

5 Summary – Beneficial or Harmful?

Beneficial aspects and possible mechanisms:

Metformin is a first-line treatment for patients with T2DM and is also used to treat polycystic ovary syndrome, hyperlipidemia, coronary artery disease, obesity, and a variety of kidney diseases
such as acute kidney disease, diabetic nephropathy, urolithiasis, renal cell carcinoma, end-stage renal disease, and renal fibrosis.
There is a lot of evidence that metformin is also beneficial
for neuroprotection and hyperalgesia.
Mechanistically, metformin can reduce inflammatory response and oxidative stress by activating AMPK, regulate autophagy and activation or expression of NaV1.
7 and TRPA1 channels, and exert analgesic and anti-analgesic effects
.
In addition, the analgesic effect of metformin was also associated with a reduction
in MGO and IR.
These results provide some basis
for metformin to become a potential drug for the treatment of DPN.

Harmful aspects and how to deal with them:

Although the association between diabetic neuropathy and metformin-induced vitamin B12 deficiency is unclear, for optimal safety, we recommend regular screening of serum vitamin B12 levels and peripheral neuropathy
in patients with T2DM who have been on metformin for a long time.
However, due to economic and medical constraints, regular testing of vitamin levels is a burden for many patients, so the researchers recommend using the metformin use index (MUI) as a risk assessment tool
to assess vitamin B12 deficiency in patients with T2DM.
MUI is the product of the dose (mg) of metformin used and its duration (years) divided by 1000, and when MUI > 5, patients are at high risk of vitamin B12 deficiency
.

Limitations of existing studies:

There are still some limitations
in the available studies.
Contrary to basic studies, metformin has not been shown to provide significant neuroprotection in patients with intermediate T2DM in clinical practice, possibly due to vitamin B12 deficiency
.
Clinical and basic research have different focuses
.
Basic research focuses on the neuroprotective effects and mechanisms of metformin, while clinical studies focus on vitamin B12 deficiency
.
In some studies, the shorter duration of metformin interventions may be due to
less reported vitamin B12 deficiency and related adverse events.

Metformin plus vitamin B12 may be beneficial
for diabetic neuropathy.
Vitamin B12 in combination with metformin in people with T2DM has been shown to reduce the incidence of peripheral neuropathy compared with metformin alone, but this trial did not include a placebo control
without metformin.
In addition, most studies were conducted in patients with T2DM, and little is known about the effects of metformin on neuropathy in people with
T1DM.

Sum up:

The therapeutic effect of metformin on DPN has been confirmed in many basic studies, and the mechanism of which is increasingly elaborated, however, clinical studies have focused on whether metformin-induced vitamin B12 deficiency will exacerbate neuropathy.

This suggests that basic and clinical practice need more communication and integration, become each other's support rather than shortcomings, and look forward to more research
in the future.